Edward C. Halperin, David E. Wazer, and Carlos A. Perez
HISTORICAL FIGURES
Wilhelm Conrad Röntgen
On March 27, 1845, in Lennep, Germany, a son, Wilhelm Conrad, was born to the merchant Friedrich Conrad Röntgen and his wife, Charlotte Constanze (Fig. 1.1). Röntgen’s father was a textile merchant, and when Wilhelm was 3, the family moved from Prussia to Apeldoorn in the Netherlands, about 100 miles to the northwest, where Wilhelm’s maternal grandparents had made their home. Wilhelm enrolled in the Utrecht Technical School in 1862. A fellow student caricatured a teacher on the fire screen of the schoolroom. The schoolmaster demanded the name of the unflattering artist, but Wilhelm refused to betray his classmate and was expelled. It seemed that his education would come to an end after this episode. Fortunately, however, the Polytechnical School in Zurich, Switzerland, accepted students based on stiff entrance examinations. The black mark of expulsion from Holland served as no impediment. Röntgen began classes in 1865 and received his diploma in mechanical engineering in 1868.167,175
Röntgen’s considerable skill in designing and constructing precision instruments for measuring physical phenomena attracted the attention of Dr. August Kundt, a theoretical physicist. Röntgen became Kundt’s assistant at the University of Zurich. When Kundt moved, in turn, to the University of Würzburg and then to the University of Strasbourg, Röntgen followed. In 1879, Röntgen struck out on his own as a professor at the University of Giessen.
In 1888, Röntgen accepted a professorship of theoretical physics at the University of Würzburg (Fig. 1.2). On November 8, 1895, Röntgen saw the effects of an unusual phenomenon while doing laboratory experiments. He presented his results to the president of the Physical Society at Würzberg on December 28, 1895174,175,325 (Fig. 1.3).
There are various accounts of Röntgen’s discovery. Among the multitude of reporters who rushed to interview Röntgen was H. J. W. Dam, an Englishman who was a correspondent for the Canadian McClure’s Magazine. Dam had a letter of introduction from the Royal Institution of Great Britain but, like all other reporters, when he arrived in Würzberg he was turned away. Dam, however, was persistent and wrote a letter in French to Röntgen insisting upon an interview. “You are very difficult, much more difficult than Berthlot, Pasteur, Dewar, and other men of science about whose discoveries I have written.” Apparently taken by Dam’s audacity and, perhaps, willing to have a sensible article written by a knowledgeable reporter, Röntgen granted Dam an exclusive interview.
Dam’s lead story in the April 1896 McClure’s is generally regarded as an accurate depiction.104 Dam told his readers that “in all the history of scientific discovery there has never been, perhaps, so general, rapid, and dramatic an effect wrought on the scientific centers of Europe as has followed, in the past four weeks, upon an announcement made to the Wurzburg Physio-Medical Society, at their December meeting, by Professor William Konrad Röntgen, professor of physics at the Royal University of Wurzberg… Röntgen’s own report arrived, so cool, so business-like, and so truly scientific in character, that it left no doubt either of the truth or of the great importance of the preceding [newspaper] reports.”325
Dam, who was able to converse with Röntgen in English, French, and German, conducted an on-site interview in Röntgen’s laboratories and had him describe the circumstances related to the discovery. Dam’s charming description, excerpted here, gives an excellent insight into Röntgen the man and the nature of his scientific inquiry.
“Now, Professor,” said I, “will you tell me the history of the discovery?”
“There is no history,” he said. “I have been for a long time interested in the problems of the cathode rays from a vacuum tube as studied by Hertz and Lenard. I had followed theirs and other researches with great interest, and determined as soon as I had time to make some researches of my own. This time I found at the close of last October. I had been at work for some days when I discovered something new.”
“What was the date?”
“The eighth of November.”
“And what was the discovery?”
“I was working with a Crookes’ tube covered with a shield of black cardboard. A piece of barium platinocyanoide paper lay on the bench there. I had been passing a current through the tube and I noticed a peculiar black line across the paper.”
“What of that?”
“The effect was one which could only be produced, in ordinary parlance, by the passage of light. No light could come from the tube, because the shield which covered it was impervious to any light known, even that of the electric arc.”
“And what did you think?”
“I did not think; I investigated. I assumed that the effect must have come from the tube, since its character indicated that it could come from nowhere else. I tested it. In a few minutes there was no doubt about it. Rays were coming from the tube which had a luminescent effect on the paper. I tried it successfully at greater and greater distances, even at two metres. It seemed at first a new kind of invisible light. It was clearly something new, something unrecorded.”
“Is it light?”
“No.”
“Is it electricity?”
“Not in any known form.”
“What is it?”
“I don’t know. Having discovered the existence of a new kind of rays, I of course began to investigate what they would do. It soon appeared from the tests that the rays had penetrative power to a degree hitherto unknown. They penetrated paper, wood and cloth with ease, and the thickness of the substance made no perceptible difference within reasonable limits. The rays passed through all the metals tested with the facility varying, roughly speaking, with the density of the metal. These phenomena I have discussed carefully in my report to the Würzburg Society and you will find all the technical results therein stated. Since the rays had this great penetrative power, it seemed natural that they should penetrate flesh, and so it proved in photographing the hand I showed you.”
A detailed discussion of the characteristics of his rays the professor considered unprofitable and unnecessary. He believes, though, that these mysterious radiations are not light, because their behavior is essentially different from that of light ways, even those light rays that are themselves invisible. The Röntgen rays cannot be reflected by reflecting surfaces, concentrated by lenses, or refracted or diffracted. They produce photographic action on a sensitive film, but their action is weak as yet, and herein lies the first important field of their development. The professor’s exposures were comparatively long—an average of 15 minutes in easily penetrable media, and half an hour or more in photographing the bones of the hand. Concerning vacuum tubes, he said that he preferred the Hittorf, because it had the most perfect vacuum, the highest degree of air exhaustion being the consummation most desirable. In answer to the question, “What of the future?” he said:
FIGURE 1.1. Wilhelm Conrad von Röntgen was born in Lennep, Germany, in 1845. He studied under Kundt in Zurich and was appointed professor of physics at Giessen in 1879 and at Würzberg in 1888. In 1895, while investigating cathode rays, he noted a new ray of greater penetrating power coming from the cathode tube. Röntgen announced his findings concerning the x-ray before the Würzberg Physical Society in 1895. He received the first Nobel Prize for Physics in 1901. Röntgen died in 1923. He is shown in this photograph with physics instruments. (From Glasser O. Wilhelm Conrad Röntgen and the early history of the Roentgen rays. Springfield, IL: Charles C. Thomas, Publisher, Ltd., 1934, with permission.)
FIGURE 1.2. Photograph of the Physical Institute of the University of Würzburg from 1896. Professor Röntgen and his wife lived on the top floor. On the left side of the upper story can be seen the conservatory, of which Röntgen and his wife were particularly fond. (From Glasser O. Wilhelm Conrad Röntgen and the early history of the Roentgen rays. Springfield, IL: Charles C. Thomas, Publisher, Ltd., 1934, with permission.)
FIGURE 1.3. Röntgen made this image on December 22, 1895, and sent it to Vienna physicist F. Exner. (From Glasser O. Wilhelm Conrad Röntgen and the early history of the Roentgen rays. Springfield, IL: Charles C. Thomas, Publisher, Ltd., 1934, with permission.)
“I am not a prophet, and I am opposed to prophesying. I am pursuing my investigations, and as fast as my results are verified I shall make them public.”
“Do you think the rays can be so modified as to photograph the organs of the human body?”
In answer he took up the photograph of the box of weights. “Here are already modifications,” he said, indicating the various degrees of shadow produced by the aluminum, platinum, and brass weights, the brass hinges, and even the metallic stamped lettering on the cover of the box, which was faintly perceptible.
“But, Professor Neusser has already announced that the photographing of the various organs is possible.”
“We shall see what we shall see,” he said; “we have the start now; the developments will follow in time.”
“You know the apparatus for introducing the electric light into the stomach?
“Yes.”
“Do you think that this electric light will become a vacuum tube for photographing, from the stomach, any part of the abdomen or thorax?”
The idea of swallowing a Crookes tube, and sending a high frequency current down into one’s stomach, seemed to him exceedingly funny. “When I have done it, I will tell you,” he said, smiling, resolute in abiding by results.
“There is much to do, and I am busy, very busy,” he said in conclusion. He extended his hand in farewell, his eye already wandering toward his work in the inside room. And his visitor promptly left him; the words, “I am busy,” said in all sincerity, seeming to describe in a single phrase the essence of his character and the watchword of a very unusual man.104
Kaiser Wilhelm II invited Röntgen to the imperial court at Potsdam in January 1896, <2 weeks after the scientist had mailed out reprints to prominent physicists. Röntgen demonstrated his findings and was decorated with the Prussian Order of the Crown, Second Class. On January 23, he gave a lecture to the Würzburg Physical-Medical Society and was startled and overwhelmed by the cheers of the audience. At the end of the talk, Röntgen invited Albert von Killiker, one of Germany’s most distinguished anatomists, to come to the podium and have his hand x-rayed. When the audience saw the bones of his hand, it erupted in thunderous applause. This was one of Röntgen’s last formal lectures on x-rays. He became flustered before large groups and, when lecturing to small groups of students, was generally regarded as lusterless and dull.
Röntgen received the Nobel Prize in Physics in 1901 from the Swedish king. He thanked him but gave no speech. He willed the prize money to the University of Würzburg.167 In the presentation speech, the president of the Royal Swedish Academy of Sciences, C. T. Odhner, commented on the enormous potential of Röntgen’s discovery for diagnosis and therapy.
The Academy awarded the Nobel Prize in Physics to Wilhelm Conrad Röntgen, Professor in the University of Wurzburg, for the discovery with which his name is linked for all time: the discovery of the so-called Röntgen rays, or, as he himself called them, x-rays. These are, as we know, a new form of energy and have received the name “rays” on account of their property of propagating themselves in straight lines as light does. The actual constitution of this radiation of energy is still unknown. Several of its characteristic properties, however, have been discovered first by Röntgen himself and then by other physicists who have directed their research into this field. And there is no doubt that much success will be gained in physical science when this strange energy form is sufficiently investigated and its wide field has been thoroughly explored. Let us remind ourselves of one of the properties that has been found in Röntgen rays—the basis of the extensive use of x-rays in medical practice. Many bodies, just as they allow light to pass through them in varying degrees, behave likewise with x-rays but with the difference that some that are totally impenetrable to light can be penetrated easily by x-rays, whereas other bodies stop them. Thus, for example, metals are impenetrable to them; wood, leather, cardboard, and other materials are penetrable as are the muscular tissues of animal organisms. Now, when a foreign body impenetrable to x-rays (e.g., a bullet or a needle) has entered these tissues, its location can be determined by illuminating the appropriate part of the body with x-rays and taking a shadowgraph of it on a photographic plate, whereupon the impenetrable body is detected immediately. The importance of this for practical surgery and how many operations have been made possible and facilitated by it is well known to all. If we add that in many cases severe skin diseases (e.g., lupus) have been treated successfully with Röntgen rays, we can say at once that Röntgen’s discovery already has brought so much benefit to mankind that to reward it with the Nobel Prize fulfills the intention of the testator to a very high degree.325
FIGURE 1.4. Thomas A. Edison experimenting with x-rays with, obviously, no radiation protection. (From Glasser O. Wilhelm Conrad Röntgen and the early history of the Roentgen rays. Springfield, IL: Charles C. Thomas, Publisher, Ltd., 1934, with permission.)
Henri Becquerel, Marie Sklodowska Curie, and Pierre Curie
Following Röntgen’s discovery, clinical and technologic advances accumulated more rapidly than did basic biologic knowledge (Figs. 1.4 and 1.5). Several scientists began investigating whether or not rays similar to x-rays might be produced by ordinary fluorescent or phosphorescent substances. Henri Becquerel placed fluorescent mineral crusts on photographic plates wrapped in light-tight black paper, exposed them to sunlight, and observed an image on the plates. In February 1896, when poor weather prevented exposing his plates to sunlight, Becquerel put the prepared plates and minerals away in a drawer. On March 1, 1896, he removed them and, for an unknown reason, developed them before any exposure to sunlight. He saw images of the crust shapes on the developed plates and concluded that neither sunlight, fluorescence, nor phosphorescence was necessary to produce the effect. This form of radiation, initially called Becquerel rays, could penetrate thin strips of aluminum and copper.31 The next day, he presented his findings at the French Academy of Sciences. Becquerel noted the first biologic effect of radium in human tissue; after carrying a small amount of the element in his shirt pocket he observed skin erythema, followed by moist desquamation and ulceration.32
Marya Sklodowska was born in Warsaw on November 7, 1867. The youngest of four sisters and a brother, she lived under Russian rule in partitioned Poland. At 17 she left home to work as a governess to the daughters of the supervisor of a large sugar beet factory northeast of Warsaw in order to save enough money to attend university. In 1891 Sklodowska enrolled at the Faculte des Sciences at the Sorbonne in Paris—one of just 23 women in a student body of about 1800. She completed degrees in mathematics and physics and in 1893 was hired by the Society for the Encouragement of National Industry to study the magnetic properties of steel. While in the process of securing additional laboratory space, she was introduced to Pierre Curie.
Curie was the son of a physician who had worked in the laboratory of Louise Pierre Gratiolet (1815–1865), who described the occipital visual pathways. Pierre Curie’s doctoral thesis, “Magnetic Properties of Bodies at Diverse Temperatures,” evaluated changes in magnetic properties of materials heated to high temperatures. He found that the magnetic properties of a substance change at a very specific temperature. This temperature is called the “Curie point” and is of great importance in studying plate tectonics, understanding extraterrestrial magnetic fields, and measuring the chemical contents of liquids. Curie also found that when crystals were pressed along their axis of symmetry, they produced an electric charge. This phenomenon is called “piezoelectricity,” from the Greek word piezin, meaning “to squeeze,” and is of importance in the operation of quartz watches, inkjet printers, autofocus cameras, and medical ultrasound.
Marya Sklodowska (now using the French form of her first name, “Marie”) and Pierre Curie wed on July 26, 1895. For her doctoral thesis, Marie chose to investigate Becquerel’s rays. She found that the intensity of the rays was affected neither by external conditions nor by any chemical process—they were an atomic property of the element. Marie observed that “it was obvious that a new science was in the course of development… I coined the word radioactivity.”372
After confirming Becquerel’s observations, Marie and Pierre Curie in 1898 published a paper entitled “Sur une substance fortement nouvelle radio-active, continue dans la pechblende (on a new, strongly radio-active substance contained in pitchblende).” The new radioactive substance was called polonium (named in honor of Poland). In November and December 1898, while working on polonium, they noticed another substance, chemically akin to barium and more radioactive than polonium. Demarcay found specific spectral characteristics of this new element, which was called radium (from the Latin word for “ray”). The Curies declined to patent their findings. Pierre said “it would be contrary to the scientific spirit.” In 1903–1904, radium-226 began to be used in the treatment of patients with skin cancer and uterine cancer.293 On June 25, 1903, Marie defended her thesis “Researches on Radioactive Substances” and became the first woman in France to receive a doctorate. Later that year the Curies and Becquerel were awarded the Nobel Prize in Physics.
On April 19, 1905, Pierre Curie was killed while crossing the Rue Dauphine near the Seine—run down by a horse-drawn carriage carrying 13,000 pounds of military equipment. Marie returned to work and described the radioactive decay series of polonium. In 1911 she became the first person to win the Nobel Prize twice, this time in chemistry. When France entered World War I, Marie assembled hospital and mobile x-ray units for the care of the wounded. The mobile units were dubbed “petites Curies.”372 In March 1912 a glass tube containing 20 mg of radium was declared the international radium standard after comparison with a similar standard prepared in Vienna. The radioactivity unit was called Curie and defined as the emanation in equilibrium with 1 g of radium. In 1975 the International Commission on Radiation Units and Measurements replaced the Curie with the Becquerel (1 Curie = 3.7 × 1010 Bq).
In 1924 Marie and Pierre’s eldest daughter, Irène, married Lieutenant Frederic Joliot. They investigated the transformation of aluminum, bombarded with alpha particles, into a radioactive state. Marie Curie died on July 4, 1934, from radiation poisoning. In 1935 her daughter and son-in-law were awarded the Nobel Prize for the discovery of artificial radioactivity.103,372,448
FIGURE 1.5. A and B: Private John Gretzer, Jr., Company D, First Nebraska volunteer injury, wounded above his left eye at long range in combat at Mariboa, Philippines. Five months after the injury he returned to duty in the military mail service. Diagnostic x-ray units were utilized by the U.S. Army Medical Department in the 1898 war with Spain and the Philippine insurrection—within 4 years of the discovery of the x-ray. (From The use of the Roentgen ray by the Medical Department of the United States Army in the war with Spain (1898).Washington, DC: Government Printing Office, 1900.)
RADIATION THERAPY BEGINS
External-beam radiation therapy quickly showed itself to be a useful form of cancer treatment. Only 8 years after Röntgen’s discovery, Dr. Charles L. Leonard, in 1903, observed that
in spite of the most diligent study, there is nothing known of the etiology and histology of malignant disease that aids its treatment. Its development and fatal termination cannot be retarded, if the diseased tissue be permitted to remain in the body. Total extirpation by surgical intervention has been the only chance of cure. Leonard, however, discerned some promise in a new form of treatment. The results obtained by the use of the Röntgen rays seems to… have demonstrated their power to alter the character of malignant cells, to prevent their spread and development, and to produce retrograde changes that result in fatty and cystic degeneration or absorption, and often terminate in a restoration of the affected part to a nearly normal state… The Röntgen treatment applied as a palliative in many hopeless, operatively impossible cases, has resulted frequently in cures, that, if not permanent, have at least restored the patient to health and given months and even years of usefulness… The results so far obtained are, therefore, very encouraging. An agent has been found which has a greater influence in retarding the growth of malignant tumors than any heretofore known. Many remarkable and apparently permanent cures have been obtained.265
Although it is controversial, most likely Leopold Freund was the first to report, in 1897, the use of ionizing radiation to “cure” a large nevus pigmentosus on the back of a young girl. Unfortunately, she later developed skin ulceration and scars.166 Another pioneer in the therapeutic use of x-rays was Victor Despeignes who, in 1896 published on the treatment of a 52-year-old man who had an advanced stomach tumor (likely a lymphoma), with “considerable improvement in the condition of the patient.”112
At the International Congress of Oncology in Paris in 1922, Coutard99 and Hautant presented evidence that advanced laryngeal cancer could be cured without disastrous, treatment-induced sequelae. By 1934, Coutard100 had developed a protracted, fractionated scheme that remains the basis for current radiation therapy and, in 1936, Paterson347 published results on the treatment of cancer with x-rays.
The use of brachytherapy, starting with radium-226 (226Ra) needles and tubes, has increased steadily in the treatment of malignant tumors in many anatomic locations. Isotopes such as cesium, iridium-192 (192Ir), iodine-125 (125I), and palladium-103 (103Pd) were generated from nuclear reactors, and the use of afterloading techniques, including remote afterloading devices and high–dose-rate brachytherapy, brought a revival of this important treatment modality.
With time, ionizing radiation became more precise; high-energy photons, electrons, protons, neutrons, and carbon ions became available; and treatment planning and delivery became more accurate and reproducible. Advances in computer and electronic technology fostered the development of more sophisticated treatment-planning and delivery techniques, leading to the development and eventually broad implementation of three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) (Box 1.1).
Box 1.1
A Call to Arms
An Institute on Cancer meeting was conducted at the University of Wisconsin in Madison in 1936. Among the prominent scientists in attendance were James Ewing, professor of oncology at Cornell University Medical College, after whom Ewing sarcoma is named; Gioacchino Failla, the famous radiation physicist of the Memorial Hospital for Cancer and Allied Diseases of New York; and Henri Coutard, pioneer radiation therapist of the Curie Institute of Paris. Glenn Frank, president of the University of Wisconsin, addressed the scientists on the first day of the meeting. Seventy-five years later, Frank’s opening address remains a moving call to arms for basic science, translational, and clinical researchers, physicists, and clinicians.353
“Down the ages, cancer has been the most hideously persistent and the most persistently hideous enemy of mankind, the suffering it lays upon men intolerably horrible, its toll of life progressively devastating, its blows falling so often just when men have reached the years of ripest usefulness to family and state. But not all these tragic consequences together are the worse evil wrought by cancer. For every body that is killed by the fact of cancer, multiplied thousands of minds are unnerved by the fear of cancer. What cancer, as an unsolved mystery, does to the morale of millions who may never know its ravages is incalculable. This is an incidence of cancer that cannot be reached by the physician’s medicaments, the surgeon’s knife, or any organized advice against panic. Nothing but the actual conquest of cancer itself will remove this sword that today hangs over every head. I can remember, as a boy in rural Missouri, that death from cancer was rarely mentioned and then only with bated breath. I realize now that this reaction was born of a feeling of utter helplessness and awe in the presence of a mysterious enemy. That almost primitive reaction to cancer has happily vanished. We have not penetrated the mystery, but, thanks to you and your colleagues the world over, we have made notable rents in the veil surrounding the mystery. The world is determined to conquer this thing that steals upon men like a thief in the night and without warning strikes down the strong and weak alike. By one thing alone can this conquest come, and that is by the tireless, painstaking, and self-sacrificing genius of scientists who, like yourselves, go to their laboratory tables as to an altar and sink their lives in the great adventure of emancipating mankind from the fact and fear of this plague. Surely, if anywhere in the secular activities of men, there is a spark of divinity in lives so dedicated!”253
Box 1.2
The Etymology of Radiate
The defining verb of the discipline of radiation oncology, radiate, is derived from the Latin verb radiatus. Radiatus is the participial stem. Some dictionaries cite the origin of the word radiate as being from other tenses of the verb such as the present infinitive radiarae or the first-person singular present indicative radio. Radiate is defined as “to spread from the common center” or “to diverge or spread from the common point” or “to issue and raise.” Radiate shares a common root and related meanings with other English words such as ray, radius, and radial. The verb radiate is more distantly related to other words. For example, if one proceeds along the ray from the political center to the extreme, then one is called radical.
The verb irradiate means “to direct rays upon” or “to cause rays to fall upon something.” In Latin, the prefix in conveys the meaning of in, within, on, upon, or against. When the prefix in is used with the word that begins with the letter r, the letter r is substituted for the letter n in the prefix to assimilate the initial sound of the verb. Thus, the verb that indicates the placement of water within or on the ground changed from inrigate to irrigate. Similarly, inradiate was changed to irradiate.
An object may be said to radiate something or to emit a ray. For example, “The block of cobalt 60 radiates gamma rays.” The verb that indicates directing rays on or into an object is irradiate. An example of proper usage would be “I recommend that we irradiate the tumor to a total dose of 45 Gy.” Incorrect usage would be “I think the primary tumor should be radiated to a dose of 45 Gy.”200
A DEFINITION OF RADIATION ONCOLOGY
Radiation oncology is that discipline of human medicine concerned with the generation, conservation, and dissemination of knowledge concerning the causes, prevention, and treatment of cancer and other diseases involving special expertise in the therapeutic applications of ionizing radiation. As a discipline that exists at the juncture of physics and biology, radiation oncology addresses the therapeutic uses of ionizing radiation alone or in combination with other treatment modalities such as biologic therapies, surgery, drugs, oxygen, and heat. Furthermore, radiation oncology is concerned with the investigation of the fundamental principles of cancer biology, the biologic interaction of radiation with normal and malignant tissue, and the physical basis of therapeutic radiation. As a learned profession, radiation oncology is concerned with clinical care, scientific research, and the education of professionals within the discipline.
Radiation therapy is a clinical modality dealing with the use of ionizing radiations in the treatment of patients with malignant neoplasias (and occasionally benign diseases). The aim of radiation therapy is to deliver a precisely measured dose of irradiation to a defined tumor volume with as minimal damage as possible to surrounding healthy tissue, resulting in eradication of the tumor, a high quality of life, and prolongation of survival at a reasonable cost. In addition to curative efforts, radiation therapy plays a major role in cancer management in the effective palliation or prevention of symptoms of the disease: pain can be alleviated, luminal patency can be restored, skeletal integrity can be preserved, and organ function can be re-established with minimal morbidity94 (Box 1.2).
In 1962, Buschke69 defined a radiotherapist as a physician whose practice is limited to radiation therapy. He emphasized the active role of the radiation oncologist:
While the patient is under our care we take full and exclusive responsibility, exactly as does the surgeon who takes care of a patient with cancer. This means that we examine the patient personally, review the microscopic material, perform examinations and take a biopsy if necessary. On the basis of this thorough clinical investigation we consider the plan of treatment and suggest it to the referring physician and to the patient. We reserve for ourselves the right to an independent opinion regarding diagnosis and advisable therapy and if necessary, the right of disagreement with the referring physician… During the course of treatment, we ourselves direct any additional medication that may be necessary… and are ready to be called in an emergency at any time.
To integrate the various disciplines and provide better care to patients, the radiation oncologist must cooperate closely with other specialists.64,395
THE PLANNING AND CONDUCT OF A COURSE OF RADIATION THERAPY
When a physician proposes administering radiation therapy to a patient, six fundamental questions must be answered. Once these questions have been answered, an appropriate first step has been taken toward the development of a comprehensive justification and plan for the conduct of a course of radiation therapy. The six questions are:
1. What is the indication for radiation therapy?
2. What is the goal of radiation therapy?
3. What is the planned treatment volume?
4. What is the planned treatment technique?
5. What is the planned treatment tumor dose and fractionation?
6. What is the radiation tolerance of surrounding normal tissues (organs at risk)?
The indication for radiation therapy is that body of data that can be brought to bear showing that radiation therapy would be efficacious for the patient’s condition. Such data might exist in the form of retrospective single-institution reviews of the specific malignancy, which provide evidence favoring the role of radiotherapy. Phase I and II studies demonstrating safety and possible efficacy could be invoked to justify a course of radiation therapy. For many physicians the gold standard, however, is a prospective, randomized, phase III trial that demonstrates the value of radiation therapy. (The quality of clinical evidence is discussed in Chapter 98). There remains a role for sound personal clinical experience. Although there is increasing reliance on published trials, and special deference is given to double-blind, prospective, randomized phase III trials, it is still appropriate for a physician to rely firmly on his or her clinical experience in the context of an intimate knowledge of the patient’s problems. A sound scientific basis and an extensive knowledge of clinical research augment the essential nature of the physician–patient relationship, but they do not substitute for it.
Radiation therapy can be justified either because it improves local tumor control, ameliorates a specific symptom, improves the quality of life, or increases the probability of cure. Any data used to justify a course of radiation therapy must have a clearly defined end point, appropriate data analysis, and accepted statistical methodology. It is incumbent on the radiation oncologist to know how to critically evaluate the scientific literature and synthesize it in the best interest of the patient.
There are two possible goals of radiation therapy. Curative radiation therapy is used for the purpose of curing the patient where one is willing to engender a small risk of significant side effects in return for the possibility of cure. An example is the use of radiation therapy for the treatment of early-stage breast cancer. In return for a high probability of cure, one is willing to engender a very small risk of pneumonitis. Palliative radiation therapy is designed to ameliorate a specific symptom such as pain, obstruction, or bleeding. In palliative radiation therapy used in the context of an incurable malignancy, one is not willing to engender a significant risk of side effects to achieve a palliative goal. Thus, if one wishes to relieve pain from lung cancer metastatic to a bone, one would pick a dose and technique of radiation therapy sufficient to relieve pain but not enough to run a risk of radiation osteonecrosis.
The questions of indication and goal are generic. They should be answered irrespective of the modality of therapy being used for the treatment of malignancy. It is reasonable to ask for indications and goal if one is planning on using chemotherapy, surgery, hyperthermia, biologic therapy, or radiation therapy. Oncologists are often better at formulating indications for curative than for palliative therapy. It is not good palliative medicine to make the patient ill from therapy while making asymptomatic metastatic masses smaller. In palliative cancer treatment, one must treat the patient and his or her symptoms and not treat the mass devoid of its context.
The next three of the six major questions, volume, dose, and technique, are not generic—they are specific to the discipline of radiation oncology. First, the radiation oncologist must consider volume (Fig. 1.6). What is the appropriate volume of tissue that needs to be irradiated for the purpose of achieving the desired curative or palliative goal in the context of the justification? Does one need to treat strictly the visualized or palpable tumor mass? Is it also appropriate to treat the mass and surrounding lymphatic drainage? Does one have to worry about the routes of spread of microscopic disease? All of these are crucial questions in formulating a plan for a course of radiation therapy. If radiation oncologists only needed to treat visible or palpable masses, then radiation oncology would be more of a physics exercise than an exercise in human medicine. Understanding a cancer’s routes of spread and the tolerance of organs surrounding the cancer requires honed clinical judgment.
FIGURE 1.6. Schematic representation of “volumes” in radiation therapy. The treatment portal volume includes the tumor volume, potential areas of local and regional microscopic disease around the tumor, and a margin of surrounding normal tissue. (Modified from Perez CA, Purdy JA. Rationale for treatment planning in radiation therapy. In: Levitt SH, Khan FM, Potish RA, eds. Levitt and Tapley’s technological basis of radiation therapy: practical clinical applications, 2nd ed. Philadelphia: Lea & Febiger, 1992, with permission.)
An example of the problem of volume in the radiation therapy of cancer is medulloblastoma, a tumor that arises in the posterior fossa of the human brain. If, however, one treats with resection alone, patients almost uniformly relapse both locally and by leptomeningeal dissemination via the cerebrospinal fluid. Thus, the treatment volume for radiation therapy of medulloblastoma, in children >3 years old, is the area within the posterior fossa wherein the tumor arises and the entire craniospinal axis. Another example of the problem of treatment volume would be in head and neck cancer. Many of these tumors, by physical examination and by diagnostic imaging, appear to be localized at their site of origin. For many of these squamous cell cancers there is, however, a high incidence of dissemination to the lymph nodes of the neck. Thus, the appropriate radiation therapy treatment volume would include both the primary tumor site and the neck.
The next question that the radiation oncologist must face is what is the appropriate technique? Radiation oncologists, in general, have two techniques at their disposal. The first, teletherapy, has a similar etymology to telephone, telegraph, and telepathy. It refers to the projection of radiation through space. Teletherapy is administered with external-beam sources such as a cobalt-60 (60Co) machine or a linear accelerator. If one elects to treat a patient with teletherapy, one must derive appropriate external-beam treatment plans. These plans include considerations such as whether the patient should be treated with photons, electrons, neutrons, carbon ions, or protons; with parallel-opposed fields, four fields, or multiple oblique fields; with IMRT; with or without respiratory gating; with or without compensators; and the like. There has been an explosion of interest in new techniques of external-beam radiation therapy (EBRT) related to improvements in diagnostic imaging and the increasing power of computers to allow manipulation of vast amounts of data.
Another technique of radiation therapy is brachytherapy. The word brachytherapy shares an etymology with words such as brachycephaly and brachydactyly. It refers to short or slow therapy (i.e., a radioactive implant). There are several broad categories of brachytherapy. These include interstitial brachytherapy, intracavitary brachytherapy, and mold therapy. Interstitial brachytherapy refers to the placement of radioactive sources directly into tissue. An example might be the implantation of the tumor bed for breast cancer or soft-tissue sarcoma. Intracavitary radiotherapy refers to the placement of a radioactive source in a body cavity such as sources placed within the nasopharynx or against and through the os of the uterine cervix. Mold brachytherapy refers to the placement of radioactive sources on the skin surface, such as treatment utilized for a superficial malignancy on the back of the hand. If brachytherapy is used, the radiation oncologist must determine the appropriate isotope and whether that isotope is to be delivered by an afterloading technique or by a direct radioactive application (a hot implant).
Once the radiation oncologist has determined the appropriate treatment volume and the treatment technique(s), he or she must determine the appropriate radiation dose. Radiation dose selection is a complex issue. One must determine the correct number of fractions of radiation per day, the correct dose per fraction, and the proposed total dose of irradiation. Furthermore, in certain situations, the dose rate (i.e., the number of cGy per minute) matters, such as in total body irradiation (TBI) for bone marrow transplantation and in brachytherapy. Decisions concerning dose will, in part, be driven by decisions concerning treatment volume and technique. Paramount in the physician’s mind will be the goal of treatment. The physician must determine what the correct dose is to achieve the proposed curative or palliative goal. In broad terms, the radiation oncologist must consider what is known about the dose–response relationship for tumor control in a particular clinical situation. This subject, addressed in detail elsewhere in this chapter, concerns the probability of tumor control within a radiation therapy field as a function of the dose administered.
Finally, the radiation oncologist must consider normal tissue tolerance. In general terms, the probability of acute and late ill effects of radiation is a function of dose. Ultimately, the prescription of a dose requires the radiation oncologist to engage in a balancing act between a sufficient dose of radiation to achieve the desired treatment goal and not giving so much dose as to engender an unacceptable risk of side effects.
The fundamental questions of radiation therapy are not for the physician alone. A patient has the right to be apprised of the physician’s views on these questions, probability of tumor control (cure, if possible), and sequelae. This information should be presented to the patient in an appropriate intellectual, social, and cultural context (i.e., in a manner in which the patient can understand) so that the patient becomes a full partner in his or her care. The signing of an informed consent document by the patient is the norm.
FIGURE 1.7. Cell killing by ionizing radiation is an exponential function of dose. It follows that the dose required for a certain level of tumor control probability (TCP) is directly proportional to the logarithm of the number of clonogenic cells in the tumor deposit. It would be reasonable to expect that subclinical extensions of disease could be controlled by a lower dose of irradiation than what is required for a bulky palpable tumor mass. It has been argued by some researchers that microscopic tumor extensions are less likely to contain hypoxic foci that will minimize the requirement for reoxygenation for their control—but this is controversial. Insofar as the dose tolerated by a tissue is inversely related to the volume of tissue irradiated, delivering a uniform physical dose requires that one choose between the risk of marginal recurrences around small volumes of high dose, central occurrences in large volumes of low dose, or excessive normal tissue damage in large volumes of high dose. A reasonable approach is to use a shrinking-field technique in which one delivers an initial external-beam field that is treated to dose X and then “cones down” to a smaller field to treat to dose X + Y. In the ideal case, doses are graded to provide a homogeneous TCP throughout the treatment volume rather than a homogeneous physical dose distribution. (Based on a concept articulated by Withers HR, Peters LJ. Biologic aspects of radiotherapy. In: Fletcher GH, ed. Textbook of radiotherapy, 3rd ed. Philadelphia: Lea & Febiger, 1980:142.)
EXTERNAL-BEAM RADIATION TREATMENT PLANNING
Treatment Volume
Tumor cell killing by ionizing radiation is an exponential function of dose. The dose required for a certain level of tumor control probability (TCP, or local control) is proportional to the logarithm of the number of clonogenic cells in the tumor. Subclinical extensions of tumor (also called microscopic disease or disease below the level of ready clinical detection) should be controlled, in general, by a lower dose of external-beam radiation than is required for a palpable tumor mass. Microscopic tumor extensions may be less likely than bulky tumors to contain hypoxic cells. This also means that they may be more readily controlled by radiation.
Insofar as the dose tolerated by normal tissue is inversely related to the volume of normal tissue irradiated, delivering a uniform physical dose of radiation requires that one choose between the risks of marginal recurrence around small volumes of high dose, central recurrences in large volumes of low dose, or excessive normal tissue damage and large volumes of high dose. We may conclude that different doses of radiation are required for a given probability of tumor control, depending on the type and initial number of clonogenic cells present.
A shrinking field technique is a rational approach to the problem of heterogeneous tumor distribution (Fig. 1.7). Withers and Taylor508 have argued that “in the ideal case, the doses would be graded to provide a homogeneous TCP throughout the treatment volume rather than a homogeneous physical dose distribution.” We are entering an era of “dose painting” where a heterogenous dose will be layered on a tumor as determined by sophisticated imaging tools.40 The radiation oncologist delivers varying radiation doses to certain portions of the tumor (periphery vs. central portion or metabolically active vs. inactive on computed tomography [CT]/positron emission tomography [PET]) or may vary the dose in cases in which gross tumor has been surgically removed.
The International Commission on Radiation Units and Measurements (ICRU) Report 50 has recommended definitions of terms and concepts for radiation therapy treatment volumes and margins:229
• The gross tumor volume (GTV) denotes demonstrable tumor. It includes all known gross disease including abnormally enlarged regional lymph nodes. In the determination of GTV, it is important to use the appropriate CT and/or magnetic resonance imaging (MRI) settings and, if appropriate, PET scan to give the maximum dimension of what is considered potential gross disease.
• The clinical target volume (CTV) denotes the GTV and subclinical disease (i.e., volumes of tissue with suspected tumor).
• The planning target volume (PTV) denotes the CTV and includes margins for geometric uncertainties. One also should account for variation in treatment setup and other anatomic motion during treatment such as respiration.
Because the PTV does not account for treatment machine characteristics, the actual treated volume is that volume enclosed by an isodose surface that is selected and specified by the radiation oncologist as being appropriate to achieve the goal of treatment. It is impossible to design a radiation therapy treatment plan that limits the prescribed dose to the PTV only. Some tissues en route to the target or near the target also will be irradiated to the same dose as the target. The treated volume is, therefore, almost always larger than the PTV and usually has a somewhat simpler shape.
• The irradiated volume is that volume of tissue that receives a dose considered significant in relationship to tissue tolerance. This would include tissues in the exit region of unopposed photon beams or in the penumbra region of a beam.
• The planning organ at risk volume refers to the definition of margins around organs at risk for injury by radiation. For example, one might define a 0.5-cm margin around the optic chiasm to avoid the risk of blindness.
Uncertainties
There are, inevitably, uncertainties in the planning and delivery of a course of radiation therapy. These were well characterized by the esteemed dosimetrist Gunilla Bentel38,39 (1936–2000), to whom we are grateful for the following discussion.
Uncertainties are divided into two general categories. First, there are uncertainties related to the delivery of dose. These include inhomogeneities in the beam, problems related to dose calculations, variables in the output of treatment machines, instability of the beam monitoring technique, and problems related to beam flatness. Spatial uncertainties in the delivery of radiation therapy may be divided into those related to mechanical inaccuracies in the equipment and those related to the patient.
Mechanical Uncertainties
• Field size settings. There can be errors related either to mechanical dials or digital settings in which the field size set on the machine is not precisely the same as that delivered.
• Rotational settings. Mechanical or digital settings that display the degree of angulation of the gantry or the collimator may be in error.
• Cross hairs. Wires in the linear accelerator designed to show the central axis or the field edges may become displaced.
• Isocenter. Deviations in the position of the isocenter may occur as a result of sagging of the gantry head.
• Light-beam congruence. The light beam within the linear accelerator may be in error. These misalignments may be caused by small shifts in the mirror or the light bulb.
• Alignment systems. The laser beam systems used for alignment may be in error. They may not intersect exactly at the isocenter, they may not be perpendicular, and some systems may display relatively thick lines allowing for errors in judgment.
• Couch top. There can be differences in sag between radiation treatment couches. In addition, there may be differences in sag between the simulator couch, the CT couch used for 3D or IMRT planning, and the accelerator couch. Sometimes, in the treatment room, a tennis racket–type insert is used. Over time, couch tops can become tilted from side to side or from end to end.
• Beam-shaping blocks or collimators. If blocks are used rather than a multileaf collimator, there may be errors in constructing the blocks related to user error or because the cutting wire becomes too hot or is moved too fast around a corner when the Styrofoam mold is cut. If multileaf collimators are used, there may be errors in alignment.
FIGURE 1.8. Precision radiotherapy treatment planning must take physiologic target motion into account. Wu et al. evaluated the treatment errors from setup and interfraction prostatic motion with port films and implanted prostate fiducial markers during conformal radiotherapy for localized prostate cancer. These histograms show the frequency distribution of prostate motion in the anteroposterior and superoinferior planes. Prostate motion can contribute to setup and treatment error in external-beam radiotherapy. (From Wu J, Haycocks T, Alasti H, et al. Position errors and prostate motion during conformal prostate radiotherapy using on-line isocentre set-up verification and implanted prostate markers. Radiother Oncol 2001;61:127–133.)
Patient-Related Uncertainties
• Target delineation. No matter how sophisticated the computerized treatment-planning system, it will be to no avail if the physician is uncertain about where the tumor is located. The inherent problems related to PET, MRI, CT, and our ability to make correlations between anatomic and functional imaging, and the location of tumor may result in difficulty determining the extent of tumor as well as in transferring anatomic information from imaging studies to the 3D or IMRT treatment-planning system.
• Organ motion. Organ motion can occur from respiration or heartbeat. In addition, it can occur from changes in the size or shape of an organ as a function of digestive or excretory function (i.e., changes in the size and position of the stomach, intestines, bladder, and rectum, and, in the last case, its influence on prostate position) (Fig. 1.8).
• Skin marks. Skin marks can shift relative to deeper tissues. This can change as a result of alterations in patient weight, patient positioning, or the use of steroids during a course of radiation therapy. A particular problem is related to the width of setup lines drawn by therapists on the patient’s skin. Variation in the width of the lines drawn and variation in the position of the light fields in relationship to the lines can cause uncertainty in treatment delivery.
• Repositioning. Day-to-day problems in reproducing the position may occur.
• Patient motion. Some patients simply will not hold still during radiation therapy. Whether this is related to the patient being anxious, in pain, demented, or subject to a neurologic disorder, it can lead to uncertainties in radiation therapy treatment delivery.
Immobilization
The magnitude of uncertainties in radiation therapy treatment delivery varies. Furthermore, some uncertainties may be additive and some may cancel each other out. The net effect, on any given day, can be quite variable.
To irradiate a tumor while minimizing the radiation dose to uninvolved normal tissue, control of patient movement must be precise and absolute. Sophisticated tumor localization, 3D treatment planning, radiosurgery, and/or IMRT will be of no use if the patient is not holding still. Often, positioning and mobilization can be the weakest link in the chain of treatment planning.201 Quality radiotherapy demands that a daily setup accuracy of a few millimeters be ensured.
Mechanical immobilization of the awake radiotherapy patient is an adjunct to patient education and psychological preparation of the patient. Although not a substitute for education and psychological preparation, mechanical aids can greatly facilitate accurate treatment. The ideal mechanical aid for patient positioning will achieve the following goals:201
1. The patient must be comfortable and secure. There must be no danger of falling. The patient should not become claustrophobic.
2. The device must satisfy the radiotherapy treatment plan regarding patient position for correct geographic irradiation.
3. The setup should be quick and easy for the radiation therapist.
4. The body part treated should be rendered immobile.
5. Position of the body part should be reproducible for daily treatment.
6. Construction of the device should be reasonably quick. It should not be difficult to train therapists, dosimetrists, and physicians in the construction procedure.
7. The stabilization device should not adversely affect beam buildup and backscatter characteristics.
8. This system should be economical.
9. If anesthesia is being used, the device must not interfere with the establishment of a secure airway, intravenous access, or the use of monitoring equipment.
A variety of immobilization devices meet these stated criteria to varying degrees. There is no perfect system. Techniques will vary among institutions. It is reasonable to expect, however, that the radiation oncologist should be knowledgeable in several techniques that can be brought to bear as the situation demands.
There are a variety of stabilization devices. These include commercially available accessories such as plastic headholders and sponges, bite blocks, thermoplastics, plaster of Paris, vacuum-molded thermoplastics, polyurethane foams, vacuum bags, intrarectal balloons to stabilize the prostate and rectal wall during prostate radiotherapy, gated radiotherapy and therapy while breath holding to minimize respiratory excursion, and mechanical devices to compensate for patient movement by compensatory couch movement or collimator leaf movement.
Accuracy of external-beam placement was typically assessed periodically with portal (localization) films. It is now more common to use online imaging verification (electronic portal imaging) devices, or online CT, fluoroscopy, or ultrasound.302,475 Portal localization errors may be systematic or occur at random. Online electronic portal imaging has been used to document inter- or intratreatment portal displacement.
Patient movement clearly adversely influences the quality of external-beam radiotherapy. In a review of 48 patients on whom multiple digital portal verification images were obtained, Bissett et al.45 noted that displacements of the field were 2.9 mm in the transverse and 3.4 mm in the craniocaudal dimensions. Mean rotational displacement was 2 degrees. The mean treatment field coverage was 95%. There were some variations in the assessment of the translational errors when observations of several radiation oncologists were analyzed. Rabinowitz et al.,371 in a comparison of simulator and portal films of 71 patients, noted some discrepancies between the simulator and the localization (treatment) portal films. With an average value of 3-mm standard deviation of the variations, the mean worst case discrepancy averaged 3.5 mm in the head and neck region, 9.2 mm in the thorax, 5.1 mm in the abdomen, 8.4 mm in the pelvis, and 6.9 mm in the extremities. Other investigators have documented similar localization errors on the basis of portal film review analysis.285,286,414 Hendrickson216 reported a 3.5% error frequency in multiple parameters (setting of field size, timer, gantry and collimator angles, and patient positioning) with one technologist working. The error rate declined to 0.82% when two technologists worked together.
Doss,122 in a study of patients with upper airway carcinoma, showed that in 21/28 patients (75%) with treatments in which 30% or more portals exhibited a blocking error, a recurrence developed, whereas tumor failure was noted in only 2/12 patients (17%) without such errors. Perez et al.384 also reported a higher incidence of failures in patients with carcinoma of the nasopharynx on whom shielding of the ear inadvertently caused some blocking of tumor volume.
TABLE 1.1 THE IMPACT OF STABILIZATION DEVICES ON EXTERNAL-BEAM SETUP REPRODUCIBILITY
TABLE 1.2 INTRAFRACTIONAL PATIENT MOTION AS A FUNCTION OF THE IMMOBILIZATION DEVICEA
TABLE 1.3 AVERAGE DIAPHRAGM MOTION DURING ACTIVE BREATHING CONTROL (ABC) (MEAN, RANGE)106,131,514
A growing body of evidence supports the benefit of stabilization devices in reducing patient motion. Marks et al.285,286 demonstrated, by systematic use of verification films, a high frequency of localization errors in patients irradiated for head and neck cancer or malignant lymphomas. These errors were corrected with improved patient immobilization; with the use of a bite block in patients with head and neck tumors, localization errors were reduced from 16% to 1%286 (Table 1.1). The growing popularity of 3DCRT and IMRT, as well as the emphasis on stereotactic body radiosurgery, has led to several excellent contributions to the literature assessing the value of stabilization devices. Such devices are particularly important in the treatment of lung, liver, and paraspinal tumors. Often, these devices include a combination of a thermoplastic body cast, vacuum pillow, arm and leg support, wooden backing and/or sides, or a carbon plate. It has been demonstrated that such devices can achieve setup errors and deviations in the 1- to 3-mm range.279,404 Some institutions rely on vacuum-molded plastic shells. These devices, similarly, will achieve displacements on the order of 1 to 3 mm.226
In a randomized trial from the Karolinska University Hospital in Stockholm, Sweden, patients with head and neck cancer were randomly assigned to be stabilized with a thermoplastic head mask or a thermoplastic head and shoulder mask. Reproducibility was assessed by comparing port films in these three-dimensionally planned patients with simulator films. This was done twice during treatment and by comparing the actual treatment table positions weekly. Patient tolerance and skin reactions were also assessed. A total of 241 patients were evaluated. There were no statistically significant differences between the head mask stabilization device or the head and shoulder mask stabilization device in terms of reproducibility. It was of note, however, that patients with the thermoplastic mask extending over the head and shoulders experienced significantly more claustrophobic reactions and greater skin reactions. This study has been criticized for its reliance on thermoplastic devices rather than the vacuum-formed clear polyethylene masks.383
Because different stabilization devices are utilized in different clinical situations, there is no simple way to know which is the best stabilization device. An excellent comparative study done at the Northeast Proton Therapy Center analyzed the length for which there is a 95% probability that the total displacement will be smaller as a result of intrafractional patient motion. It is reasonable to expect that customized closely fitting molds should achieve intrafractional stabilization of 2 to 7 mm, with the best stabilization being obtained in precision treatment of the brain utilizing a rigid halo and bite block (Table 1.2).144
We may expect further benefits from research on stabilization. For example, air-filled rectal balloons have been shown to decrease prostate motion during prostate radiotherapy. The perturbation of the radiation dose near the air–tissue interface appears to produce some sparing of the rectal mucosa without incremental detriment to the dose to the prostate.443 Active breathing control, gated radiotherapy, and compensatory motion of the treatment couch to account for patient motion are also all under active investigation.126
Respiratory-Dampened, Respiratory-Gated, and Respiration-Synchronized Radiotherapy
The movement associated with respiration affects the position of multiple organs. If the radiation oncologist wishes to administer highly conformal fractionated or single-fraction treatment(s) to tumors of the liver, lung, pancreas, kidney, retroperitoneum, thoracic wall, mediastinal region, and adjacent structures, it will be necessary to either account for respiration-induced movement by putting a larger margin around the tumor or use an intervention to reduce this movement.
One method for limiting respiratory motion during radiotherapy is the abdominal compression method. This involves placing a plate or some other restrictive device above or around the abdomen and chest, sometimes in association with supplemental oxygen, in an effort to minimize the amount of diaphragmatic motion during radiotherapy.31 This is also referred to as respiratory-dampened radiotherapy.454 Another technique involves general anesthesia and high-frequency jet ventilation to minimize diaphragm motion during liver radiosurgery.169
Respiratory-gated radiotherapy involves turning the beam on only during portions of the respiratory cycle. One such method calls for the patient to hold his or her breath during the irradiation. A device called the Active Breathing Coordinator (ABC, Elekta, Norcross, GA) attempts to standardize breath holding. The patient is coached to hold his or her breath at a certain consistent depth of inspiration by watching a monitor. The ABC device uses a mouth piece, nose plug, bacterial filter, tubing, and balloon valve that, when triggered to inflate by the caregiver, will prevent airflow to and from the patient. The patient controls the switch, which must be enabled to allow the operation of the device. Using the ABC system, the caregiver can initiate a patient’s breath hold at a predetermined title volume. At the time of simulation, the patient practices inhale-exhale breath hold under guidance of the radiation therapist. At the moment of fixed inspiration, a valve device engages to prevent additional inspiration or expiration. The beam-on time is coordinated with breath holding.107,131,514
Investigation of the ABC system has focused on treatment of lung and liver. As seen in Table 1.3, the system can be used to minimize diaphragmatic motion and, therefore, reduce the amount of hepatic excursion during precision radiation therapy.
DNA DAMAGE BY IONIZING RADIATION
The biologic effects of ionizing radiation are largely the result of DNA damage, which is caused directly by ionization within the DNA molecule or indirectly from the action of chemical radicals formed as a result of local ionizations in water. The general forms of DNA damage are base damage, DNA-protein cross-links, single-strand breaks, double-strand breaks, and complex combinations of all of these.
Normal mammalian cells repair a significant proportion of radiation-induced DNA damage. Long-term biologic consequences are the result of those injuries, which are irreparable or misrepaired. The cell will attempt to repair DNA injury induced by radiation via several pathways. Key genes affecting these radiation-repair pathways include ATM (associated with ataxia telangiectasia), Ku (involved in repair of double-strand DNA breaks), and XRCC2.
There is some evidence that clustered local damage to DNA, such as a double-strand break accompanied by additional breaks, base damage, or DNA-protein cross-links, is especially difficult for cells to repair. Even lesions that are potentially repairable may be repaired incorrectly (misrepaired) if lesions are accumulating very rapidly because of high–dose-rate or dose-rate radiation or if the cell enters M phase and attempts DNA synthesis while repair is in progress. Conversely, radiation, which is given at a low dose rate or is highly fractionated, provides the best opportunity for repair of radiation-induced lesions and recovery from injury. DNA damage that is not repaired may cause cell death, prevent cell division, or permanently give rise to heritable lesions such as point mutations, small and large deletions and translocations of DNA sequences, and a wide variety of DNA aberrations276 (Tables 1.4 and 1.5).
TABLE 1.4 THE MICROENVIRONMENT AND THE RADIATION RESPONSE
TABLE 1.5 THE NANO-TO-PICO ENVIRONMENT AND THE RADIATION RESPONSE
RELEVANCE OF RADIOBIOLOGIC CONCEPTS IN CLINICAL RADIATION THERAPY
Radiation and Cancer Biology’s Contributions to the Clinical Practice of Radiation Oncology
Generations of radiation oncologists have grappled with the question of radiation and cancer biology’s contribution to the clinical practice of radiation oncology. The question was posed and addressed in two classic lectures: first by Stanford’s Henry S. Kaplan244 in his 1970 Failla lecture to the Radiation Research Society and then by Harvard’s Herman D. Suit429 in his 1983 Failla lecture. Treading on the ground prepared for us by Kaplan and Suit, we will reconsider the question in the context of the explosion of knowledge concerning the molecular and cellular basis of cancer at the start of the 21st century.
One can look at the history of cancer biology’s contribution to the clinical practice of radiation oncology in terms of two debates: empiricism versus research-based radiation oncology and biology versus physics.
Empiricism Versus Research-Based Radiation Oncology
Empiricism harkens to the views of David Hume (1711–1776) and other British philosophers of the 17th and 18th centuries and their distrust of the power of unaided reason. In the philosopher’s view of empiricism, the best contact between one’s understanding of knowledge and the world is not the point at which a mathematical proof crystallizes, but the point at which you see and touch a familiar object. Their paradigm was knowledge by sensory experience rather than by reason alone.47,315,419
Empirical radiation oncologists rely on accumulated clinical experience, also known as “what has worked in the past.” They are suspicious of therapies based on theories and laboratory research and feel safest when treading the pathway of tested experience. One can find very strong signs of empiricism in the radiation oncology literature: case reports; single-institution retrospective clinical series; and a marked concern with retrospective clinical analyses of radiation therapy that mine clinical experience to aid the selection of radiation treatment volume, dose, and treatment techniques.
There can be no doubt that the development of radiation oncology has been extensively based on empiricism. As Fowler wrote: “If therapists had waited for a fully scientific basis for treating the first patient, radiotherapy would not have started yet.”158,159 We must note, however, that radiation biologists worked closely with the early radiation oncologists. It would be erroneous to suggest that the early history of radiation oncology was completely devoid of reliance on radiation biology.
The theme of hostility to empiricism and support for finding a firm basis for clinical radiation oncology in radiation and cancer biology research is also easily identified in the development of the specialty. “Some people do the same thing wrong for 30 years and then call it accumulated clinical experience,” said one critic; or it has been said, “If radiation oncologists were put in charge of the war against polio, they certainly would have perfected the iron lung by now.” Knowledge of the genome, proteomics, secondary messengers, solid tumor biology, angiogenesis, oxygenation, and cell-cycle control are changing the present and future of medicine. If clinical radiation oncologists have a future, these individuals say, then they must actively participate in the investigation of the molecular and cellular basis of cancer and in translational research.
Physics Versus Biology
One also may formulate the debate over the role of basic biology in clinical radiation oncology as a pull and tug between physics and biology. Medical radiation physics has dominated the thinking of clinical radiation oncologists. Among the major achievements of this discipline are the following:
• The identification and characterization of physical units of radiation dose.
• Significant changes in photon and electron radiation therapy apparatus (initially, kilovoltage and later 60Co, high-energy linear accelerators, the Gamma Knife [Elekta Corp., Stockholm, Sweden], and the CyberKnife [Accuray, Sunnyvale, CA]).
• The development of 3D treatment planning for identification of tumor volume and characterization of irradiated normal tissue.
• IMRT for improved conformality of treatment beams.
• Particle therapy including neutrons, protons, pions, and stripped nuclei.
• Improved stabilization devices to aid the reproducibility of treatment.
• Advances in brachytherapy technology including new isotopes, the afterloading technique, and remote high–dose-rate machines.
• The apparatus for intraoperative radiation therapy (IORT).
• Equipment for heat deposition in tumors leading to the clinical applications of hyperthermia.
At present, a considerable effort in clinical radiation oncology is focused on the tools and techniques provided to the physician by the physicist. Radiation oncology meetings are dominated by discussions of IMRT, radiosurgery/conformal radiation, and innovations in equipment. Simply put, these techniques all offer better radiation dose distributions, which, one hopes, will lead to an increase in local control of tumors and a decrease in normal tissue toxicity. At present, a better dose distribution is the solution physics offers to the problems of oxygenation, monitoring of tumor blood flow, tumor pH, secondary messengers, tumor-suppressor genes, oncogenes, the biology of metastasis, normal tissue radioprotectors, and tumor radiosensitizers. Could it be that “if all you have is a hammer, then everything looks like a nail”?
What has cancer biology ever done for the clinical radiation oncologist? It is, we think, a generally fair question, although it might be characterized as somewhat narcissistic, along the lines of “What have you done for me lately?”158,159,429,486 Among the areas one should consider on the list of laboratory contributions to the clinic are the following:
• As early as 1906, Bergonie and Tribondeau42 enunciated a series of famous laws of radiosensitivity. This was followed by the work of the French investigators Regaud and Ferroux,373 who demonstrated that whereas a single dose of radiation to the testes always produced maximal damage to the scrotal skin, fractionated exposure spared the skin but destroyed spermatogenesis. They speculated that this same technique of fractionation might be differentially advantageous in the treatment of tumors. This led to Coutard’s98–100 studies that culminated in the fractionated EBRT techniques of today.
• The identification of the relationship between radiation dose and cell kill led to the characterization of the radiation cell survival curve. This contributed to our understanding of radiation therapy dose and fractionation and, consequently, contributed to our understanding of radiation repair. This development placed our understanding of radiation fractionation on sound footing and led to investigations of alternative fractionation schemes. This has contributed to improved tumor control as well as limitation of normal tissue toxicity. Ultimately, the radiation cell survival curve also provided the underpinnings for our understanding of elements of the dose–response relationship for tumor control and normal tissue toxicity.
• In 1909, Schwarz400 demonstrated that compression of the skin to diminish capillary blood flow reduces severity of cutaneous radiation reactions. This may have been the first demonstration of the “oxygen effect.”336 L. H. Gray185 pointed out the relevance of the “oxygen effect” to radiation oncology by identifying the fact that human neoplasms contain a significant subpopulation of hypoxic cells.451 A series of important developments has driven home the centrality of hypoxia to our understanding of radiation’s effects on tumors. Clearly, histopathologic studies and invasive measurements of intratumoral partial oxygen pressure have shown that many human tumors contain regions with low oxygen tension.61 We now believe that there are at least two different mechanisms, called diffusion-limited and perfusion-limited hypoxia, behind this observation. Some have called these permanent and transienthypoxia.336 Diffusion-limited hypoxia results from inadequate angiogenesis, whereas perfusion-limited hypoxia is associated with intermittent closure of tumor vessels, leading to acute hypoxic conditions for tumor cells downstream from the obstruction. In addition, we now understand how hypoxia activates genes and may produce tumor differentiation and increase a tumor’s metastatic potential. Clinical studies have associated the prognostic value of hemoglobin level with tumor local control.219,336 The characterization of the hypoxia problem has led to a variety of strategies to overcome it. One has been to have the patient breathe high–oxygen-content gas mixtures or to irradiate patients in hyperbaric oxygen chambers. Another option involves the use of oxygen-mimetic chemicals. Other treatment strategies include blood transfusions or the specific use of hypoxic-specific cytotoxins such as mitomycin-C.
• There has been considerable growth in our understanding of cell proliferation, the cell cycle, and cell repair mechanisms. We now understand that cells are more sensitive to radiation in M phase and more sensitive to hyperthermia in S phase. Our understanding of the differential sensitivity of cells to radiation during the cell cycle helps provide a rational basis for the use of radiation and chemotherapy. Furthermore, our understanding of the influence of the cell cycle on sensitivity has led to work on the halogenated pyrimidine analogs, which appear to sensitize cells to radiation’s lethal effects by increasing the yield of nonrepairable double-strand breaks.262 A large number of clinical trials have resulted. Although this line of research has not, to date, borne major clinical fruit, it has been a rationally based area of investigation that may yet prove itself.
• As an extension of the knowledge associated with the radiation cell survival curve, clinicians obviously need to have a good understanding of the radiation dose and response for both normal and malignant tissue. The development of research involving the lethal dose 50% (LD50), local control rates, and normal tissue toxicity in animal models has led to an improved understanding of the radiation dose–response relationship. Correlates of this understanding have included the use of the progressive shrinking-field technique; IORT; brachytherapy as “boost”; and the use of increasingly conformal beams associated with our improved understanding of how radiation dose should be associated with tumor volume and dose painting. One expects, in the future, to see increasing work in intentional dose heterogeneity as a technique for improving local control.
TABLE 1.6 PRINCIPLES OF RADIATION ONCOLOGY DERIVED FROM THE INITIAL WORK OF SUIT
In his 1983 Failla lecture, Herman Suit429 considered the evolution of the principles of clinical radiation therapy. He prepared a table in which he attempted to articulate the principles of radiation therapy invoked in the United States in 1956 and 1982. This is reproduced in the first two columns of Table 1.6. The authors of this chapter have added a third column identifying the appropriate principles for 2013. One can see, by scanning across the table, the significant changes that have taken place in our discipline. It is clear that the future holds a role both for empiricism and for research-based radiation oncology as well as a role for improvements in physics and biology. Through cooperation and constructive dialogue, all may contribute to the future of cancer care. Box 1.3 and Table 1.7 explain logarithmic cell kill.
Coleman,91 in a summary of the International Conference on Translational Research in Radiation Oncology, emphasized the importance of radiation oncologists remaining current with newer scientific findings that will be critical in the development of improved therapeutic strategies. Approaches that alter the content of cyclins or activation of cyclin p34 may overcome cellular resistance. By exploitation of cellular mechanisms related to apoptosis, it may be possible to kill cells with irradiation by inducing changes other than unrepaired DNA damage. With understanding of the tumor microenvironment and new techniques such as complementary DNA (cDNA) microarrays, as well as an understanding of how growth factors may alter cellular processes, innovative bioinformatics and improved combined-modality strategies may emerge. The ability to study many genes simultaneously will provide information beyond the era when biologic effects were attributed to a single gene. Better understanding of hypoxia may improve clinical outcome with antihypoxia strategies, including hypoxic cell radiosensitizers and hypoxic cytotoxic agents. Cyclins and growth factors may be useful as clinical radiation modifiers.
There is a critical need to balance the investment in technical aspects of radiation therapy with concepts and innovative approaches derived from better understanding of cancer biology. Coleman91,92 has presented a complex model of the biologic factors influencing radiation oncology. These scientific developments will greatly alter the way in which we practice our discipline.
Box 1.3
Logarithmic Cell Kill
Among the simplest exercises a radiation oncologist–in-training can undertake is the creation of a table of logarithmic cell kill. At first, such an exercise seems trivial. The effort expended on this somewhat tedious exercise will, however, be repaid many times over.
Let us assume that we have a tumor that follows a typical cell survival curve. These tumor cells have a 50% probability of cell survival after a radiation dose of 2 Gy. If we assume, for the purpose of this exercise, that there are no changes in the probability of cell kill wrought by changes in tumor oxygenation, pH, or other factors during the course of treatment; that there is no accelerated repopulation; and that only the simplest conditions apply (i.e., that there is 50% kill for each dose), then we can create a table showing the number of cells killed and the number of cells remaining after each dose (Table 1.7).
Let us assume that we begin with a relatively small tumor (i.e., a spherical tumor a bit more than 1 cm in diameter containing, say, 109 cells). At each dose of 2 Gy, 50% of the cells are killed. Thus, after the first dose, 500 million cells are killed and 500 million cells remain. At each successive dose 50% of the cells are killed. Therefore, by the end of the course of radiation, very few cells are killed with each individual dose.
One can see, from going through the exercise, that even for a very small tumor the number of initial cells is very large and the marginal killing of the absolute number of cells, with the last few doses, is small. It is not surprising, therefore, that for a tumor of average radiation sensitivity, quite a high dose of radiation is required.
Obviously, the exercise would change if we were to use a different radiation dose per fraction, producing a different probability of survival, or if the intrinsic radiosensitivity of the tumor cell line were different and the probability of survival were different.
Based on Suit HD. Radiation biology: a basis for radiotherapy. In Fletcher GH, ed. Textbook of radiotherapy. Philadelphia: Lea & Febiger, 1966.
TABLE 1.7 VARIOUS LEVELS OF IRRADIATION WILL YIELD DIFFERENT PROBABILITIES OF TUMOR CONTROL, DEPENDING ON THE SIZE OF THE LESION
RADIOSENSITIVITY AND RADIOCURABILITY
In 1906, Bergonie and Tribondeau42 formulated a law relating radiosensitivity to reproductive capacity of cells, based on their experiments on rat testis in which they were able to destroy the germinal cells while the interstitial tissue and Sertoli syncytium remained unimpaired. They wrote that “X-rays are more effective on cells which have a greater reproductive activity; the effectiveness is greater on those cells which have a longer dividing future ahead… From this law, it is easy to understand that roentgen radiation destroys tumors without destroying healthy tissues.” Fletcher150 felt that this observation, which was interpreted to indicate that radiosensitivity of tumors was linked to that of the mother organ, did much harm to clinical radiation therapy, leading to the erroneous concept that undifferentiated tumors with mitotic activity were radiosensitive and that more differentiated tumors were radioresistant.
In 1914, Schwarz399 introduced the concept of fractionation by postulating that it was inefficient to deliver the total radiation dose in one treatment because cells were in different states of radiosensitivity and because there was a better chance that multiple exposures could hit the cells in a radiosensitive phase (e.g., mitosis). Fractionation was assumed to create a favorable therapeutic ratio because the tolerance of normal tissues increased relative to that of tumors and because malignant cells had a greater reproductive capacity and were, therefore, more likely to be in a radiosensitive phase.
Based on these and other observations, the term radiocurability was coined. It refers to the eradication of tumor at the primary or regional site and reflects a direct effect of the irradiation; this does not necessarily equate with the patient’s cure from cancer. In contrast, radiosensitivity is a measure of tumor–radiation response, thus describing the degree and speed of regression during and immediately after radiotherapy. However, for most malignant tumors no significant correlation exists between the responsiveness of a tumor to irradiation and its radiocurability.
The response of human tumors to irradiation is a key issue for radiation oncologists and has been addressed by many leading radiobiologists. At least four explanations have been considered that could alone or in combination account for the different radiosensitivities of tumors:194,457
1. Hypoxia. To explain the spectrum of clinical radioresponsiveness on this basis, it is likely that the less responsive tumors either have a high hypoxic fraction, have failed to reoxygenate during fractionated treatment, or both.423Direct oxygen electrode measurements have shown that cervical cancer, breast cancer, and squamous cell cancers are human tumors reported to have mean oxygen pressures below those of the surrounding tissue.220,239,240,474Despite a wide range of values, the oxygen pressure in tumors tends to decrease with increasing tumor size.473 Although it is not possible to prove that hypoxia is unimportant in conventional radiation therapy, some doubts about its importance have been expressed based on the limited success of neutron therapy or hypoxic cell radiosensitizers.111,127 Recent studies have shown that hypoxia can act as an important determinant of selecting for tumor cells of a more malignant phenotype that is likely to adversely affect treatment outcome.111,239,240
2. Proportion of clonogenic cells. Proliferating cells are more radiosensitive and have a greater turnover (cell loss) rate. Tumor regression during irradiation may be proportional to the total number of proliferating cells (growth fraction) or the proliferative rate, which may accelerate for certain tumor cells as a result of adaptive processes (accelerated repopulation) during fractionated irradiation.
3. Inherent radiosensitivity of tumor cells. Fertil and Malaise147 and Deacon et al.108 established a positive correlation between the steepness of the initial slope of the oxic cell survival curve for human tumor cells and their response to radiation. The magnitude of differences between cell lines at low doses is sufficient to explain the range of curability observed clinically. Steel and Peacock423 analyzed human tumor radiosensitivity in light of existing concepts of cell killing based on the linear-quadratic (LQ) equation. However, despite encouraging correlations in some studies, these radiobiologic parameters have not been accepted for routine clinical use.
4. Repair of radiation damage. Repair of sublethal damage (split-dose effect) is observed in almost all tumor cell lines.134,135 Potentially lethal damage repair after a single dose varies considerably from one cell line to another and has been reported by Weichselbaum and Little492 to correlate with clinical radiocurability, with less curable tumors showing the greatest degree of potentially lethal damage recovery. To date, these repair parameters have not been confirmed in larger clinical experiences to justify their use as predictors of radiotherapy outcomes (see later in this chapter).
Some investigators have reported a correlation between the clinical or pathologic response of a tumor after the completion of irradiation with ultimate probability of local tumor control.432 For this analysis to be valid, it is necessary to compare patients with the same initial stage because, in general, more advanced lesions have a greater probability of tumor persistence at the completion of radiation therapy, and local recurrence may be more frequent. Barkley and Fletcher27 reported 82% tumor control in 88 patients with tumors of the oropharynx that had regressed completely at the end of therapy, in contrast to 41% in 237 patients with persistent tumor at completion of therapy. Sobel et al.418 concluded that local tumor control in head and neck carcinomas could be predicted with the greatest accuracy and consistency 1 to 3 months after completion of radiotherapy. They noted that the prediction was 80% accurate in favorable tumors (T1 and T2) but decreased to 50% to 60% in more advanced primary lesions; complete tumor clearance was a more accurate predictor of tumor control. This was confirmed for the radiotherapeutic management of N2 (>3 cm) neck disease, where complete clinical resolution of tumor within 8 weeks of completion of irradiation correlated with a >90% freedom from neck failures.305
Tumor Radiosensitivity and Predictive Assays
Since the inception of the use of ionizing radiation, many investigators have categorized the response of tumors according to their sensitivity to irradiation. Wetterer498 in 1913 characterized tumor radiosensitivity based on histologic types, and Paterson347 divided tumors into three groups: radiosensitive, intermediate, and radioresistant. The first category included germ cell tumors and reticuloses; the second included squamous cell and adenocarcinomas; and the third group included soft-tissue and bone sarcomas and melanomas. However, depending on variation in proliferative rates and cell loss, end points for response assessment may vary substantially, as has been pointed out for malignant melanoma.395 Attempts have been made to predict the response of tumors to radiation depending on several parameters, such as the assay proposed by Glucksmann177 consisting of differential cell counts of mitotic, resting, and degenerating cells in biopsy samples from the growing edge of the tumor before and after initiation of radiotherapy. It is generally accepted that tumors contain mixed-cell populations of stem cells with differing sensitivity to antineoplastic agents and that therapy can be selected for resistant cell populations or, in the case of certain cytotoxic agents, to induce cellular resistance.73 Peters et al.356,357 described a predictive assay to assess tumor response in vitro and the difficulties in predicting the probability of tumor control by irradiation in a given patient. Unfortunately, despite promising correlations between radiosensitivity in vitro and radioresponsiveness of normal tissues and tumors,41,461 sufficiently powered predictive assays have not been identified. Given the inherent intertumor variability of predictive parameters, such as SF246,283 or TPOT,379,380 a single predictive assay is unlikely to carry sufficient predictive power. The incorporation of multiple radiobiologic tumor–cell parameters (e.g., markers for radiosensitivity and proliferation potential) into TCP (see later in this chapter) models appears more promising but awaits broader validation in clinical trials.66
Probability of Tumor Control
For many histologic types of cancer, higher radiation doses produce better tumor control. Numerous dose–response curves for a variety of tumors have been published. The first dose–response data were reported for skin cancer by Miescher303 in 1934; 10 years later Strandqvist428 published a dose–response curve for skin cancer. The Strandqvist plots were refined by von Essen,479 who demonstrated from a large skin carcinoma experience that the slopes for 97% tumor control and 3% skin necrosis differed and permitted, through appropriate fractionation schedules also considering the volume of disease, a dissociation of the two end points. As Fletcher151 pointed out, meaningful dose–response curves can be generated only when a group of homogeneous tumors is given a range of radiation doses, indicating that tumor control is a probabilistic event. For every increment of radiation dose, a certain fraction of cells will be killed; therefore, the total number of surviving clonogenic cells will be proportional to the initial number present and the fraction killed with each dose.134,135 Thus, various levels of irradiation will yield different probabilities of tumor control, depending on the extent of the lesion (number of clonogenic cells present). For subclinical disease in squamous cell carcinoma of the upper respiratory tract or for adenocarcinoma of the breast, doses of 45 to 50 Gy will result in disease control in more than 90% of patients.151,301 Subclinical disease has been referred to as deposits of tumor cells that are too small to be detected clinically and even microscopically but, if left untreated, subsequently may evolve to clinically apparent tumor.344 It must be emphasized that microscopic evidence of tumor, such as at the surgical margin, should not be regarded as subclinical disease; cell aggregates ≥106/cm3 are required for the pathologist to detect them. Therefore, these volumes must receive higher doses of irradiation, in the range of 60 to 65 Gy, in 6 to 7 weeks for epithelial tumors. This distinction of disease extent is re-emphasized by clinical results, demonstrating the need for irradiating patients with likely subclinical carcinoma to postoperative doses near 60 Gy.506
For clinically palpable head and neck tumors, doses of 65 (for T1) to 75 to 80 Gy or higher (for T4 tumors) are required at 2 Gy/day using five fractions weekly. This dose range and probability of tumor control have been documented for squamous cell carcinoma and adenocarcinoma.150,151–152,301,405–407 Even with preoperative irradiation, the dose effect on probability of tumor control can be documented.
Baclesse24,25 introduced the concept of different doses of irradiation for various portions of the tumor. The higher dose administered through small portals to residual disease is called a boost, which is delivered in an effort to achieve the same probability of tumor control as for subclinical aggregates.151 One consequence of the concepts discussed earlier is use of portals that are progressively reduced in size. This shrinking field technique administers higher radiation doses to the entire gross tumor where more clonogenic cells (including hypoxic cells) reside, relative to lower doses to tissues in the immediate proximity of the clinically apparent (gross) tumor. The tissues making up the “tumor margin” contain a lower number of tumor clonogens that are better oxygenated (see Fig. 1.3).
FIGURE 1.9. Difference in cell survival curves for acute and late radiation effects with single or multifractionated doses of irradiation. (From Fowler JF. Fractionation and therapeutic gain. In: Steel GG, Adams GE, Peckham MT, eds. Biological basis of radiotherapy. Amsterdam: Elsevier Science, 1983:181–194, with permission.)
FIGURE 1.10. Graph showing the relationship between dose and size of area irradiated (healthy skin in an “average” site) to produce moist desquamation for various overall treatment times (daily irradiation at about 50 R/min for each exposure with radiation of half-value layer 1.5 mm Cu). (From Paterson R. The treatment of malignant disease by radium and x-rays. Baltimore: Williams & Wilkins, 1949:39, with permission.)
Normal Tissue Effects
A variety of normal tissue changes are induced by ionizing radiation, depending on the total dose, fractionation schedule (daily dose and overall treatment time), and volume treated. These factors are closely interrelated (Fig. 1.9).
It has been postulated that for many normal tissues the radiation dose necessary to produce a particular sequela increases as the irradiated fraction of volume of the organ decreases. This concept was demonstrated for skin by Paterson,345 who plotted doses delivered with orthovoltage x-rays that would produce moist desquamation (Fig. 1.10). The same phenomenon later was reported for supervoltage irradiation of other organs421 and for brachytherapy.
Several authors have observed higher tolerance doses (TDs) than initially reported for a variety of organs,305,315,333,382,406,407 which stresses the importance of updating this information in light of more precise treatment planning and delivery of irradiation and more accurate evaluation and recording of sequelae. Excellent examples are radiation dose escalation studies, using conformal radiotherapy delivery techniques, for prostate204 and lung carcinomas (Radiation Therapy Oncology Group [RTOG] trial 93–11). A compilation from the literature of data on tolerance doses for whole or partial organ irradiation was published by Emami et al.141 The comprehensive update of this compilation, QUANTEC, is described in Chapter 13.
In studying late radiation effects, an organ can be considered to be made up of multiple functional subunits (FSUs) that are arranged serially or in parallel.398,508 For serially structured organs, such as gastrointestinal tract or nervous tissue, damage to one portion of the organ may render the entire organ dysfunctional. In contrast, in organs with parallel structure, FSU damage may not impair the entire organ function because the remaining FSUs operate independently from the damaged group, and clinical injury occurs only when a critical volume of the organ (or proportion of FSUs) is damaged and the surviving FSUs are unable to maintain organ function. Therefore, the sensitivity of an organ depends on the number of FSUs. Marks287 discussed the importance of organ structure in determining late radiation effects and pointed out that conventional dose–volume histograms (DVHs) and normal tissue complication probability (NTCP) models are frequently inadequate because they ignore functional and structural heterogeneities. Such considerations will be particularly important for partial irradiation of lung, liver, and kidney to doses that approach the tolerance of the organs’ functional units. Yorke et al.526 developed a biologically based model for NTCP as a function of dose and irradiation volume fractions for kidney and lung in which the organ was assumed to be composed of FSUs arranged in a parallel architecture. Jackson et al.232 presented a thorough discussion of the subject, including its mathematical basis, and addressed the problem of calculating NTCP for inhomogeneously irradiated organs with parallel architecture. They showed that variations in FSUs and functional reserve in a patient population may produce NTCP dose–response curves, the widths of which are comparable with those observed clinically.
Structural alterations without anatomic or functional impairment may be noted, whereas in other instances substantial injuries with tissue destruction, severe dysfunction, or even death may occur.143 Normal tissues have a substantial capacity to recover from sublethal or potentially lethal damage induced by radiation (at tolerable dose levels). Injury to normal tissues may be caused by the radiation effect on the microvasculature or the support tissues (stromal or parenchymal cells).457
Rubin et al.387,388 indicated the usefulness of assigning a certain percentage of risk of complication, depending on the dose of the radiation. The minimal tolerance dose is defined as TD5/5, which represents the dose of radiation that could cause no more than a 5% severe complication rate within 5 years after treatment. (Some authors use the equivalent terms “tissue tolerance dose,” or TTD5/5. Both the TD5/5 and the TTD5/5 are based on treatment at 2 Gy per fraction, five fractions per week.) An acceptable complication rate for severe injury is 5% in most curative clinical situations. Moderate sequelae are noted in varying proportions (10% to 25% of patients), depending on the dose of irradiation given and the organs at risk.
Chronologically, the effects of irradiation are subdivided into acute (first 3 months) and late effects (more than 3 months after irradiation), according to the National Cancer Institute Common Toxicity Criteria. The gross manifestations depend on the kinetic properties of the cells (slow or rapid renewal) and the total radiation dose given.
Early applications of time–dose considerations were applied by Baclesse24,25 based on observations by Coutard98–100 that various degrees of mucositis and moist desquamation were repaired by re-epithelialization of the mucosa and skin from the periphery of the irradiated field and from cells surviving in the center of the field. Protracted fractionation schedules for carcinoma of the breast with lower daily doses over 10 to 12 weeks were successful in avoiding acute moist desquamation,24 but the higher radiation doses caused severe tissue damage in a large number of patients.70
No correlation has been established between the incidence and severity of acute reactions and the occurrence of late effects. In 286 patients irradiated for head and neck carcinomas, Geara et al.173 observed no significant difference in local tumor failure rates in patients with maximum grade 1 or 2 versus grade 3 or 4 acute mucositis (28% and 18%, respectively) (p = .17). Also, no correlation was found between severity of late reactions and local tumor control. Withers et al.511 compiled data depicting isoeffect lines for acute or late effects in several organs. The slopes for late reactions were steeper than for acute effects, and there was a lack of correlation between the doses producing similar severities of acute or late effects.445,446 This may result from the difference in the slopes of cell survival curves for acute or late-reacting tissues158 (Fig. 1.11).
Combining irradiation with surgery or cytotoxic agents frequently modifies the tolerance of normal tissues to a given dose of irradiation, which may necessitate adjustments in treatment planning and dose prescription. The lack of correlation between acute and late-reacting tissues represents one rationale for combining radiotherapy with chemotherapy. As long as the enhanced acute toxicities of combined treatment can be managed, no significant increased damage in late-reacting tissues is expected.446
FIGURE 1.11. A: Theoretical curves for tumor control and complications as a function of radiation dose with and without chemotherapy. TR is the therapeutic ratio, or the difference between tumor control and complication frequency. (From Perez CA, Thomas PRM. Radiation therapy: basic concepts and clinical implications. In: Sutow WW, Fernbach DJ, Vietti TJ, eds. Clinical pediatric oncology, 3rd ed. St. Louis, MO: CV Mosby, 1984:167–209.) B: Hypothetical dose–response curves for tumor control and for normal tissue injury. Because the tumor control and the normal tissue complication curves are approximately parallel in shape and are sufficiently separated, the dose levels necessary to cure a high percentage of patients can be administered without producing excessive normal tissue damage (indicated by the vertical dotted line). C: Human tumor model. The slope of the tumor-control curve is less steep than the normal tissue–complication curve; thus, for an acceptable level of normal tissue injury, the probability of tumor control is decreased compared to the hypothetical model. Because of the volume effect, reducing the volume of normal tissues shifts the curve to the higher dose region, thereby effectively increasing the separation of the dose–response curves. Consequently, a higher dose can be given to the tumor, improving the probability of tumor control without increasing the probability of normal tissue injury. (From Leibel SA, Fuks Z, Zelefsky MJ, et al. Intensity-modulated radiotherapy. Cancer J 2002;8[2]:60–166, with permission.)
QUANTITATION OF TREATMENT TOXICITY
There is a critical need to accurately assess and record morbidity of treatment because this, in addition to therapeutic efficacy, is a crucial parameter in the evaluation of new regimens and in the selection of therapy for an individual patient. Multiple schemata have been developed, although a complete consensus has not been reached as to ideal grading scores. Toxicity grading systems for various organs were developed by RTOG and the European Organisation for Research and Treatment of Cancer (EORTC). Overgaard and Bartelink337 stressed the importance of proper recording of morbidity in clinical radiation oncology, with quantification of the normal tissue effects and description of the treatment-related factors correlating with morbidity.
The evolution of radiation treatment planning and delivery, with innovative techniques (3DCRT, IMRT, image-guided radiation therapy, image-guided brachytherapy) allowing for better definition of target and sensitive structure volumes and more precise quantitation of dose, has introduced more complexity into the evaluation of radiation effects on organs at risk. Recently a supplement of the International Journal of Radiation Oncology, Biology, and Physics (Vol. 70 [Supplement 3], 2010) was dedicated to a series of articles on the “Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC),” which provided an updated review of knowledge in this area and practical guidance on toxicity risks, and attempted to identify future research to elucidate radiation effects in normal tissues and organs. (See Chapter 13.)
FIGURE 1.12. Different therapeutic ratios exist in different clinical circumstances depending on the radiosensitivity (dose–response curves) for the tumor versus critical normal tissue in the treatment field. A: Favorable. B: Unfavorable. (From Rubin P. Clinical oncology: a multidisciplinary approach for physicians and students, 7th ed. Philadelphia: W.B. Saunders, 1993, with permission.)
FIGURE 1.13. Treatment outcomes. Uncomplicated curves (dashed line) are the desired results of treatment. This is illustrated as a function of the therapeutic ratio; that is, the greater the separation of the tumor-control curve and the normal tissue–complication curve, the greater the number of uncomplicated cures that will result. The letters A, B, and C represent three different dose levels, which, if chosen, would lead to three different outcomes: A would result in few tumor cures but no complications; C would lead to complete cure in many cases, but virtually all patients would suffer complications. The optimal choice in this group of dose levels is B, which would result in the greatest number of cured patients without complications. (From Mendelsohn ML. The biology of dose-limiting tissues. In: Time and dose relationships in radiation biology as applied to radiotherapy. Brookhaven National Laboratory (BNL) Report 5023 (C-57). Upton, NY: Brookhaven National Laboratory, 1969:154–173.)
Therapeutic Ratio (Gain)
The improved definitions of TCP and NTCP,332 imply that there is an optimal radiation dose that produces a maximum tumor control with a minimum (reasonably acceptable) frequency of complications, also called treatment sequelae. The farther the TCP and NTCP curves diverge, the more favorable is the therapeutic ratio (Fig. 1.12). The therapeutic ratio or therapeutic gain factor (TGF) of a given regimen could be expressed as a ratio:
The higher the TGF, the more efficient a particular therapy. Such a quantitative expression could be used to compare different therapeutic strategies. Mendelsohn300 expressed this concept in terms of “uncomplicated tumor ablation” (Fig. 1.13). The selection of a dose must weigh the probability of major complications for any potential enhancement of tumor control. Models for decision making, using Bayesian theory, incorporate values assigned to positive or negative outcomes.300 Positive outcome is considered tumor cure without complication, whereas negative outcomes include tumor cure with significant complications or tumor recurrence with or without complications.
Impact of Local Tumor Control on Survival
Over the past two decades, systemic chemotherapy was emphasized as a therapy that could improve survival of cancer through control of systemic metastatic disease. The effect of locoregional tumor control on patient survival has been emphasized repeatedly.212,488 Clinical experiences and randomized trials394 demonstrate for cancers with high metastatic potential, such as breast, prostate, and lung, that improved locoregional control by radiotherapy with or without chemotherapy enhances overall survival. This has revived the interest in locoregional radiotherapy as a survival-prolonging treatment modality, also confirming earlier clinical experiences in patients with carcinoma of the lung, prostate, and uterine cervix.
Because of the emphasis on control of systemic disease, assessment of the importance of locoregional tumor control in patients with malignant tumors has been relatively underemphasized. In a large proportion of patients with cancer seen in the United States, locoregional recurrence is just as prevalent (69% of patients dying with locoregional disease) as distant metastases. A large proportion of patients (50%) have both locoregional recurrence and distant metastases (see Table 1.6).
Clinical data have matured over the past decade, demonstrating that tumor persistence after initial therapy does, because of tumor progression, carry as poor a prognosis as treatment of a more advanced cancer. In addition, radiotherapy has been shown for tumor with high metastatic potential, such as breast, prostate, and lung, to prolong overall survival if higher radiation doses are delivered and achieve improved local control rates.92,204,395
DOSE–TIME FACTORS
Dose–time considerations constitute complex relationships that express the interdependence of total dose, time, and number of fractions in the production of a biologic effect within a given tissue volume. This phenomenon, from a radiobiologic viewpoint, is closely related to the four Rs of ionizing radiation:
1. Repair of sublethal and potentially lethal damage;
2. Repopulation of cells between fractions;
3. Redistribution of cells throughout the cell cycle (partially the result of radiation-induced synchrony secondary to transient arrest at cell-cycle checkpoints and cell-cycle–dependent cell killing); and
4. Reoxygenation occurring during repeated radiation exposures.
The advantages of dose fractionation include:
1. Reduction in the number of hypoxic cells occurs through cell killing and reoxygenation. There is increased oxygenation in the tumor after irradiation, whereas changes in normal tissue oxygen are slight or nonexistent.79
2. Reduction in the absolute number of clonogenic tumor cells by the preceding fractions with the killing of the better-oxygenated cells. Assuming a constant supply of oxygen, fewer cancer cells will have access to an increased amount of oxygen.
3. Blood vessels compressed by a growing cancer are decompressed secondary to tumor regression, thus permitting better oxygenation despite the constant diffusion distance of oxygen in tissue near 200 μm.
4. Fractionation exploits the difference in recovery rate between normal, acute, and late-reacting tissues and tumors. Radiation-induced redistribution of cells within the cell cycle tends to sensitize rapidly proliferating cells as they move into the more sensitive phases of the cell cycle.
5. The acute normal tissue toxicity of single radiation doses can be decreased with fractionation. Thus, patients’ tolerance of radiotherapy will improve with fractionated irradiation.
In general, fractionated irradiation will spare acute reactions because of compensatory proliferation in the epithelium of the skin or the mucosa, acceleration of which can be measured experimentally 2 or 3 weeks after initiation of therapy, but most likely starts with initiation of irradiation.41,110,161,396 However, a prolonged course of therapy with small daily fractions will decrease early acute reactions but not necessarily protect from serious late damage to normal tissues. This approach also promotes accelerated repopulation and permits the growth of rapidly proliferating tumors. A major research effort in clinical radiobiology is and will be devoted to the optimization of dose–time-fractionation schedules for various tumors that are individualized depending on cell kinetic characteristics, molecular biology, and clinical observations.66,101,459 Fowler159 published theoretic considerations based on a series of assumptions of the values used in the LQ equation with a time factor in which he attempted to predict the optimal dose-fractionation schedules for tumors with various cell-doubling times. He concluded that optimal overall times depend primarily on the doubling time of the tumor cells and intrinsic radiosensitivity, alpha (assumed to be proportional to α/β). Short overall treatment times are required for tumors with a low α/β ratio or fast proliferation. For median potential doubling times of 5 days and intermediate radiosensitivity, overall times of 2.5 to 4 weeks would be optimal. More slowly proliferating tumors should be treated with longer overall times (Fig. 1.14). In vitrotechniques to assess tumor radiosensitivity in biopsy specimens ultimately may be helpful as predictive assays.
FIGURE 1.14. Log cell kill in tumors as a function of overall time, for schedules using five fractions per week to a total dose that gives the same late effects as 30 fractions of 2 Gy (assuming α/β = 3 Gy for late effects). Each curve is for the stated proliferation doubling time (average over the overall time). The diamond-shaped symbols show the maximum cell kill for that doubling time, at the optimum overall time for that number of fractions per week. If there is no diamond, the optimum overall time is longer than 7 weeks. The dotted line is drawn arbitrarily at 9 logs of cell kill. (From Fowler JF. How worthwhile are short schedules in radiotherapy? A series of exploratory calculations. Radiother Oncol 1990;18:165–181.)
FIGURE 1.15. Various types of fractionation used in radiation therapy.
TABLE 1.8 COMPARISON OF VARIOUS FRACTIONATION SCHEDULES
Altered Fractionation
Without a solid biologic basis and out of empiricism and convenience, the “standard fractionation” for radiation therapy has evolved into five fractions weekly. Other fractionation schedules have been proposed that deliver multiple fractions daily or six fractions weekly or use a hyperfractionation split-course regimen (Fig. 1.15). The characteristics for hyperfractionation, accelerated fractionation, or split-course schedules as well as potential advantages or disadvantages are summarized in Table 1.8. Based on the narrow window between improvements in tumor control and enhanced normal tissue toxicities,355 any altered fractionation schedule is potentially harmful and must be approached with great caution. However, the improved quality of clinical trials by national study groups and by individual institutions has generated a growing body of clinical outcome data that, together with improved biologic modeling, allows relatively accurate predictions of clinical outcomes based on relative biological effectiveness (RBE) calculations.308
Multiple daily fractions are likely to be more effective in rapidly growing tumors with a high growth fraction. Normal tissues behave as actively proliferating cells for expression of acute reactions but as slowly proliferating cells in the manifestation of late injury.509 As suggested by several biologic studies,163 clinical trial results conducted by EORTC and RTOG demonstrated that a minimum of 6 hours interfraction interval should be allowed when multiple daily fractions are used to allow maximum repair of normal tissues. This is supported by reduced complication rates in patients irradiated for carcinoma of the lung and a highly uniform cohort of patients with tonsillar squamous cell carcinomas.160,506
Accelerated fractionation aims at shortening the overall treatment time. Schedules may use larger than standard size fractions five times weekly or more than five fractions per week of 2 Gy. In addition, multiple fractions of radiation may be given daily exclusively or in combination with standard fractions of 2 Gy. Some reduction in the total dose delivered may have to be used for fractions >2 Gy for normal tissue sparing. These schedules may be preferable with hypoxic cell sensitizers or other chemical modifiers of radiation response that require the presence of a high concentration of the compound in the tumor at the time of the radiation exposure.
With hyperfractionation, a larger number of smaller-than-conventional dose fractions are given daily; the total daily dose is usually 10% to 20% greater than with standard fractionation; the total period of time is minimally changed; and the total dose needs to be escalated to achieve tumor toxicity similar to that of standard fractionation. The aim of hyperfractionation is to achieve the same incidence of late effects on normal tissue as observed with a comparable conventional regimen while increasing the probability of tumor control through dose escalation.507
Accelerated Repopulation
Withers and Taylor508 described experimental observations documenting accelerated repopulation of tumor cells during fractionated radiotherapy and provided convincing evidence that this phenomenon occurs in clinical situations (Figs. 1.16–1.18). Although Withers and Taylor’s analyses suggested that accelerated repopulation occurs preferentially after the 4th week of radiotherapy, reanalysis of the same data by Bentzen40 and Thames et al.445 and independent derivations by Fowler161 suggested that repopulation starts early during fractionated irradiation. The latter is supported by experimental data of Schmidt-Ullrich et al.,396 showing that molecular processes of accelerated repopulation, mediated through radiation-induced receptor activation and cellular growth stimulation, occur after a single radiation exposure of 2 Gy. The effectiveness of a course of fractionated irradiation depends in part on the killing by individual fractions as well as on the rate of proliferation of surviving cells between irradiation fractions. Neoadjuvant chemotherapy also may lead to increased proliferation of surviving tumor cells after partial regression of the lesion, which could result in decreased cell killing by subsequent fractionated irradiation.
Isoeffect Graphs
To express an equal biologic effect produced by various fractionation schedules, isoeffect lines have been generated. Kronig and Friedrich254 first published the observation that a specific physical dose of irradiation is less biologically effective if given in multiple fractions, which embodies the original concept of recovery between fractions. Later, MacComb and Quimby281 and Reisner374 established the rate of recovery in experimentally produced skin reactions in patients.
In 1944, Strandqvist428 published a monograph describing the results of treatment of 280 patients with skin cancer (squamous cell and basal cell carcinoma); most tumors were treated within 14 and 29 days, and only one was treated within 45 days. An isoeffect line was drawn, with a slope of 0.22. He fitted the recovery factors of MacComb and Quimby and Reisner using an extrapolated value of 0.35 per day as the time for a single dose. He also produced a graph for various degrees of radiation reaction on the skin, ranging from erythema to necrosis (Fig. 1.19). It should be emphasized that in these curves, the vertical coordinate represents the total dose given, and the abscissa represents the total duration in days after the first irradiation. However, some authors have plotted similar graphs representing the number of fractions in the horizontal coordinate. It is critical to identify these two parameters because one could deliver 60 Gy in 6 weeks in 30 fractions given five times weekly or the same dose delivered in 18 fractions given three times weekly. The effects on normal tissues certainly would be different. Von Essen,479 using the Strandqvist data as well as his own, pointed out the importance of the volume irradiated when isoeffect parameters are studied and generated a 3D display of these data.
Dutreix et al.130 published observations on the influence of fraction size in patients with cancer of the lung, on whom one of the supraclavicular areas received a single exposure and the other area received two exposures separated by 6 hours. They noticed that two fractions of 1 Gy produced the same skin reaction as one fraction of 2 Gy. As the fraction size increased, however, it took a higher dose in the two-fraction schedule to produce the same reaction as with the single-fraction schedule. With mucositis of the faucial arch used as an end point, researchers at M.D. Anderson Cancer Center observed that 10 Gy per week given in five fractions of 2 Gy is equivalent to 11 Gy given in 10 fractions, twice a day, separated by 3 hours.150
The slopes for reactions for various normal tissues differ, as do slopes of tumor curability and normal tissue late effects. In general, the slope for tumor curability is less steep than that for normal tissue reactions. Isoeffect lines for various squamous cell carcinomas of the head and neck, different stages, have slopes varying from 0.33 to 0.38.152,421 Furthermore, as stated earlier, tolerance of normal tissues is strongly related to the volume irradiated. Whereas 60 Gy could be given safely in 5 weeks for a small glottic tumor with a 5-cm by 4-cm portal, the same dose delivered in the same period for a supraglottic carcinoma, with a larger portal covering the entire larynx, would result in more severe acute and late sequelae152 (Box 1.4).
FIGURE 1.16. A: Schematic diagram indicating that cell survival during a course of fractionated irradiation depends not only on the proportion of cells killed with each dose (equal for the two curves shown) but also on the rate of proliferation of surviving cells between dose fractions, which differs for the two curves. B: Hypothetical diagram to illustrate the number of surviving cells in a tumor during treatment with irradiation alone (solid line) or during radiation therapy delivered to a tumor that has responded to chemotherapy (i.e., cell number reduced to 1% at start of irradiation) but where proliferation has been stimulated (dashed line). Note that cell survival is similar after fractionated irradiation, despite the initial response to drugs. (From Tannock IF. Combined modality treatment with radiotherapy and chemotherapy. Radiother Oncol 1989;16:83–101.)
FIGURE 1.17. Dependence of tumor control probability (TCP) on the position of a single treatment gap in 533 patients. Gap duration ranged from 3 to 20 days. Position of a gap is defined by its starting point. Each point shows the TCP averaged over 3 consecutive days (± SD). (From Skladowski K, Law MG, Maciejewski B, et al. Planned and unplanned gaps in radiotherapy: The importance of gap position and gap duration. Radiother Oncol 1994;30:109–120.)
Linear-Quadratic Equation (α/β Ratio)
Formulations based on dose survival models have been proposed to evaluate the biologic equivalence of various doses and fractionation schedules. These assumptions are based on an LQ survival curve represented by the equation:
in which α represents the linear (i.e., first-order dose-dependent) component of cell killing, and β represents the quadratic (i.e., second-order dose-dependent) component of cell killing. Thus, β represents the more reparable (over a few hours) component of cell damage (Figs. 1.20–1.22). The dose at which the two components of cell killing are equal constitutes the α/β ratio.
In a study of 17 human tumor cell lines, Steel and Peacock423 observed that the average surviving fraction at 2 Gy is 0.44 from the α component and 0.88 from the β component. The β effect at that dose level appears to be similar in radiosensitive and radioresistant tumors; thus, among radiosensitive tumors in which the survival from the α component is below 0.3, the β effect makes a very small contribution to overall radiosensitivity in the lower dose region. The overall effect of many small fractions is to amplify the dominance of the α component. The β effect is unimportant because repair will be almost complete. In the more radiocurable tumors, cell killing by the α component represents the predominant fraction of tumor cell killing.
FIGURE 1.18. Complication probability correlated with irradiation dose for (A) brain, (B) spinal cord, (C) kidney, and (D) lung. (From Burman C, Kutcher GJ, Emami B, et al. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys1991;21:123–135.)
FIGURE 1.19. Strandqvist’s curves on log paper. The slope of the curves (0.22) is the same for the tumoricidal dose for squamous cell carcinoma for various degrees of skin reactions. (From Strandqvist M. Sutdien uber die kumulative wirkung der rontgenstrahlen bie frakionierung. Acta Radiol [Stockh]1944;55[Suppl]:1–300.)
FIGURE 1.20. A: At a dose equal to the α/β ratio, the log cell kill due to the α-process (nonreparable) is equal to that due to the β-process (reparable injury); α/β is thus a measure of how soon the survival curve begins to bend over significantly. The α/β ratio for late effects on normal tissue generates a “curvier curve” than the α/β ratio for radiation’s effects on acutely reacting normal tissue and tumor cells. Thus, the relative effect of dose per fraction is higher for late-responding tissue than for acutely responding tissues. In particular, for the central nervous system, high-dose-per-fraction radiation therapy is associated with an increased risk of late effects. An α/β ratio of 2 to 3 commonly is used in calculations of radiation effects on late-reacting tissue, whereas the ratio of 10 is used more commonly for acute-responding tissues or tumor. (From Fowler JR. Fractionation and therapeutic gain. In: Steel GG, Adams GE, Peckham MJ, eds. The biological basis of radiotherapy. Amsterdam: Elsevier Science, 1983:181–194.) B: A schematic representation of biologic data relating dose per fraction to effect on tumors, early reacting, and late-reacting normal tissues. (From Saunders MI. Programming of radiotherapy in the treatment of non-small-cell lung cancer—a way to advance cure. Lancet Oncol 2001;2[7]:401–408.)
FIGURE 1.21. Hypothetical survival curves for the target cells for acute and late effects in normal tissues exposed to x-rays or neutrons. The α/β ratio in the equation for surviving fractions (SF = e−αD + βD2) is higher for late effects than for acute effects in x-irradiated tissues, resulting in a greater rate of change in effect in late-responding tissues with change in dose. At dose A, survival of target cells is higher in late-effects than in acute-effects tissues, whereas at dose B, the reverse is true. Therefore, increasing the dose per fraction from A to B results in a relatively greater increase in late rather than acute injury. In the case of neutrons, the α/β ratio is low, with no detectable influence on the quadratic function (eβD ± D2) over the first two decades of reduction in cell survival, implying that accumulation of sublethal injury plays a negligible role in cell killing by doses of neutrons of clinical interest. At these doses, the relative biologic effectiveness is higher for late effects than it is for acute effects. (From Fowler JR. Fractionation and therapeutic gain. In: Steel GG, Adams GE, Peckham MJ, eds. The biological basis of radiotherapy. Amsterdam: Elsevier Science, 1983:181–194.)
Box 1.4
Nominal Standard Dose and Time–Dose Factor
The nominal standard dose (NSD) concept is of historic interest. For 20 years NSD was used frequently to express equivalency of clinical doses of irradiation based on human skin tolerance and curability of squamous cell carcinoma. Cohen89 pointed out that the regression coefficient for squamous cell carcinoma was different from that of normal skin (0.24). In 1969, Ellis137 suggested that if one number could be used to represent the dose of irradiation that reached normal tissue tolerance, this would be advantageous in comparing different techniques. This figure should represent the normal connective tissue tolerance because this was, in his thinking, the limiting factor in most tumor therapies.
The unit for NSD expression was the ret. It could never be assumed that the NSD value represented a “single equivalent dose” because the isoeffect time calculated by Ellis used data from four to 30 fractions. Another flaw of the NSD calculation was that it did not allow for the effect of variations in volume treated or for interruptions of therapy (split-course therapy). Orton330 estimated that NSD calculations were misused about 50% of the time by unaware clinicians comparing different radiation therapy regimens. The NSD formula did not predict isoeffect in pig skin irradiation with 60Co using two to five fractions per week. Moreover, early reactions did not predict the magnitude of late damage when dose fractionation was altered from conventional daily schedules.
In 1973, Orton and Ellis334 published a simplification of the NSD concept more applicable to clinical radiation therapy, stating that when a treatment did not result in normal connective tissue tolerance, treatment effectiveness should be described in terms of partial tolerance. Although there was no definite basis for the application of the time–dose factor (TDF) concept to clinical radiation therapy, equivalency of various dose schedules is sought constantly. For split-course regimens, the TDF values (in units of ret) were used by adding the TDF value for each of the partial tolerance factors corresponding to each component of the treatment and correcting for the decay of the first part of the treatment TDF.
In 1974, Orton332 defined TDF values for continuous irradiation that could be used with temporary or permanent brachytherapy implants, using various isotopes. A standard radium therapy regimen of 60 Gy in 168 hours was used for comparison with other equivalent techniques. According to Ellis,139 this was equivalent to 1,800 ret of fractionated external irradiation.
The shape of the dose survival curve with photons differs for acutely and slowly responding normal tissues. This difference in shape is not observed with neutrons. The severity of late effects changes more rapidly with a variation in the size of dose per fraction when a total dose is selected to yield equivalent acute effects. With a decreasing size of dose per fraction, the total dose required to achieve a certain isoeffect increases more for late-responding tissues than for acutely responding tissues. Thus, in hyperfractionated regimens, the tolerable dose would be increased more for late effects than for acute effects. Conversely, if large doses per fraction are used, the total dose required to achieve isoeffects in late-responding tissues would be reduced more for late effects than for acute effects. In general, tumors and acutely reacting tissues have a high α/β ratio (8 to 15 Gy), whereas tissues involved in late effects have a low α/β ratio (1 to 5 Gy). Some values obtained in animal experiments and clinical studies are summarized in Table 1.9.
The values for α and β can be obtained from graphs in which the reciprocal of the total dose (Gy−1) and the dose per fraction (Gy) are plotted. A straight line is obtained. The intercept of this line with the zero dose-per-fraction axis is proportional to α and equal to α/ln S, wherein S is the natural logarithm of survival. The slope is proportional to β and equal to β/ln S.
The algebraic functions to derive the straight line from the reciprocal total dose per fraction plot are as follows: Tumor cell survival following n fractions, each of dose d:
Dividing both sides by total dose nd:
Withers et al.506 proposed a method for using these survival curve parameters for calculating the change in total dose necessary to achieve an equal response in tissue when the dose per fraction is varied, using the α/β ratios. This calculation accounts only for the effect of repair of cellular injury. The isoeffect curves vary for different tissues. A biologically equivalent dose (BED) can be obtained using this formula:
If one wishes to compare two treatment regimens, the following formula can be used:
in which Dr is the known total dose (reference dose), Dx is the new total dose (with different fractionation schedule), dr is the known fractionation (reference), and dx is the new fractionation schedule.
Let’s consider an example of the use of this formula (with some reservations). Suppose 50 Gy in 25 fractions is delivered to yield a given biologic effect. If one assumes that the subcutaneous tissue is the limiting parameter (late reaction), it is desirable to know what the total dose to be administered will be using 4-Gy fractions. Assume α/β for late fibrosis equals 2 Gy.
Using the above formula:
Thus,
The basic LQ equation addresses the inactivation of a homogeneous population of cells. One should be wary, however, of accepting the basic equation as being complete. Because it is likely that accelerated repopulation of tumor clonogens occurs during the course of radiotherapy, and that cell-cycle redistribution and reoxygenation also occur, we should consider how these factors can be accounted for in the formula.58,194,522
Repopulation may be accounted for, in broad approximation, by describing the number of clonogens (N) at time t as being related to the initial number of clonogens (No).
Then,
The parameter λ determines the speed of cell repopulation and is given by
where Tpot is the effective doubling time of cells in the tumor. If we ignore spontaneous cell loss, then Tpot is approximately the same as the measurable in vitro doubling time of tumor cells. Reported values of Tpot are 2 to 25 days with a median value of approximately 5 days. For late-responding tissues, Tpot is so large that λ is effectively zero.
Incorporating the allowance for tumor proliferation, with t representing time, the LQ equation becomes
Let’s assume an α/β for an acutely reacting tissue, such as a tumor, of 10, and an α of 0.3 with a Tpot of 5. The BED of 70 Gy of 2 Gy/fraction, five fractions per week, in 46 days, is
Now let’s add the correction for tumor repopulation during the course of treatment:
The decrease in clonogens by radiotherapy is attenuated, in part, by the repopulation of the surviving clonogens.
In the LQ equation, redistribution in the cell cycle and reoxygenation may be modeled by a single term called resensitization. Immediately after a dose of radiation, the average radiosensitivity of the cell population falls and then gradually returns to greater sensitivity. In contrast to tumor proliferation, resensitization probably increases as overall treatment time increases. Not enough is known about resensitization’s clinical importance to make it useful to incorporate a numeric value for it in the LQ formula.
The LQ model can be used to construct a biologically oriented dose distribution algorithm for clinical radiation therapy.280 A physical dose distribution can be translated to a BED using published biologic parameters. We are certainly not in a position to begin the routine use of this approach in clinical radiation therapy, although it may help clinicians to optimize treatment plans, and the technique may be used for outcome analysis in clinical research when the biologic parameters and the assumptions can be validated.
FIGURE 1.22. Values of α and β. If the reciprocal of total dose (for several multifraction schedules) is plotted against dose per fraction, a straight line will be obtained. The intercept of this line with the zero dose-per-fraction axis is proportional to α (α/ln S). The slope is proportional to β (β/ln S). The α/β ratio is readily determined. For absolute values of α and β, clonogenic assay is necessary for the end point. (From Fowler JR. Fractionation and therapeutic gain. In: Steel GG, Adams GE, Peckham MJ, eds. The biological basis of radiotherapy.Amsterdam: Elsevier Science, 1983:181–194.)
FIGURE 1.23. The dose-rate effect as a result of repair of sublethal damage, redistribution in the cycle, and cell proliferation. The dose–response curve for acute exposures is characterized by a broad initial shoulder. As the dose rate is reduced, the survival curve becomes progressively shallower as more and more sublethal damage is repaired, but cells are “frozen” in their positions in the cycle and do not progress. As the dose rate is lowered further and for a limited range of dose rates, the survival curve steepens again because cells can progress through the cycle to pile up at a block in G2, a radiosensitive phase, but still cannot divide. A further lowering of dose rate allows cells to escape the G2 block and divide; cell proliferation then may occur during the protracted exposure, and survival curves become shallower as cell birth from mitosis offsets cell killing from the irradiation. (Based on the ideas of Dr. Joel Bedford, and from Hall EJ. Radiobiology for the radiologist, 4th ed. Philadelphia: J.B. Lippincott, 1994, with permission.)
FIGURE 1.24. Low–dose-rate irradiation. Isoeffect dose equivalent to 60 Gy in 7 days. Two sets of parameters have been considered for the computation, which would presumably correspond to skin and mucosa early reactions and to the effect on the epithelioma (α/β = 10 Gy, Tr = 1 hour) and to late reactions (α/β = 3 Gy, Tr = 1.5 hour). (From Dutreix J. Expression of the dose rate effect in clinical curietherapy. Radiother Oncol 1989;15:25–37.)
DOSE RATE
The radiation dose rate may significantly influence the biologic response, particularly for sparsely ionizing radiations such as x-rays and γ-rays. Three main biologic processes are involved in the dose-rate effect (Figs. 1.23 and 1.24).194,212
1. Repair of sublethal damage occurs when radiation is delivered at a low dose rate, and the treatment time is extended to a point where it is comparable to the repair half-time. As the dose rate is reduced, more sublethal damage is repaired because the radiation injury is spread over a longer period. The cell survival curves become progressively less steep, and at the same time the extrapolation number approaches unity.
2. Cell proliferation occurs during protracted radiation exposure if the dose rate is low enough or the cell cycle time is short enough.
3. Redistribution and accumulation of cells throughout the cell cycle occur with a low dose rate in which proliferation is decreased because cells are arrested and accumulate in G2. This phase of the cycle is relatively radiosensitive. As a result, cell killing may be greater for a lower dose rate. This effect occurs over a narrow dose-rate range and is known as the inverse dose-rate effect.
With the advent of moderate– and high–dose-rate remote control afterloading devices, increased emphasis has been placed on the biologic effects of dose rate. Many in vitro and in vivo experimental observations indicate variations in cell killing and repair of sublethal or potentially lethal damage with varying dose rates. The so-called dose-rate effect is most dramatic between 1 cGy/minute and 1 Gy/minute.191 The biologic effect achieved by a given irradiation dose decreases as the dose rate diminishes, chiefly as a result of the increase in cell repair that occurs during continuous prolonged irradiation, because cell proliferation is virtually negligible in the range of treatment times used in low–dose-rate brachytherapy.129
In some experiments, a bending of the cell survival curve at very low dose rates has been noted, instead of the expected exponential result, possibly because of cell redistribution529 or a decline in the repair capacity with large doses.470 At a very low dose rate, because the cell killing is caused only by direct lethal events that are considered independent of the dose rate, cell repair is also negligible. The induction of sublethal injury is relatively slow compared with the rate of repair, and cell killing, by accumulation of sublethal injury, remains minimal. Variation of the isoeffect dose occurs mainly in the range of medium dose rates (1 to 10 Gy/hour), and it vanishes at very high dose rates because the cell repair is negligible during the short treatment time.129
The dose-rate effect in clinical brachytherapy was described initially by Green and Paterson and reiterated by Ellis and Orton.138,332,346 The historic isoeffect curve showed a significant increase in dose when time was increased from 2 to 7 days. However, the validity of Paterson’s curve was questioned by Pierquin et al.,360 who used the same dose of 70 Gy with treatment times ranging from 3 to 8 days for the treatment of head and neck tumors with 192Ir implants and did not observe any difference in the control rate or incidence of necrosis. The agreement with Paterson’s curve is acceptable when the α/β value equals 3 Gy and repair half-time (Tr) equals 1.5 hours, but the curve is shallower when α/β equals 10 Gy and Tr equals 1 hour. One should expect Paterson’s curve to correspond to late reactions and to overestimate the variation for early reactions and control of squamous cell carcinoma.
Several important concepts should be considered regarding the clinical relevance of dose rate:58,191
1. At ultra-high doses and instantaneous dose rates (i.e., 10 Gy pulsed in nanoseconds), the rapid deposition of energy consumes oxygen too quickly for diffusion to maintain an adequate level of oxygenation, and dose–response curves are characteristic of hypoxia. There is little interest in clinical application of this approach.
2. Based on laboratory data, it may be possible to design schedules with a pulse width of several minutes and a pulse interval of about 1 hour to achieve cell killing equivalent to that obtained with a continuous 30 Gy in 60 hours (0.5 Gy/hour).
3. Using the LQ equation, it is possible to estimate the equivalency of high–dose-rate (HDR) and low–dose-rate (LDR) exposures with a variety of fractionation schedules (remembering that a lower number of fractions may result in enhanced late effects).
Special consideration should be given to the effect of HDR brachytherapy on normal tissues. The tumor dose must be decreased 30% to 50% in comparison with that delivered with conventional low dose rates.333,335 (For further discussion, see Chapters 22–25.)
In the past, there was some interest in continuous LDR irradiation with external cobalt units.505 Pierquin et al.359 used a modified 60Co unit with a small industrial source (activity 45 Ci). Radiation was delivered at 1 to 1.39 Gy/hour to administer daily tumor doses of 8 to 10 Gy in 7 to 8 hours. A minimum of five treatments was given per week, although occasionally weekends and holidays caused schedule modifications. Patients were given short rest periods every 1 or 2 hours. Tumor doses of approximately 63 Gy were delivered in eight to 11 fractions, with the volume reduced to 8 by 10 cm after 45 Gy. Nineteen patients with advanced tumors of the mouth and pharynx were treated; 15 had no evidence of tumor 3 months after treatment. Only three patients developed recurrences. Of 19 patients, two developed moist desquamation and six developed dry desquamation; the others had only erythema. No significant late effects on the skin or the subcutaneous tissues were noted; 16/19 patients developed severe mucositis. Seven patients developed necrosis, six in large areas of the oral cavity and pharynx and, in several instances, at the tumor site.
FIGURE 1.25. Frequency distribution of patients treated to different probabilities of complication. (From Orton CG. Other considerations in 3-dimensional treatment planning. In: Bagne F, ed. Computerized treatment planning systems. HHS Publication FDA 84–8223. Washington, DC: U.S. Government Printing Office, 1984:136–141.)
IMPORTANCE OF TREATMENT PLANNING IN RADIATION THERAPY
The predicted consequences of external-beam radiation therapy are based on the precision with which the dose and the irradiated volume are defined. An imprecise treatment system could lead to a high incidence of necrosis with, paradoxically, a low probability of tumor control (Fig. 1.25).331 Decreasing irradiation doses to avoid complications will further reduce the probability of achieving tumor control if such action is based on the wrong assumption that the tumor control/complication ratio is related only to radiation dose levels. The ICRU recommends a ± 5% accuracy for dose-delivery computations.229 However, every effort should be made to develop accurate dose-calculation algorithms, including methods to correct for inhomogeneities in tissue density and the shape of the patient’s body, and to develop practical treatment-planning capabilities to obtain the highest possible dose optimization in the irradiated volume (tumor and normal tissues). There are benefits of reducing the treatment volume in an effort to deliver higher doses of irradiation. This may improve the quality of tumor control without excessively irradiating surrounding normal tissues, thereby decreasing treatment-related morbidity.
Various steps can be taken to decrease toxicity in normal tissues, including precise treatment-planning and irradiation techniques, selective decreased volume receiving higher doses dictated by estimated cell burden, and maneuvers to exclude sensitive organs from the irradiated volume. With the emphasis on organ preservation, treatment planning is critical to achieve maximum TCP and satisfactory cosmetic results.
Optimal dose distribution may be achieved by a combination of multiple stationary beams or by moving-beam therapy, such as in arc or full-rotational techniques or IMRT. In addition, the optimal dose distribution in many tumors requires more than one modality or beam energy. A combination of external beams and intracavitary or interstitial therapy also may be required, depending on the location of the tumor.
Three-Dimensional Treatment Planning
Advances in computer technology have augmented accurate and timely computation, display of 3D radiation dose distributions, and DVHs.182,368 These developments have stimulated sophisticated 3D treatment-planning systems, which yield relevant information in evaluation of tumor extent, definition of target volume, delineation of normal tissues, virtual simulation of therapy, generation of digitally reconstructed radiographs, design of treatment portals and aids (e.g., compensators, blocks), calculation of 3D dose distributions and dose optimization, and critical evaluation of the treatment plan.180,351,370
The potential benefits of 3D planning and delivery systems are great. It is, however, not clear which specific disease sites and treatment situations will be benefited by 3D planning.412 With advanced computerized and display technologies, contiguous CT slices are used to define anatomic structures and target volumes. External radiation beams of any possible orientation are simulated. A significant feature of these systems is the so-called beam’s eye view, in which patient contours are viewed as if the observer’s eye is placed at the source of radiation looking out along the axis of the radiation beam.369 These systems allow simulation of the geometric setup; evaluation of the plan for dose optimization still is made on the merits of volumetric dose distributions.
Quantitative treatment-planning evaluation is crucial in selection of the best portals and radiation beams to deliver an optimal dose to the tumor with relative sparing of normal tissues. The ICRU Report 50 and its supplement G2 define 3D volumes for the prescription and reporting of EBRT.229 The GTV is defined as the gross demonstrable extent and location of malignant growth; the CTV allows a margin around the GTV for subclinical disease; the PTV allows margins on the CTV for variation in position, size, and shape so that the prescribed dose is received by the CTV; and the treated volume is that area receiving a dose considered appropriate to the purpose of treatment such as tumor eradication or palliation (see Fig. 1.2).
The DVH is useful as a means of dose display, particularly in assessing several treatment plan dose distributions.85 A DVH provides a complete summary of the entire 3D dose matrix, showing the amount of target volume or critical structure receiving more than a specified dose level. Because a DVH does not provide spatial dose information, it cannot replace the other methods of dose display; it can only complement them.
Models for optimization of 3D dose distribution using biologic models of tumor and normal tissue responses correlated with physical radiation doses have been described.384 Mohan et al.,308 in a theoretical analysis, concluded that for certain clinical situations it is not sufficient to specify objectives of optimization purely on the basis of pattern of irradiation dose and that dose–volume effects and biologic indices also must be incorporated into the formulation.
Niemierko et al.324 described a technique for optimization of 3D conformal radiation therapy plans with biologic models of tumor and normal tissue response to irradiation as well as with scores based on physical dose. Optimization programs attempted to minimize dose gradient across the target volume, match specified isodose contours to the target and critical organs, match specified dose–volume constraints, minimize integral dose to the entire volume of patient treated, minimize maximum dose to critical organs, and constrain dose to specified normal tissues below a tolerance-dose level. The solutions were based on TCP, NTCP, various dose levels given to specified volumes of the patient, discrete or continuous values of beam parameters, number of beams, and logical combination of any constraints.
Intensity-Modulated Radiation Therapy
An increasingly popular approach to 3D treatment planning and conformal therapy optimizes the delivery of irradiation to irregularly shaped volumes through a process of complex inverse (or forward) treatment planning and dynamic delivery of irradiation that results in modulated fluence of photon beam profiles and a more conformal dose to the target volume(s), with enhanced sparing of surrounding normal tissues.56
Treatment planning begins with the determination of the GTV and the CTV, which contains the GTV, and an estimate of where the tumor may spread. CT, MRI, and fluorodeoxyglucose positron emission tomography (FDG-PET) imaging along with image fusion have enhanced the possibilities for determining the target more accurately. The PTV accounts for inaccuracies in positioning patients and organ motion.
In “forward” planning, software calculates the dose distribution, displays it with a 3D anatomic model, and provides analytical and graphical metrics for assessing the adequacy of tumor treatment and normal tissue avoidance. The physician decides if the plan is acceptable. If not, an alteration is made in the beam arrangement, and the process is repeated.
Computerized optimization techniques have led to “inverse” planning. Goals of an acceptable treatment plan are delineated, and the inverse planning algorithm searches through many thousands of possibilities to find a plan that best satisfies the goals. In IMRT, the beams are broken up into “beamlets” (on the order of 0.5 by 0.5 or 1 by 1 cm) that can each have a different intensity. IMRT may improve the ability to treat with a high radiation dose while minimizing dose to nearby critical structures.
There are a variety of forms in which IMRT can be administered:
1. The North American Scientific (NOMOS) Corporation (Chatsworth, CA) Peacock system: an array of individual beamlets, each consisting of a narrow incident arc photon beam that exposes the target. The radiation fluence is modulated with a small dynamic multileaf collimator (MLC) (MIMiC) activated by a preprogrammed controller.
2. A linear accelerator and multileaf collimation, with a variety of beam configurations at various angles, may be used; the MLC determines the portal shape of each of the portals. Photon-modulated fluency may be obtained (a step-and-shoot method).
3. Dynamic computer-controlled IMRT is delivered when the configuration of the beams outlined with the MLC is changing at the same time that the gantry or the accelerator is changing positions around the patient.
4. In helical tomotherapy, the photon fan beam continually rotates around the patient as the couch transports the patient longitudinally through the ring gantry. The verification processes for helical tomotherapy are enabled by the use of the ring gantry; the geometry of a CT scanner allows tomographic processes to be reliably performed. Dose reconstruction is a key process of tomography; the treatment detector sinogram computes the actual dose deposited in the patient. The length of the beam is 40 cm at the central axis and has a width that can vary between 0.5 and 5 cm. Like the NOMOS MIMiC MLC, the lengths of the MLC in helical tomography are temporarily modulated or binary in the sense that they are rapidly driven either in or out by air system actuators rather than beam slowly pushed by motors driving lead screws as in the conventional MLC.
5. The robotic IMRT system consists of a miniaturized 6-MV photon linear accelerator mounted on a highly mobile arm and a set of ceiling-mounted x-ray cameras to provide near real-time information on patient position and target exposure during treatment.
The majority of the IMRT systems use 6-MV x-rays, but energies of 8 to 10 MV may be more desirable in some anatomic sites (to decrease skin and superficial subcutaneous tissue dose). Higher energies will increase neutron contamination of the therapeutic beam(s). The dose distribution and field-shaping parameters are based on inverse 3D planning using a specially defined minimal dose to target and dose constraints for surrounding normal tissues.57,77,526 Inverse planning starts with an ideal dose distribution and finds through trial and error or multiple iterations (simulated annealing) the beam characteristics (fluence profiles), then produces the best approximation to the ideal dose defined in a 3D array of dose voxels organized in a stack of two-dimensional (2D) arrays.337,491
A back-projection technique through careful choice of filters, beam placement, and shaping of the portals conforms the irradiation dose to the shape of the tumor, minimizing dose to critical adjacent structures. When this technique is used, it is critical to adhere to basic concepts of treatment planning and evaluation of the pathobiology of malignant disease. Well-designed treatment plans based on radiographic imaging (CT or MRI), which in most instances demonstrates gross disease, are necessary to minimize the risk of missing or underirradiating adjacent microscopic or subclinical tumor.
Given the added time and labor involved in IMRT, numerous issues require study:
1. Can the tumor be localized with sufficient accuracy to take advantage of the improved dose localization?
2. Treatment plans that produce a rapid drop in dose between the edge of the tumor and the normal tissue require more exact patient positioning; otherwise, there is a high risk of underdosing the tumor or overdosing normal tissue.
3. Some IMRT plans treat the center of the tumor with a very high dose to achieve an acceptable dose at the edge. This may not be optimal.
4. Many IMRT techniques spread a low dose over a larger volume or normal tissue. This may increase the risk of secondary malignancies years later.
HEAVY PARTICLE BEAMS
The vast majority of radiation therapy is administered with photon or electron external beams or photon-generating brachytherapy sources. Physicians and physicists have explored the possibility that alternative forms of ionizing radiation might be clinically useful.
One can imagine two possible mechanisms by which one could improve on therapeutic x-rays with an alternative particle. First, the alternative particle could have energy deposition characteristics that lead to a superior dose distribution. A beam, conceivably, could have more skin sparing than x-rays, better stopping characteristics, and/or less side scatter. This might allow a more conformal therapy. Second, the alternative particle could have advantageous radiobiologic properties. It might be more toxic than x-rays to hypoxic cells or cells in the late S phase of the mitotic cell cycle. Such a particle would have, perhaps, a lower oxygen enhancement ratio (OER) and a higher RBE than x-rays. These two possible mechanisms of improving on x-rays are not mutually exclusive. A particle could have both superior physical dose distribution and radiobiologic properties.
The effort to identify improved alternatives to x-rays has focused on the group of particles called hadrons. These are particles constituted of strongly interacting particles called quarks and gluons. The hadrons include the mesons and the baryons. The latter include protons, neutrons, negative pions, and the nuclei of heavier atoms such as He2 (helium), C6 (carbon), O8 (oxygen), Ne10 (neon), and Ar18 (argon). All of these forms of radiation are distinguished from x-rays and electrons by their greater masses. These alternative radiation modalities are relatively difficult to produce, are expensive, and are considerably more difficult to control.
Proton, heavy ion, and hadron beams have attracted radiation oncologists because they offer interesting and potentially beneficial dose distribution characteristics. Radiobiologically, their properties are not significantly different from x-rays. When a heavy particle beam traverses tissue, the dose is deposited in an approximately constant rate. The rate of energy loss (also called the “stopping power”) of a heavy charged particle is proportional to the square of the particle charge and inversely proportional to the square of its velocity. As a proton or heavy ion slows down, its rate of energy loss increases and so does the ionization or absorbed dose to the tissue. Near the end of the proton’s range, the deposition of energy rises very sharply before dropping to almost zero. This peaking of dose near the end of the particle range is called the Bragg peak. As a result of the Bragg peak effect and minimal scattering, the proton offers the potential advantage and the ability to concentrate dose inside and immediately adjacent to the tumor volume and minimize dose to surrounding normal tissues. There are proton treatment facilities operational and under construction throughout the economically developed world. The technology has been evaluated most extensively in the management of choroidal melanoma, base of skull tumors, soft-tissue sarcomas, and prostate cancer. Box 1.5 provides a helpful glossary of terms related to heavy particle beam radiation therapy.
This section of Chapter 1 offers only the briefest overview of proton and neutron therapy. For a thorough discussion of these two forms of radiation, as well as a consideration of pi meson therapy and charged nuclei therapy such as helium ions and neon ions, the reader is referred Chapters 19 and 20 of this volume.
BORON NEUTRON CAPTURE THERAPY
The fundamental concept of boron neutron capture therapy is the production of high–linear energy transfer (LET) particles (7Li3+ and 4He2+) when one “tags” or “labels” a tumor cell with a compound having a large cross-section capable of capturing a “slow” (thermal) neutron. After the compound captures the neutron, it goes into an excited state. The excited fission of the 11B nucleus will release energy, which drives the heavy ion products over short distances comparable to the dimensions of one cell. A 0.48-MeV photon is also produced in 94% of the fission events. This is useful for monitoring the reaction but is of little consequence for cell killing (Fig. 1.26).
The neutron has a mass of 0.782 MeV, more than that of the proton. Neutrons were identified in 1932 by Chadwick81 at Cambridge University’s Cavendish Laboratory. Subsequently, Fermi146 discovered that neutrons react most efficiently with a number of elements after they are slowed by passage through a hydrogen-rich substance such as paraffin. Chadwick and Goldhaber,82 Taylor and Goldhaber,441 and Burcham and Goldhaber,67 showed that slow neutron bombardment of specific stable isotopes of boron, lithium, and nitrogen yield charged particle tracts in photographic plates. The tracts from boron’s interaction with neutrons were short and straight and were consistent with the formation of two particles traveling in opposite trajectories. In photographic gelatin, their average travel distance was 7.6 μm. The boron neutron capture process is highly localized. In principle, one could kill a tumor cell containing boron while sparing an adjacent normal cell that does not contain boron. Box 1.6 provides a glossary of terms related to neutron capture therapy.
Box 1.5
A Glossary of Terms Pertinent to Heavy Particle Beam Radiation Therapy
Baryon: A hadron made from three quarks. The proton and the neutron are both baryons. They also may contain additional quark–antiquark pairs.
Bragg, William Henry (1862–1942): He was born in Westward, Cumberland, and educated at King William’s College, Isle of Mann; Trinity College, Cambridge; and the Cavendish Laboratory. In collaboration with his son (vide infra), he developed techniques of systematically analyzing crystal structures using x-rays. This was recognized by the awarding of the Nobel Prize in Physics jointly to father and son in 1915.
Bragg, William Lawrence (1890–1971): He was born in Adelaide, South Australia, where his father was a professor. He came to England with his father (vide supra) and entered Trinity College, Cambridge. He and his father published X-rays and Crystal Structure in 1915. Later in his career he used x-ray analysis to investigate the structure of proteins. Having been awarded the Nobel Prize with his father, he was, at 25 years of age, the youngest-ever Nobel laureate.
Bragg peak: The region of high dose at the end of the range of a heavy charged particle.
Charge: A quantum number carried by a particle. Determines whether the particle can participate in an interaction process. A particle with electric charge has electrical interactions, one with strong charge has strong interactions, and so forth.
Electric charge: The quantum number that determines participation in electromagnetic interactions.
Electromagnetic interaction: The interaction resulting from electric charge; this includes magnetic effects that have to do with moving electric charges.
Electron: The least massive electrically charged particle, hence absolutely stable. It is the most common lepton, with electric charge –1.
Fermion: Any particle that has odd-half-integer (1/2, 3/2, …) intrinsic angular momentum (spin). As a consequence of this peculiar angular momentum, fermions obey the Pauli exclusion principle, which states that no two fermions can exist in the same state at the same place and time. Many of the properties of ordinary matter arise because of this rule. Electrons, protons, and neutrons are all fermions, as are all the fundamental matter particles, both quarks and leptons.
Gluon: The carrier particle of strong interactions.
Hadron: A particle made of strongly interacting constituents (quarks and/or gluons). These include the mesons and baryons. Such particles participate in residual strong interactions.
Lepton: A fundamental fermion that does not participate in strong interactions. The electrically charged leptons are the electron, the muon, the tau, and their antiparticles. Electrically neutral leptons are called neutrinos.
Meson: A hadron made from an even number of quark constituents. The basic structure of most mesons is one quark and one antiquark.
Neutron: A baryon with electric charge zero; it is a fermion with a basic structure of two down quarks and one up quark (held together by gluons). The neutral component of an atomic nucleus is made from neutrons. Different isotopes of the same element are distinguished by having different numbers of neutrons in their nucleus.
Nucleon: A proton or a neutron; that is, one of the particles that makes up a nucleus.
Nucleus: A collection of neutrons and protons that forms the core of an atom.
Particle: A subatomic object with a definite mass and charge.
Photon: The carrier particle of electromagnetic interactions.
Pion: The least massive type of meson, pions can have electric charges +1 or 0.
Proton: The most common hadron, a baryon with electric charge (+1) equal and opposite to that of the electron (–1). Protons have a basic structure of two up quarks and one down quark (bound together by gluons). The nucleus of a hydrogen atom is a proton. A nucleus with electric charge Z contains Z protons; therefore, the number of protons is what distinguishes the different chemical elements.
Quark: A fundamental fermion that has strong interactions. Quarks have electric charge of either +2/3 (up, charm, top) or –1/3 (down, strange, bottom) in units where the proton charge is +1.
Strong interaction: The interaction responsible for binding quarks, antiquarks, and gluons to make hadrons. Residual strong interactions provide the nuclear binding force.
Subatomic particle: Any particle that is small compared to the size of the atom.
These definitions are derived from Welsh JS. Quarks, leptons, fermions, bosons: the subatomic pharmacology of radiation therapy. Science Med 2005;10:124–136; The Nobel Museum (www.nobel.se/physics/laureates); The Atlas Experiment (http://atlasexperiment.org/glossary.html); and Khan FM. The physics of radiation therapy, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2003.
Box 1.6
A Glossary of Terms Pertinent to Neutron Capture Therapy
Epithermal neutrons: Energetic neutrons pass through an intermediate energy range on the way to becoming slow or thermal neutrons. This intermediate energy range is called epithermal.
Fast neutrons: Fast neutrons are highly energetic and travel quickly.
Moderation: Neutrons generated from the fission process or from particle bombardment of materials have significant energy. They lose that energy by colliding with atoms in their environment and create energetic recoil atoms. After a sufficient number of collisions, the neutrons lose essentially all of their energy and become thermal. This process of energy loss is called moderation. The material that provides the atoms the fast neutrons collide with is called a moderator. Water is the usual moderator.
Slow neutrons: Slow neutrons have little energy. They also are referred to as thermal neutrons because they have the same average kinetic energy as gas molecules in their environment.
Thermalize: Epithermal neutron beams, as they penetrate tissue, become additionally moderated. This is called becoming thermalized.
From Yanch JC, Shefer RE, Busse PM. Boron neutron capture therapy. Science Med 1999;January/February:18–27.
FIGURE 1.26. The bombardment of stable Bo10 by a thermal neutron results in a nuclear reaction. This reaction yields Li7 nuclei and α-particles. These fission products have short path links and a high linear energy transfer (LET). This high-LET radiation, over a short path length, offers the possibility of a lethal effect highly localized within a cell.
The complete chemical reaction is as follows:
The attraction of boron neutron capture therapy (BNCT), for many clinicians, has been the notion of the “magic bullet.” The idea that one could specifically label tumor cells with a compound with an enlarged cross-sectional area, not label surrounding normal tissue, and therefore deposit radiation only in the tumor is most attractive. Unfortunately, reality is far different from the ideal.
Fast neutrons differ from x-rays in the mode of their interaction with tissue. Whereas x-ray photons interact with the orbital electrons of atoms via the Compton or photoelectric process and set fast electrons in motion, neutrons interact with the nuclei of the atoms of the absorbing tissue. Neutrons put fast recoil protons, α-particles, and heavier nuclear fragments in motion. At energies above about 6 MeV, inelastic scattering by neutrons takes place. A neutron may interact, for example, with a carbon or an oxygen nucleus to produce α-particles. These lead to nuclear fragments called spallation products. The LET is considerably higher for neutrons than for x-rays. Because the LET of neutron radiation is higher, the slope of the cell survival curve becomes steeper and the size of the initial shoulder gets smaller. This produces a beam with a lower OER than x-rays—neutrons are considerably more toxic to hypoxic cells than x-rays. Also, neutrons are more toxic to cells in phases of the cell cycle that are relatively radioresistant to x-rays. Thus, the RBE of neutrons is higher than x-rays.
In 1936, Locher278 published a theoretical account of the possible biologic effects and therapeutic possibilities of boron neutron capture. In a prescient comment, he wrote:
The possibility of destroying or weakening cancerous cells, by the general or selective absorption of neutrons by themselves and particularly there is the possibility of introducing small quantities of neutron absorbers into the regions where it is desired to liberate ionizing energy. A simple illustration would be the injection of a soluble non-toxic compound of boron, lithium, or gold into a superficial cancer followed by bombardment with slow neutrons.
In a 1950 paper by Conger and Giles95 from Oakridge National Laboratories, they reported that the trace amounts of boron normally present in lily bulbs were responsible for most of the radiation changes in the plants following exposure to slow neutrons. This demonstrated the biologic fact clearly and led William H. Sweet436 and others to see if the normal brain could exclude enough boron and if tumor tissue could take up enough boron to produce an appropriate therapeutic ratio.
Sweet began work at the Brookhaven National Laboratory in New York with a 20-MW nuclear reactor in 1950. He initially treated 10 glioblastoma multiforme patients who had undergone gross total resection of their tumors at the Massachusetts General Hospital in Boston. Sweet described the initial clinical work:
A portion of the shielding atop the reactor was removed to permit placing the lateral aspect of the patient’s intact scalp and skull at the specially designed portal. To prevent scalp damage, we tied off the external carotid arteries and covered the entire scalp with tight elastic bandages in an attempt to prevent boron-containing blood from entering the scalp. These tactics, however, did not prevent the development of several large radiation erosions of the scalp. Five patients received a single radiation dose and the remaining 5 were given the treatment in 2 to 4 fractions. Although there were no life threatening complications of therapy, all of the patients died from 6 to 21 weeks after the first session of neutron capture therapy, which was usually the case in the 1950s for glioblastoma patients treated by any means. Postmortem studies done in 6 of the patients showed abundant viable tumor. Their painful scalp lesions together with the inadequacy of the radiation dose lead us to attempt to deliver the thermal neutron beam directly to the grossly normal but microscopically tumor-infiltrated brain. The Rockefeller Foundation made this approach possible with a $500,000 gift to the Massachusetts Institute of Technology [MIT] to provide additional features to a nuclear reactor that was then being constructed. Included was a surgical operating room immediately beneath the reactor core. This permitted us to turn down the scalp, bone, and dural flap used in the prior removal of gross tumor. At reopening the cerebrospinal fluid replacing tumor was also drained away to give maximally unimpeded access of the thermal neutrons through sterile air to the tumor-infiltrated brain.436
Sweet treated 18 patients at MIT. They died from 10 days to 11.5 months after radiation. In every patient the cause of death was cerebral, and extensive irradiation necrosis of the brain was induced in nine cases. In two cases only recurrent tumor was seen, and in one patient there was extensive radiation necrosis and tumor.
Some of the initial work with BNCT was highly controversial and, decades later, led to investigations concerning the nature of informed consent for these human experiments. President William J. Clinton created, by executive order, a commission to study the ethics of cold war–era medical experimentation using radiation. One of the collateral effects of this commission’s report was that Sweet and his colleagues were sued for malpractice 40 years after the BNCT experiments. Although the plaintiffs were awarded substantial damages at trial, the decision was eventually overturned on appeal.199
Clinical trials, largely in Japan, have argued that there is benefit to BNCT of glioblastoma multiforme. However, to date, no randomized clinical trials of BNCT have been performed. Although Japanese investigators have reported a survival rate for grade 3 and 4 malignant glioma patients as high as 58% with BNCT, this has been called into question by Laramore et al.258 They investigated 14 U.S. patients who were treated with BNCT for glioblastoma multiforme in Japan. A comparison of the survival of these patients with a matched set of conventionally treated patients using the prognostic factors of the RTOG showed no statistical difference compared to the BNCT patients. This is almost certainly the result of patients with relatively favorable characteristics being selected for BNCT such as lower histologic grade, young age, good functional status, and superficial location. A 2011 report from Ibaragi, Japan, of 23 glioblastoma multiforme patients treated with 15 to 18 Gy of BNCT described a median survival time of 20 months and a 6% 5-year survival.242 Because neutron beams have a significant normal tissue toxicity, and because their depth-dose characteristics are not superior to x-rays, their applicability has been limited, and clinical results, to date, have been quite mixed. Clinical studies have been reported concerning the use of neutrons in salivary gland and other head and neck tumors, soft-tissue sarcomas, and prostate cancer.
Lack of progress in BNCT may be attributed to two primary factors: inadequate tumor specificity of the boron compounds used to localize in the tumor and poor penetration into tissue of the thermal neutrons. In addition, the thermal and antithermal neutron beams produced by nuclear reactors have considerable contamination with γ-rays and fast neutrons. These can cause normal tissue damage even in the absence of boron concentration in tissues. In addition, there are a number of compounds in normal tissue that can interact with thermal neutrons and have capture events of their own, producing biologic damage even to non–boron-containing tissue.
The development of suitable boron-carrying agents remains a stumbling block to clinical programs. The ideal agent will be nontoxic, will have a high tumor-to-normal-tissue ratio, and will have a high absolute boron concentration. Three classifications are helpful for defining boron agents:
1. Global agents have little selectivity for tumor cells. The clinician is relying on a conformal neutron beam to achieve selectivity rather than selective accretion of boron.
2. Tumor-selective agents accumulate selectivity in tumors. L-4-dihydroxyborylphenylanine has been used as a boron-carrying agent (Fig. 1.27). This compound is a dopamine analog in the melanin synthetic pathway and concentrates in pigmented tumors. It was synthesized over 50 years ago and was first used clinically in 1988–1989.30 It has been thought to be of potential use in the treatment of melanoma, and initial clinical trials are under way. Tumor-selective agents include, in addition to borylphenylalanine compounds, investigations of boronated porphyrins, amino acids, and nucleic acids that are borinated. Melanin is an intracellular protein synthesized from the amino acid tyrosine. Incorporating boronic acid into the paraposition of phenylalanine, producing p-borophenylallanine, would result in a molecule that behaved like tyrosine and might be able to selectively put boron-10 into melanoma cells. These compounds are capable of achieving a tumor-to-normal-tissue ratio of 3 or 4 to 1. It is not, however, because they are a substrate for tyrosinase, the first enzyme in the pathway to melanin. Nonetheless, they are capable of producing high levels of boron-10 in tumors. For brain tumors, drug uptake may be superior with intracarotid administration.30
3. Tumor-targeted and delivery agents have a structural feature that either binds to a specific portion of the cancer cell or facilitates drug delivery. Tumor-targeted agents include the use of polycomplex peptides, known as starburst dendrimers, which may allow boron to be attached to an antibody without causing a loss of specificity and carry boron in low-density lipoprotein vesicles. Other techniques for drug delivery include carbon nanotubes and gold nanoparticles.72
Investigations of improved ways of delivering thermal neutrons have centered on two areas: the use of nuclear reactors and useful alternatives to reactors. For reasons of safety, reactors generally use a low enriched fuel with uranium. However, one would have considerable doubts about the political and social feasibility of the placement of such units in major medical centers in populated areas. Therefore, some investigators have been pursuing nonreactive sources of thermal and epithermal neutrons with a sufficiently high flux to be used for BNCT.
The most intense way to generate a neutron beam is with a nuclear reactor. Despite the high neutron intensities available from these reactors, it is widely recognized that alternative neutron sources will be necessary for BNCT to be performed. First of all, there are few suitable nuclear reactors in operation. A patient would have to travel a long distance for treatment. Second, nuclear reactors, for political and social reasons, are not likely to be sited near major population centers in the future. A major reactor facility located far from a population center would have to be provided with its own clinical infrastructure, and it is not obvious that the target patient population would be large enough to support the operation of more than a few medical reactors. Therefore, some investigators have been pursuing nonreactive sources of thermal and epithermal neutrons with a sufficiently high flux to be used for boron neutron capture therapy.88,258,436,489
An alternative to the reactor would be a neutron source from radioactive decay such as californium-252 (252Cf). However, production of a neutron beam with sufficient intensity for BNCT would require more than the entire present annual supply of 252Cf. Another alternative source is a particle accelerator. Accelerator-based neutron beams are created when light ions such as protons or deuterons are accelerated in an electric field and are made to bombard target materials. Several accelerator techniques now exist that may be capable of producing intense beams for boron neutron capture therapy.
Several current clinical protocols are under way, or have recently been completed, concerning BNCT. These trials attempt to evaluate patients with advanced-stage melanoma of the extremities and are designed to determine the maximally tolerated dose of boron neutron capture therapy to the skin and overlying connective tissue. Other studies are evaluating treatment with BNCT of glioblastoma multiforme or brain metastasis from malignant melanoma. Animal studies and phantom dosimetry calculations have been reported on BNCT synovectomy for treatment of rheumatoid arthritis.206,489,516
FIGURE 1.27. P-borophenylallanine (BPA) was synthesized in the late 1950s for use in boron neutron capture therapy. It has been shown to accumulate selectively in B16 melanoma cells both in vivo and in vitro. Clinical trials have been performed of BPA-mediated boron neutron capture therapy for cutaneous melanoma. The compound also has been studied in brain tumor therapy.
EFFECTS OF IRRADIATION ON CELLS
The radiation-induced lesion most detrimental to cell survival involves damage to the DNA. This may result in either mitotic cell death or apoptosis. If the cell survives and repairs the damage, it may achieve a normal status. If there is misrepair, it may be associated with permanent mutations and induction of carcinogenesis. The physical interaction of ionizing radiation with the molecular infrastructure of the cell results in chemical reactions that occur within 10−18 to 10−3 seconds.485 Absorption of the photon energy destabilizes the target molecule, resulting in molecular breaks or release of energetic electrons and secondary energy-attenuated photons, which may interact with other cellular molecules, leading to a chain reaction that produces a variety of short-lived ions and chemically unstable free radicals. The most common radicals are produced from the radiolysis of cellular water and include hydroxyl radicals (•OH), hydrated electrons (eaq), hydrogen atoms (H•), and hydrogen peroxide (H2O2). Free radicals are extremely unstable and interact nearly instantaneously with neighboring molecules to produce chemically stable lesions. This process can be modified by free radical scavengers or by oxygen, which have opposing effects on the number of stable lesions and on the level of cellular radiosensitivity. However, if all factors remain constant, the permanent damage is linear with dose. Experiments in which the cell nucleus and the cytoplasm were selectively irradiated show that the dose required in the cytoplasm to kill a cell is larger than doses required in the nucleus.91,312 It is generally accepted that most target molecules for radiation-induced cell killing are located in the nucleus and involve damage to the DNA.114 However, other targets such as the cell membrane and the membrane of mitochondria have been proposed as the origin of apoptotic cascades that follow irradiation also contributing to cell death.
In many cells, radiation-induced lethality is not instantaneous because cells continue to function and even undergo several divisions before final mitotic death occurs.410 Noncycling lymphocytes, thymocytes, and hematopoietic cells were shown to undergo an interphase cell death without progressing through the mitotic phase of the cell cycle.9,513 Two patterns of morphologic changes are associated with cell death in mammalian cells. Cell necrosis, which is degenerative, is the most usual type of cell damage. Necrotic cell death results from collapse of cellular metabolism and depletion of its adenosine triphosphate storage.508 The final events of necrosis involve membrane rupture, loss of lysosomal enzymes, degradation of nuclear chromatin, and karyolysis. The other process of radiation-induced cell death is apoptosis. Programmed cell death, or apoptosis, is a physiologic process that involves a series of characteristic, genetically controlled steps. These include chromatin condensation and segmentation, fragmentation of the nucleus into apoptotic bodies, cell shrinkage, and loss of cellular contact with neighboring cells.243,244,518,519Apoptosis culminates in the engulfment of the cell by neighboring cells, such as macrophages, without a concomitant inflammatory response.289 Apoptosis occurs spontaneously in various solid tumors and contributes to the balance between tumor cell gain and cell loss.248
Within minutes after irradiation, signal transduction pathways mediated by protein kinase C and tyrosine kinase are stimulated.83 Genes and enzymes involved in genetic control of radiation damage repair are activated, stress genes are induced, and growth factors and cytokines that modulate response of mammalian cells to ionizing radiation are activated.177 Radiation-induced stimulation is probably critical to induction of many genes and proteins, including early response genes, which, in turn, activate other genes, including those for tumor necrosis factor, fibroblast growth factor, and transforming growth factor.91 In addition, new proteins, such as tissue plasminogen activator, are synthesized.157 This cascade of gene activation and transcription and protein synthesis is related to key cellular functions that the cell invokes in an attempt to survive a dose of radiation157 (Table 1.10).
TABLE 1.9 RATIO OF LINEAR (α) TO QUADRATIC (β) TERMS FROM MULTIFRACTION EXPERIMENTS AND CLINICAL DATA
Modifiers of Radiation Response
Several approaches have been used to enhance the therapeutic ratio in radiation therapy:
1. Physical modifiers of low-LET radiations. IMRT, three-dimensional treatment planning, improvements in anatomic and functional imaging, the increasing power of computer hardware and software, and linear accelerator improvements have led to better photon and electron dose distributions; less side scatter; less differential absorption in bone and normal tissues; and, with charged heavy particles, selective energy deposition at specific depths.
2. High-LET radiations. The importance of tumor hypoxia and cells residing in relatively resistant phases of the mitotic cycle are factors that are less likely to cause unsatisfactory results with neutrons, pi mesons, and heavy ions than with standard radiation doses delivered with low-LET beams.162
3. Hyperbaric oxygen or tourniquet techniques. These techniques involve use of increased oxygen tension to improve the effects of irradiation on the tumor or use of a tourniquet to produce severe hypoxia in the surrounding normal tissues so that higher irradiation doses can be delivered.435 Theoretically, these approaches yield better tumor control without damaging normal tissues. Interest in the tourniquet technique waned years ago. Some investigators continue to evaluate hyperbaric oxygen. The logistics are formidable, and clinical trials have not been conclusive.87,116,217,469
4. Hypoxic sensitizers. Compounds with electron affinity, from the nitroimidazole group, theoretically produce free radicals in a manner similar to that of oxygen, selectively sensitizing hypoxic cells to radiation. Misonidazole (RO-07–0582) was evaluated in numerous clinical trials by the RTOG, with no evidence of clinical efficacy;489 however, in the Danish Head and Neck Cancer trial there was a highly significant survival benefit in the subgroup of patients with pharynx tumors.339 New compounds, such as SR-2508, have been tested in phase I and II studies without clearly positive results.
5. Perfluorocarbons. These agents are administered in emulsion (they are insoluble in water) in sufficient concentrations coupled with inhalation of 95% to 100% oxygen to enhance oxygen transport and release in the presence of low oxygen tension. Their potential application in the treatment of patients with cancer is under evaluation.249,384
6. Cytotoxic agents. Actinomycin-D, doxorubicin, 5-fluorouracil, cyclophosphamide, cisplatin, methotrexate, bleomycin, and others have been shown to interact with radiation in several forms to maximize tumor cell killing. In some instances, increased normal tissue reactions have been observed.
7. Epidermal growth factor receptor (EGFR). EGFR, a member of the ErbB family of receptor tyrosine kinases, is activated in several epithelial cancers. Radiotherapy increases the expression of EGRF in cancer cells and blockade of EGFR signaling can sensitize cells to radiation. Cetuximab is a chimeric monoclonal antibody that targets EGFR. The drug appears to improve locoregional tumor control and survival in locally advanced squamous cell carcinoma of the head and neck.6
8. Radioprotectors. Sulfhydryl-containing compounds, such as cystine and cysteamine, have been used in animals to protect normal tissues against irradiation. Amifostine (WR-2721), a thiophosphate derivative of cysteamine, has been shown to selectively protect normal tissues, including bone marrow, salivary glands, and intestinal mucosa, in animals, with little effect on tumor response to irradiation.466 Amifostine undergoes dephosphorylation by cellular-bound alkaline phosphatase to an active metabolite, WR-1065. This alkaline phosphatase–dependent activation is thought to contribute to selective normal tissue protection because of a higher concentration of alkaline phosphatase in normal tissue. Cytoprotection is believed to be the result of the elimination of free radicals.412 The compound was widely investigated in phase II and III clinical trials.60 It is now approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the reduction of xerostomia in patients with head and neck cancer undergoing radiotherapy.412 A meta-analysis has shown that amifostine does not reduce overall or progression-free survival in patients treated with radiotherapy or chemoradiotherapy—arguing against amifostine protecting tumor tissue.52
9. Hyperthermia. Heat at temperatures of more than 42.5°C kills cells by itself or enhances the effects of irradiation and numerous cytotoxic agents. Heat selectively kills cells that are chronically hypoxic, acidotic, and nutritionally deficient—characteristics shared by tumor cells in comparison with the better-oxygenated and better-nourished normal cells. Furthermore, heat preferentially kills cells in the S phase of the proliferative cycle, which are known to be relatively resistant to irradiation.113,444
A complete review of these topics will be found in Chapters 29, 31, and 32.
GENES AND THE BIOLOGY OF CANCER
The infectious nature of some cancers was demonstrated by Francis Peyton Rous (1879–1970) in a 1910 experiment showing that defined, submicroscopic, filterable agents (viruses) isolated from a chicken sarcoma could induce new sarcomas in healthy chickens. Rous and his work languished in obscurity before being rediscovered and recognized with the Nobel Prize in Physiology or Medicine in 1966 (Fig. 1.28).326 In his Nobel Lecture, “The Challenge to Man of the Neoplastic Cell,” Rous considered the possible existence of growth-promoting genes—what he called oncogens and what are now called oncogenes.
Tumors destroy man in a unique and appalling way, as flesh of his own flesh which has somehow been rendered proliferative, rampant, predatory and ungovernable. They are the most concrete and formidable of human maladies, yet despite more than 70 years of experimental study they remain the least understood. This is the more remarkable because they can be evoked at will for scrutiny by any one of a myriad chemical and physical means which are left behind as tumors grow. These had acted merely as initiation. Few situations are more exasperating to the inquirer than to watch a tiny nodule form on a rabbit’s skin at a spot from which the chemical agent inducing it has long since been gone, and to follow the nodule as it grows, and only too often becomes a destructive epidermal cancer. What can be the why for these happenings?
Every tumor is made up of cells that have been so singularly changed as to no longer obey the fundamental law whereby the cellular constituents of an organism exist in harmony and act together to maintain it. Instead the changed cells multiply at its expense and inflict damage that can be mortal. We term the lawless cells neoplastic because they form new tissue, and the growth itself is a neoplasm; but on looking into medical dictionaries, hoping for more information, we are told, in effect, that neoplastic means “of or pertaining to a neoplasm,” and turning to neoplasm learn that it is “a growth which consists of neoplastic cells.” Ignorance could scarcely be more stark.
The chemical and physical initiators ordinarily are called carcinogens; but this is a misleading term because they not only induce the malignant epithelial growths known as carcinomas but also other neoplasms of widely various kinds. In this chapter the less often used term oncogenes will be used, meaning “thereby capable of producing a tumor.” It hews precisely to the fact…
What can be the nature of the generality of neoplastic changes, the reason for their persistence; for their irreversibility; and for the discontinuous, steplike alterations that they frequently undergo? A favorite explanation has been that oncogenes cause alterations in the genes of the body—somatic mutations as these are termed. But numerous facts, when taken together, decisively exclude this supposition.326
Rous, it turned out, was unequivocally wrong about oncogenes. Theodor Boveri53 was right. In 1914 he used his studies of normal mitosis in sea urchins and worms as a platform for suggesting that cancer might be caused by the abnormal gain or loss of chromosomes and their function. In a 1929 English translation of his 1926 book, The Origin of Malignant Tumors, Boveri wrote:
The unlimited tendency to rapid proliferation in malignant tumor cells [could result] from a permanent predominance of the chromosomes that promote division… Another possibility [to explain cancer] is the presence of definite chromosomes which inhibit division… Cells of tumors with unlimited growth would arise if those “inhibiting chromosomes” were eliminated … [since] each kind of chromosome is represented twice in the normal cell, the depression of only one of these two might pass unnoticed.53
Boveri predicted that the genetic abnormalities leading to the development of cancer are of two sorts: growth-promoting genes and growth-suppressing genes. If the growth-promoting genes are excessive in number or activity, they lead to cell proliferation. If, however, the growth-suppressing genes are defective in amount or activity, they fail to halt cell proliferation and lead to unbridled cell replication (Fig. 1.29). These growth-promoting genes are called oncogenes. The growth-suppressing genes are called tumor-suppressor genes.
FIGURE 1.28. Peyton Rous won the Nobel Prize in 1966 for experiments he began in 1910. He demonstrated that a sarcoma could be transmitted from one chicken to another via a very small carcinogenic agent—a virus. (A: Rous as a young investigator; B: At the time of the receipt of the Noble Prize) (From Weinberg RA. The biology of cancer. New York: Garland Science, Taylor and Francis Group, 2007.)
FIGURE 1.29. Oncogenes can act in multiple ways. One method is for a growth factor receptor, which ordinarily is only active when it binds to a ligand, to become active all the time even in the absence of a growth factor binding to it. This is called “being constitutively active” and is the result of an oncogenic mutation. (From Weinberg RA. The biology of cancer. New York: Garland Science, Taylor and Francis Group, 2007.)
We may think of oncogenes and tumor-suppressor genes as analogous to the accelerator pedal and the brake pedal of an automobile. The car can move forward when it is idling with the transmission in drive either by pushing on the accelerator pedal, by taking pressure off the brake pedal, or by doing both simultaneously. Similarly, cell growth and proliferation, leading to cancer, can occur either by the activity of the oncogenes or inactivity of the suppressor genes.
There are clearly a wide variety of physiologic conditions that call for the effective use of growth-promoting and growth-suppressing genes. There must be a mechanism to cause the fetus to grow and then, at the appropriate time, to restrain growth. There must be a way of causing fibroblasts to proliferate to heal a wound and then, at the appropriate time, halt the fibroblasts (except in the case of keloid formation). Uncontrolled cell growth, or cancer, may be thought of as a set of physiologic controls of cell growth gone awry.
Oncogenes
The experiments that initially identified oncogenes were based largely on transformed retroviruses in transplantable tumors in chickens, mice, and rats.257 Oncogenes were described as the genetic material carried by RNA tumor viruses that resulted in rapid malignant transformation of target cells. The name oncogene was given to virus-encoded single genes that alone or in combination with other genes induced a transformed phenotype in affected cells.38
The definition of an oncogene (from the Greek onkos, a “mass” or “tumor”) is still under debate. Many oncogenes are those found in retroviruses. However, not all cellular genes capable of transforming cells have been identified within the genome of known retroviruses. It is accepted that an oncogene is a gene capable of contributing directly to the conversion of a normal cell to a tumorigenic one and that a proto-oncogene is a cellular gene convertible to an oncogene by various molecular mechanisms: sequence mutations, gene amplification, chromosomal translocation, viral transduction, and insertional mutagenesis. In general, these perturbations result in two net effects: altered regulation or augmented expression of an oncogene through mutation or rearrangement of the nucleotide sequences that constitute signals for control of transcription, messenger RNA (mRNA) processing, and stability via insertion of a strong foreign promoter or by increased gene dosage; and altered biochemical function or ectopic expression of a protein product as a result of a mutation or translocation within the protein-coding region of the oncogene. Proto-oncogene products are involved in the regulation of normal cellular growth and differentiation.
A large number of viral oncogenes have been identified. In addition, oncogenes have been identified that are not associated with RNA tumor viruses but are recognized either by their activity in transformation or by their association with chromosome translocations.326 When DNA-probing techniques were used, it was found that sequences homologous to the oncogene region of the virus were present in the DNA of all tissues of virus-free chickens. The normal cellular sequences are proto-oncogenes.427 The oncogene carried by a virus is referred to as v-onc, whereas the proto-oncogene is referred to as c-onc. In the normal cell the expression of proto-oncogene is well controlled and appears to play a role in the growth and development of the organism. The function of some of these genes has been determined, whereas for others a close association between cell proliferation and gene expression has been established.
Stimulation of a nonmalignant cell into a proliferative state often depends on an external signal, which is received by a receptor on the cell membrane and transferred through the membrane into the cytoplasm and ultimately to the nucleus where DNA synthesis is initiated. Proto-oncogenes have been found that function at each step of this pathway. The erb-B oncogene is homologous to the gene encoding for cell membrane receptor of epidermal growth factor (EGF). The interaction of EGF with this receptor reduces the proliferation of epidermal cells such as breast epithelium.
Strong evidence suggests that malignancy induction may be associated with genetic changes in the cell. Examples of this are the finding of specific chromosome abnormalities in malignant cells, association of tumor development with DNA-damaging agents such as ionizing irradiation and chemical carcinogens, and increasing incidence of cancer in hereditary diseases such as xeroderma pigmentosum. It is recognized that oncogenes are normal cellular genes that may contribute to the development of the malignant cell if their expression is altered through mutation, translocation, amplification, or some other mechanism. Evidence suggests that several genetic changes are needed to produce a cancer cell, and oncogene studies support this concept.
Chromosome translocations occur at a high frequency in some types of tumors, suggesting that they may play a role in their development. Examples of translocations are the t(9;22) Philadelphia chromosome in chronic myelogenous leukemia (CML), the t(15;17) in promyelocytic leukemia, and several translocations involving chromosome 8 seen in lymphatic malignancies. Common sites of translocations in malignant cells are frequently near an oncogene.386 Those translocations such as the t(9;22) in CML can result in the formation of a new protein that is intimately involved in the tumorigenic transformation of the cell. In the CML example, the ber-gene is translocated next to the abl-oncogene, forming the new bcr-abl gene. The proteinaceous product of this newly formed gene is a hyperactive protein kinase that provides permanent growth signals to the cell.
Role of Proto-Oncogenes in Normal and Transformed Cells
Proto-oncogenes are genes with apparent oncogenic potential, and because they are apparently present in all animals, it is speculated that some kind of activation of proto-oncogenes could be associated with the initiation and progression of neoplasia. Activated oncogenes are detected in a large percentage of human tumors, suggesting a prominent role of these genes in their development; association between activated oncogenes and neoplastic diseases must have some kind of specificity for both the oncogene and the tumor.
Proto-oncogenes can be activated by genetic changes that affect either protein expression or structure. As succinctly stated by Weinberg:
The somatic mutations that caused proto-oncogene activation could be divided into two categories—those that caused changes in the structure of encoded proteins and those that led to elevated, deregulated expression of these proteins. Mutations affecting structure included the point mutations affecting ras proto-oncogenes and the chromosomal translocations that yielded hybrid genes such as bcr–abl. Elevated expression could be achieved in human tumors through gene amplification or chromosomal translocations, such as those that place the myc gene under the control of immunoglobulin enhancer sequences…
Gene amplification occurs through preferential replication of a segment (the amplicon) of chromosomal DNA. The result may be repeating end-to-end linear arrays of the segment, which appear as homogeneously staining regions (HSRs) of a chromosome when viewed under the light microscope. Alternatively, the region carrying the amplified segment may break away from the chromosome and can be seen as small, independently replicating, extra-chromosomal particles (double minutes). Gene amplification does not always result in overexpression of the gene…
A variety of structural changes in proteins can also lead to oncogene activation. Examples include alterations in the structure of growth factor receptors (such as the EGF receptor) and translocations that fuse two distinct reading frames to yield a hybrid protein (such as Bcr-Abl). Both types of alterations deregulate the proteins, causing them to emit growth-promoting signals in a strong, unremitting fashion.494
Oncogene protein products can be grouped into several classes depending on their location and reactivity: nuclear, cytoplasmic, and membrane protein kinases; cytoplasmic guanosine triphosphate–binding proteins; growth factors; and others. The protein products of the proto-oncogenes src, abl, and ras are cytoplasmic in location. The proto-oncogene products of myc, fos, ski, and myb are nuclear in location and are believed to play an important role in the control of cell division. The expression of these genes may be responsible for the entry of the cell into DNA synthesis. Growth factors are proteins that act at the cell surface to stimulate cell growth.
Current evidence suggests that ras oncogenes contribute to both initiation and progression of human neoplasia. The incidence of proto-oncogene amplifications in biopsy specimens from tumors, although highly variable, is usually low. However, there may be a tendency toward association of amplification of specific proto-oncogenes and particular types of tumors. Amplifications of the c-erb-B-2/neu proto-oncogene (also referred to as her-2) may be involved in the etiology of human breast, salivary gland, and ovarian cancers and might serve as a useful prognostic marker for these malignancies.410 Slamon et al.411 observed that the erb-B-2/neu locus is amplified in 30% of primary breast carcinomas and that amplification is associated with a worse prognosis.
Amplification of another proto-oncogene, C-myc, occurs mainly in adenocarcinomas, squamous cell carcinomas, and sarcomas but not in hematologic malignancies, whereas N-myc amplification occurs most frequently in neuroblastomas and occasionally in retinoblastomas and a few small-cell lung carcinomas.
Tumor-Suppressor Genes
The concept that a gene product could inhibit or suppress proliferation of cells in a tumor was derived from experiments using somatic cell genetics.207 Different chromosomes from normal human cells carry tumor suppression genes that are able to block tumor formation by the cancer cell. The cancer cells must sustain mutation in both alleles of these genes to develop the ability to produce tumors.267
These somatic cell genetic experiments relied on cell fusion. In the first type of experiment, a cancerous cell that was able to form a tumor in an animal was fused with a normal cell. The hybrid cell no longer produced tumors in animals. One could conclude that there was an element in the normal cell that was able to suppress the tumorigenic potential of the cancerous cell. It was found that, on occasion, one of the hybrid cell lines produced by fusion of cancerous and normal cells was tumorigenic. Why? These malignant cell lines were missing genetic material supplied by the normal parent cells. Further investigation identified the presence of tumor-suppressing genes from the normal parent. Eventually, several specific tumor-suppressor genes were identified and named.
The next important part of the story of tumor-suppressor genes comes from studies of the ocular tumor of infancy—retinoblastoma. Retinoblastoma can be either unilateral and unifocal or bilateral and multifocal. The disease also can be heritable or nonheritable based on the presence of a positive family history. In a classic study, Alfred Knudson250 noted that heritable retinoblastoma was more often bilateral and multifocal and occurred in younger children rather than nonheritable unilateral retinoblastoma, which occurred in older children. Knudson postulated that there was a gene that renders children susceptible to retinoblastoma. Patients with early-onset bilateral, multifocal disease inherit one defective copy of this gene and one normal allele. With a very high frequency, mutations develop in the normal allele, and children develop the tumor. However, patients with nonheritable retinoblastoma inherit two normal alleles. Only if two independent mutations develop in the same gene, completely obliterating the function of that gene, will a cancer arise.
Knudson concluded that it requires two genetic injuries in two alleles to produce retinoblastoma. This is called the “Knudson two hit” hypothesis. The hypothesis predicts that if only one of the two gene copies remains active, there is sufficient growth suppression activity to keep the cell normal. Only if both copies are inactivated is there sufficient loss of genetic activity to allow unbridled cell proliferation. The retinoblastoma gene, Rb, was isolated on the long arm of chromosome 13. Because the short arm of chromosomes is abbreviated as p and the long arm as q, the deletion of the Rb gene is abbreviated as 13q-.
How could one find tumor-suppressor genes when their existence was most apparent by their absence? Robert Weinberg explains:
The dominantly acting oncogenes, in stark contrast, could be detected far more readily through their presence in a retrovirus genome, through the transfection-focus assay, or through their presence in a chromosomal segment that repeatedly undergoes gene amplification in a number of independently arising tumors…
A more general strategy was required that did not depend on the chance observation of interstitial chromosomal deletions or the presence of a known gene … that, through good fortune, lay near a tumor suppressor gene on a chromosome. Both of these conditions greatly facilitated the isolation of the Rb gene. In general, however, the searches for most tumor suppressor genes were not favored by such strokes of good luck.
The tendency of tumor suppressor genes to undergo LOH [loss of heterozygosity] during tumor development provided cancer researchers with a novel genetic strategy for tracking them down. Since the chromosomal region flanking a tumor suppressor gene seemed to undergo LOH together with the tumor suppressor gene itself, one might be able to detect the existence of a still-uncloned tumor suppressor gene simply from the fact that an anonymous genetic marker lying nearby on the chromosome repeatedly undergoes LOH during the development of a specific type of human tumor.
The use of more powerful mapping techniques allowed geneticists to plant polymorphic markers more densely along the genetic maps of each chromosomal arm. Within a given chromosomal arm, some markers were found to undergo LOH far more frequently than others. Clearly, the closer these markers were to a sought-after tumor gene (i.e., the tighter the genetic linkage), the higher was the probability that such markers would undergo LOH together with the tumor suppressor gene. Conversely, markers located further away on a chromosomal arm were less likely to LOH together with the tumor suppressor gene. To date, genetic analyses of DNAs prepared from various types of human tumors have revealed a large number of chromosomal regions that frequently suffer LOH. A subset of these regions have yielded to the attacks of the gene cloners, resulting in the isolation of more than 30 tumor suppressor genes.494
A number of distinctions separate the oncogenes from the tumor-suppressor genes (Table 1.11). It is almost certain that, in most human cancers, there is a multistep pathway to tumor development, which involves the accumulation of mutations in a series of oncogenes and suppressor genes.267
Over 30 tumor-suppressor genes have been cloned (APC, BRCA, DCC, MLM, NF1, NF2, Rb, p53, VHL, and WT1). The suppressor p53 gene resides in 20 kilobase (kb) of DNA located in chromosome 17p13.1. The gene is a nuclear phosphoprotein composed of 393 amino acid residues in humans.267 p53 mutations have been detected in a wide variety of malignant human tumors. The p53 gene encompasses 16 to 20 kb of DNA on the short arm of human chromosome 17. Loss of normal p53 function is associated with cell transformation in vitro and development of neoplasms in vivo. Abrogation of the normal p53 pathway is a common feature in human cancers, and it appears to be critical in the pathogenesis and progression of these tumors.73 In some cases, candidate tumor-suppressor genes have been identified based on an association between loss or inactivation and tumor development, the causal connection being only inferred.
TABLE 1.10 APPLICATION OF RADIOBIOLOGIC CONCEPTS TO RADIATION THERAPY
TABLE 1.11 PROPERTIES OF PROTO-ONCOGENES AND TUMOR-SUPPRESSOR GENES
FIGURE 1.30. The phosphorylation of the retinoblastoma gene product protein, depicted as the red circle, helps to control the cell cycle. As the cell moves from M to G1, the protein is unphosphorylated; as the cell progresses through G1, the protein is hypophosphorylated; and after passing the R point (the restriction point), it is hyperphosphorylated. This process of phosphorylation is controlled by cyclins. (From Weinberg RA. The biology of cancer. New York: Garland Science, Taylor and Francis Group, 2007.)
Cell-Cycle Control
The cell cycle, which consists of four phases (G1, S, G2, and M), regulates the duplication of genetic information and distribution of duplicated chromosomes to daughter cells. The phrases “cell-cycle control” or “cell-cycle clock” are used to describe the cell’s molecular circuits operating in the nucleus that process and integrate afferent signals and decide if the cell will actively proliferate or remain quiescent. If the “go/no go” decision is to “go” into proliferation, the circuitry is engaged to launch the biochemical changer necessary to allow the cell to double its contents and divide into two daughter cells. Key providers of the afferent information are tyrosine kinase receptors, G-protein-coupled receptors, transforming growth factor-b receptors, integrins, and the cell’s nutritional status494 (Fig. 1.30).
The Nobel Prize in Physiology or Medicine for 2001 was awarded to Leland H. Hartwell, R. Timothy Hunt, and Sir Paul M. Nurse for their discoveries regarding the control of the cell cycle. The Nobel presentation speech by Professor Anders Zetterberg succinctly describes the important controls of cell replication elucidated by these three scientists.
Cell division is a fundamental process of life. All living organisms on earth are descended from an ancestral cell that appeared about 3 billion years ago, and which has undergone an unbroken series of cell divisions since then. Each human being also began life as one single cell—a cell that divided repeatedly to give rise to all one hundred thousand billion cells that we consist of… Every second millions of cells divide in our body.
The cycle of events that a cell completes from one division to the next is called the cell cycle. During the cell cycle the cell grows in size, duplicates its hereditary material—that is, it copies the DNA molecules in the chromosomes—and divides into two daughter cells.
This year’s Nobel Laureates have discovered the key regulators of the cell cycle—cyclin dependent kinase (CDK) and cyclin. Together these two components form an enzyme, in which CDK is comparable to a “molecular engine” that drives the cell through the cell cycle by altering the structure and function of other proteins in the cell. Cyclin is the main switch that turns the “CDK engine” on and off. This cell-cycle engine operates in the same way in such widely disparate organisms as yeast cells, plants, animals, and humans.
How were the key regulators CDK and cyclin discovered? Lee Hartwell realized the great potential of genetic methods for cell-cycle studies. He chose baker’s yeast as a model organism. In the microscope he could identify genetically altered cells—mutated cells—that stopped in the cell cycle when they were cultured at an elevated temperature. Using this method Hartwell discovered, in the early 1970s, dozens of genes specific to the cell-division cycle, which he named CDC genes. One of these genes, CDC28, controls the initiation of each cell cycle, the “start” function. Hartwell also formulated the concept of “checkpoints,” which ensure that cell-cycle events occur in the correct order. Checkpoints are comparable to the program in a washing machine that checks if one step has been properly completed before the next can start. Checkpoint defects are considered to be one of the reasons behind the transformation of normal cells into cancer cells.
Paul Nurse also used the genetic approach in his cell-cycle studies but in a different kind of yeast. In the late 1970s and early 1980s he discovered the gene CDC2, which could be mutated in two different ways. Either the cells did not divide, or they divided too early. From this he correctly concluded that CDC2 controls cell division. He later discovered that CDC2 not only controls cell division, the final event of the cell cycle; it also has a key regulatory function for the whole cell cycle, including that described for CDC28 in baker’s yeast. This key function was shown to be that of CDK in the cell-cycle engine. By moving human genes into yeast cells, in 1987 Nurse isolated a human CDC2 gene. This human CDC2 gene functioned perfectly in yeast cells. Thus, the CDK function in the cell-cycle engine had been conserved through more than 1 billion years of evolution—from yeast to man.
Tim Hunt discovered the other key component of the cell-cycle engine, the protein cyclin, which regulates the function of the CDK molecule. Working with sea urchin eggs as a model organism, in 1982 he discovered a specific protein that increased in amount before cell division but disappeared abruptly when the cells divided. Because of these cyclic variations, he named the protein cyclin. These experiments not only led to the discovery of cyclin, but also demonstrated the existence of periodic protein degradation in the cell cycle—a fundamental control mechanism. Hunt also showed the existence of cyclins in other, unrelated species. Thus cyclins, like CDK, had been conserved during evolution.
It is now almost 50 years since the structure of the DNA molecule—the double helix—was discovered, leading to a molecular explanation of how a gene can make a copy of itself. With the discoveries of CDK and cyclin we are now beginning to understand, at the molecular level, how the cell can make a copy of itself.326
To ensure that the daughter cells possess a full complement of genetic information, checkpoints exist to ensure fidelity of DNA duplication and accuracy of chromosome segregation.312 Checkpoint pauses permit editing and repair of genetic information so that each daughter cell receives a full complement of genetic information identical to the parent cell (see Fig. 1.30). In some cells, there are checkpoints for initiation of mitosis. Mutation of the checkpoint genes allows the cell to enter mitosis after x-irradiation.313 For example, the rad-9 gene is a G2/M checkpoint gene because it responds to two different types of signals.314 Experimental observations suggest that the p53 gene, shown to be a transcriptional activator,366 may be critical for G1 checkpoint control. p53 has been shown to induce transcription of p21, which in turn inhibits the association of CDK 4,6 with proliferating cell nuclear antigen and cyclin D. As a consequence, the retinoblastoma protein cannot be phosphorylated and stays in complex with the transcription factor E2 F, effectively blocking the transcription of cell-cycle-promoting proteins and causing a cell-cycle arrest.
Checkpoints are signal-transduction systems that must receive a signal, amplify it, and transmit it to other components that regulate the cell cycle. Double-strand DNA breaks, unexcised ultraviolet light-induced dimers in DNA, and centromeres not engaged by the spindle are potential signals.36,209 Checkpoints ensure the fidelity of genomic replication and segregation. Biologically significant levels of spontaneous damage require checkpoint control for cells to maintain a high fidelity of chromosome transmission. Therefore, restoration of compromised checkpoints could slow cancer cell evolution even in the absence of exogenous sources of DNA damage.209 Many signal-transduction systems, including checkpoint controls, exhibit adaptation; that is, in the presence of a constant stimulus, the response diminishes with time. As a consequence, the cell may proceed through the cell cycle, although the original perturbation has not been removed or cannot be repaired.223 Checkpoint activation may induce a variety of cell responses, including cell death. The checkpoint controlling entry into S phase in mammalian cells includes p53. One function under the control of this pathway is apoptosis. Restoration of defective checkpoints could restore the apoptotic response of cancer cells and increase their sensitivity to DNA-damaging agents. It may be possible to achieve specificity for certain types of cancer cells because not all cells respond to the same apoptotic signals.504,518,519
Growth Factors and Signal Transduction
Transmission of biochemical signals to the cellular nucleus leads to altered expression of a wide variety of genes involved in microgenic and differentiation responses.417 A number of growth factors exert their effects through receptors possessing intrinsic protein tyrosine kinase activity. On activation, these receptors phosphorylate both themselves and other intracellular proteins on the amino acid tyrosine. Among the receptors for growth factors are epidermal growth factor, platelet-derived growth factor, insulin, nerve growth factor, and macrophage colony stimulatory factor. The mitogenic signaling pathway activated by protein tyrosine kinase receptors involves the activation of ras proteins. Ras undergoes conformational change and interacts with additional downstream targets. A protein kinase cascade is activated, which conveys the growth factor–initiated signal to the nucleus via the raf, mek, map kinase, and other proteins.
Telomeres
Human chromosomes are linear. At each end of the chromosome are structures known as telomeres, from the Greek telo for “end” and mere for “structure.” Telomeres are composed of specialized DNA and DNA-binding proteins. As chromosomes are replicated, telomeres shorten each time during the process of cell division. Continued cycles of cell division result in shortened telomeres. The telomeres, for example, in the fibroblasts of older adults are shorter than those in children. Normal human cells senesce when the telomeres shorten to a critical length.
Stem cells and cancer cells must maintain their telomere lengths to prevent senescence. Two mechanisms of telomere maintenance have been identified: expression of the telomerase enzyme, and the recombination of telomeres.
The telomere hypothesis states that critical telomere shortening prevents somatic cells from dividing. In contrast, the maintenance of telomere length allows cancer cells to continue to divide. An increasing body of experimental evidence supports the telomere hypothesis and its association with cancer.
The capacity of cells to respond to ionizing radiation is determined by multiple factors. There are a variety of syndromes associated with molecular defects that are characterized by clinical radiosensitivity. These include ataxia, telangiectasia, Nijmegen breakage syndrome, and ataxia telangiectasia–like disorder. These syndromes all have defective telomere maintenance in common. It has been hypothesized, therefore, that the radiosensitivity phenotype and the telomere dysfunction phenotype may be linked. A variety of experimental models suggest that telomere maintenance and radiosensitivity are associated, and this may offer the opportunity for a therapeutic target.
Apoptosis
Apoptosis or programmed cell death, a phenomenon distinct from necrosis, was described in 1972 by Kerr et al.248 Apoptosis is programmed by specific signals in the cell that cause an endonuclease to cleave DNA at internucleosomal sites.
Apoptosis is detected by histologic evaluation of membrane blebbing and chromatin condensation, by flow cytometry using fluorescent nucleotides and terminal transferase to detect fragmented DNA, by detecting apoptotic cells that are usually very small with characteristic profiles of right-angle and forward light scattering, or by using DNA fluorochrome to detect a decrease in fluorescence as small DNA fragments diffuse from the cell that is undergoing apoptosis.86,518,520 An early change in apoptosis, the flip-flop of the phospholipid phosphatidylserine (PS) from the inner to the outer leaflet of the bilayer membrane, also can be detected using a fluorescently labeled annexin V protein that has a high binding affinity to PS. Several oncogenes, cytokines, and growth factors have been reported to play a role in promoting or reducing radiation-induced apoptosis.114
Most radiation-induced cell lethality (loss of reproductive integrity) for dividing cells appears to be caused by mitotic-linked death resulting in loss of genetic information as cells with chromosomal aberrations divide. Apoptosis, frequently seen within 4 to 6 hours after irradiation, occurs spontaneously and is enhanced by radiation as observed in vivo in the intestinal crypt and salivary and lacrimal glands with nondividing cells and nondividing lymphocytes. Apoptotic cells are eliminated rapidly in vivo, making it difficult to quantify. In contrast, this cell death mechanism is easy to quantify in vitro because apoptotic cells persist in culture for many hours. However, cell division of nonapoptotic cells complicates quantification.114 In cell lines susceptible to apoptosis, this process sometimes occurs early before cells enter mitosis or later after the cells divide. Late apoptosis may be associated with mitotically linked death and, in fact, may be triggered by chromosomal aberrations. Apoptosis may be quite important for clinically relevant doses of fractionated irradiation, even if it causes a relatively small reduction in clonogenic survival. However, this requires that cells be recruited into the apoptotic-susceptible fraction after each dose fraction.
It appears that with progression of certain tumors, spontaneous and therapy-related apoptosis occurs less frequently. The apoptotic response to irradiation can be modified by cytokines to protect normal tissues171 or to induce tumor cell killing.197,214,215 Tumor necrosis factor increases apoptosis after irradiation in some tumors while protecting the hematopoietic compartment, possibly by blocking apoptosis.321 Irradiation prevents extensive cellular proliferation by increasing differentiation in both tumors and normal tissues. Also, irradiation appears to increase the aging of normal cells. Another mechanism of reversible loss of proliferative capacity induced by irradiation is necrosis, which occurs with high doses of irradiation and is a major mechanism seen with large dose fractions such as in stereotactic irradiation.
THE BIOLOGY OF METASTASIS
The prefix meta is of Greek origin and is defined as “after,” “beyond,” or “over.” It is used to denote change or transformation. The word stasis means “stand” or “stationary.” Thus, when the two words are combined to form metastasis, the new word is used to represent a change in location of a disease or its manifestations. It also means the transfer of a disease from one organ or body part to another organ or body part not directly connected. The oncologist uses the term metastasis to refer to the manifestation of malignancy that arises from the primary growth but is now in a secondary site.
It is clear that the pattern of metastatic spread of cancer is not random. The distribution of some secondary tumor deposits can be explained on mechanistic grounds (i.e., that the tumor cells are shed into the bloodstream and lodge in the first narrow capillary network that they encounter downstream). This would explain, for example, why the liver is the most common site for secondary tumors in patients with primary cancer within the catchment area of the hepatic portal vein, such as gastrointestinal malignancies. Similarly, the lung would be a favored site in patients with primary tumor spilling into the systemic veins. There can be no doubt that vascular drainage patterns influence the distribution of secondary tumor deposits from some types of primary cancer.
It is also clear, however, that the distribution of some metastatic tumors cannot be explained solely by patterns of encountering and lodging in the nearest narrow capillary bed. This is called “metastatic tropism”: carcinomas form detectable metastases in only a limited subset of possible distant organ sites. The seminal paper addressing this problem was by Stephen Paget (1855–1926). Paget was the fourth and youngest son of the famous British physician Sir James Paget. Stephen Paget worked as an assistant surgeon at the West London and Metropolitan Hospitals in England. Later in life, he devoted himself to public health issues and became a highly regarded biographer and essayist.341 Writing in the Lancet on March 23, 1889, on “The Distribution of Secondary Growth in Cancer of the Breast,” Paget wondered:
The question ought to be asked, and if possible answered: “What is it that decides what organs shall suffer in a case of disseminated cancer?” If the remote organs in such a case are all alike passive and, so to speak, helpless—all equally ready to receive and nourish any particle of the primary growth which may “slip through the lungs,” and so be brought to them—then the distribution of cancer throughout the body must be a matter of chance. But if we can trace any sort of rule or sequence in the distribution of cancer, any relation between the character of the primary growth and the situation of the secondary growths derived from it, then the remote organs cannot be altogether passive or indifferent as regards embolism… Every single cancer cell must be regarded as an organism, alive and capable of development. When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.342
Paget observed, in a large number of autopsies of women with breast cancer, that the lymph nodes, liver, lung, bone, and brain commonly were involved. However, he found that the kidney and spleen rarely were involved despite receiving a significant amount of blood flow. He was struck by the discrepancy between the relative blood supplies and the relative frequencies of metastatic tumors in various organs. From his data, Paget expounded his “seed and soil hypothesis.” He argued that metastasis required both a willing seed (intrinsic cellular factors) and hospitable soil (host organ). There must be intrinsic cellular factors that lead to a satisfactory interaction between the tumor cell and the host organ resulting in successful metastasis. In contemporary terms, we understand this to mean that the tumor cell must have favorable adhesion molecules, and the host organ must be accepting receptors on its endothelial cells, which results in appropriate sites for the circulating tumor cells to bind, migrate into the organ, and subsequently grow, or, perhaps, that tumor cells promote up-regulation of adhesion receptors in specific stromal cells.
Metastasis formation is an inefficient process. Fidler and colleagues148 injected melanoma cells into the peripheral vein of a mouse whose DNA had been labeled with radioactive iodine. They found that, shortly after the injection, most of the injected cells rested in the lung (i.e., the nearest narrow capillary bed). Most of the tumor cells, however, went on to die in the lung. Only a few live cells continued to circulate. Within a day, only 1% of the injected cells were alive, and after 2 weeks, no known metastasis could be seen in the lungs. Only 0.1% of the cells originally injected were still alive.148 Bloodborne metastasis must be a highly selective process. Only a very small proportion of malignant cells that enter into the bloodstream are able to survive and grow.
There are three major pathways of metastasis. They are:
• Across body cavities such as the peritoneal cavity or within the cerebrospinal fluid. This is the way, for example, that medulloblastoma disseminates via the leptomeninges or that ovarian tumors form on the peritoneal surface of the intestine.
• Via the lymphatic system. Axillary masses following breast cancer, that are easily palpable, would be a common example.
• Hematogenously, usually via veins rather than arteries. The spread of a limb sarcoma to the lungs would be an example (Fig. 1.31).
The molecular mechanism of tumor metastasis is a multistep process involving many tumor cells—host–cell interactions as well as cell–matrix associations.427 This process is sometimes called the invasion-metastasis cascade. The crucial processes are as follows:
• Tumor cell adhesion to other tumor cells at the site of the primary malignancy, host cells, or components of the extracellular matrix;
• Proteolysis of the extracellular matrix during invasion;
• Tumor cell motility through the extracellular matrix to reach the vascular or lymphatic endothelium;
• Intravasation into the lumina of blood vessels or lymphatics—this is facilitated by molecular changes that promote the ability of carcinoma cells to cross the pericytes and endothelial cell barriers;
• Embolism into the lymphatic system and/or the blood circulation;
• Tumor cell survival despite both the mechanical trauma endured by the cell in transit in the vascular system as well as the body’s immunologic assault directed against the circulating tumor cell (insofar as most tumor cells have a diameter of 20 to 30 μm and capillaries have a diameter of ~ 8 μm, most tumor cells in circulation are probably quickly trapped in capillary beds);
• Adherence to the endothelium when the tumor cell comes to rest at the metastatic site in the secondary organ;
• Dissolution of the cell–cell junction and the basement membrane of the blood vessel or lymphatic into the organ parenchyma;
• Survival in the new host organ microenvironment and interaction with that new microenvironment in the host organ to permit growth of the tumor deposit; and
• Tumor cell proliferation in the new organ and angiogenesis to achieve metastatic colonization.
FIGURE 1.31. The development of metastasis is a multistep process that is highly inefficient. In order to form a metastasis, the tumor must breach the basement membrane and enter either a blood vessel or a lymphatic, travel through the bloodstream or the lymphatics and not be destroyed either by attack of the immune system or mechanical trauma, adhere to the endothelium at a distant anatomic site, invade the organ parenchyma, draw a blood supply into the metastatic deposit, and colonize the new organ. (From Weinberg RA. The biology of cancer. New York: Garland Science, Taylor and Francis Group, 2007.)
Only if all of these steps can be negotiated successfully can the tumor cell ultimately “set up shop” as a metastatic focus. The fact that only a small fraction of tumor cells survive and successfully establish a metastasis would suggest that the ultimately successful cells must be quite unusual. It would be reasonable to believe that they represent a subpopulation of tumor cells that are endowed with particular characteristics that make for successful metastasis. As the population of tumor cells evolves, it is likely that aggressive subpopulations, having diverse properties, will arise and that their frequency in the population increases under selective pressure of the host immune defenses. This will lead, ultimately, to the emergence of cells with enhanced malignancy.427 Many people believe that tumor cells evolve via a Darwinian selection. Genetic variation continuously occurs in the tumor population and clones with a survival advantage become overrepresented. These cells have “metastasis virulence genes” enabling their spread. The successful metastatic cells will possess characteristics of neoplastic transformation—the ability to turn on an angiogenic switch, an invasive phenotype, and the capacity to evade the immune response—as well as favorable cell adhesion and motility characteristics.154–156,467,494
Metastatic progress involves not only the tumor’s cells but also those cells’ ability to recruit the aid of stromal cells. As tumors progress the stroma becomes increasingly “reactive”—akin to the tissue of wound healing or chronic inflammation.
THE MOLECULAR BIOLOGY OF THE METASTATIC PHENOTYPE AND ANGIOGENESIS
Tumor progression is the acquisition of permanent, irreversible, qualitative changes in one or more characteristics of neoplasm that ultimately will lead to the tumor becoming more autonomous and malignant.426 A genetic analysis of the stages of tumor progression has led scientists to formulate the multistep theory of tumorigenesis. The multistep theory involves activation of oncogenes, inactivation of tumor suppression genes, and identification of many tumor-associated molecules. The metastatic phenotype appears to require cells to have the additive effect of positive modulators (oncogenes) as well as the loss of negative effectors (tumor-suppressor genes, invasion- and metastasis-suppressor genes). Thus, the molecular biology of a metastatic cell is clearly a multistep process of diversification and clonal selection for aggressive cells.
The mutated ras oncogene sequences, when transfected into mouse embryo-derived fibroblasts (NIH 3T3 cells), cause those transfected cells to produce numerous metastases.509 This finding has been confirmed in both fibroblasts and epithelial cells of human and rodent origin. A number of other metastasis-associated genes have been described. These include NM23-1 and stomelysm-3 (ST-3). NM23-1 has features similar to a transcription factor and may play a role not only in c-myc expression but also in the response of cells to transforming growth factor-β. ST-3 is a member of the matrix proteinase family.426
It would be far too simplistic to conclude that the metastatic phenotype arises only from genetic alterations associated with the acquisition of aggressive tumorigenicity. Cells clearly can be transformed by oncogene transfection, but not all cells acquire a metastatic phenotype after this oncogene transfection. Simply stated, we must bear in mind that there is separation between the genetic changes that drive tumorigenicity and the metastatic phenotype. Invasion and metastasis will require the activation of additional effector genes or loss of suppressor local inhibitors above those genetic changes required for uncontrolled growth alone.
The successful development of a metastatic focus requires new blood vessel growth. Recent evidence has identified angiogenesis promoters and inhibitors that may be modified or removed during the tumor-induced angiogenic response. Tumor angiogenesis in the nascent metastasis is a tightly regulated process in a delicate balance between the pro- and antiangiogenic factors.268
Angiogenesis
The success of growth of a tumor is, in part, governed by a complex interplay between the tumor cells and the surrounding normal tissue. A dramatic example of this interplay is the process of tumor angiogenesis (also called tumor neovascularization).
The growth of the tumor depends on the tumor’s access to nutrients and oxygen as well as its ability to eliminate metabolic waste and carbon dioxide. In very small tumors, these requirements are addressed by diffusion. As the tumor enlarges, however, diffusion is inadequate. The growing tumor requires direct access to the circulatory system.
Tumor access to the circulatory system is secured through angiogenesis, through which the tumor cells encourage the ingrowth of capillaries and larger vessels from the adjacent normal tissue. The tumor cells recruit these vessels through the release of angiogenic factors. These cause the proliferation of endothelial growth factor and, almost certainly, tissue growth factor-β. The generation of tumor vessels is the result of a delicate balance between angiogenesis-promoting factors and angiogenesis-inhibiting factors. These factors have now provided a growing body of therapeutic targets in the treatment of cancer.
Some authorities encourage us to think about the tumor as a structure composed of varied compartments including the actual clonogenic cells, a connective structure, and the blood vessels. Utilizing this way of thinking about tumors, we envision cancer treatment as striking at different components of the tumor (i.e., antiangiogenesis agents directed against the vasculature and anticlonogenic agents directed against proliferating cells). Experimental evidence suggests that, in certain tumor systems, the combination of radiation and antiangiogenic agents is a fruitful way of treating cancer. We may expect to see an increasing body of evidence for the use of combinations of radiation, chemotherapy, hormonal therapy, and antiangiogenesis agents in the coming years.
The hallmark of an invasive cancer is its ability to disrupt the epithelial basement membrane and the presence of cancer cells in the stromal compartment. It makes sense, therefore, that two broad classes of molecules have been implicated repeatedly in contributing to the metastatic ability: cell–cell adhesion molecules and motility molecules play a crucial role in the development of metastatic potential.55 The ability of tumor cells to adhere to other tumor cells, cells of the host, or components of the extracellular matrix affect multiple components of the metastatic cascade. These interactions depend on several classes of molecules expressed on the cell surface. Cadherins are calcium-dependent molecules that mediate homophilic cell–cell adherence. Integrins are heterodimeric transmemory proteins that are formed by the noncovalent association of α- and β-subunits. The binding of the extracellular matrix ligands to integrins is known to initiate similar transduction pathways. These pathways lead to cell proliferation, differentiation, migration, or cell death. Selectins act through a terminal calcium-dependent lexon domain. They are prominently involved in heterotypic cell–cell adhesion between blood cells and endothelial cells.65
Tumor adherence to the extracellular matrix and cell motility is the next crucial component of the metastatic cascade. Tumor cells are able to attach to a specific lipoprotein of the extracellular matrix such as fibronectin, collagen, and laminin. These adherences are formed either through integrin or nonintegrin cell-surface receptors. CD44 is a crucial transmembrane glycoprotein with a large echo domain and a single cytoplasm domain. CD44 is involved in cell adhesion to hyaluronan416 (Box 1.7).
The potentially metastatic cell must overcome a series of tissue barriers. These include the basement membrane and connective tissue. These must be traversed by the tumor cells during the metastatic process. Five classes of naturally occurring proteinases have been associated with aggressive tumor cells and implicated in metastases. These include members of the gene family of matrix metalloproteinases. These enzymes, each of which is secreted by a proenzyme that subsequently requires activation, may be divided into three general subclasses: interstitial collagenase, type 4 collagenase (gelatinases), and stromelysins. Once having dissolved barriers, active tumor cell motility is required for the penetration of the basement membrane and the interstitial stoma. Successful migration of metastatic cells requires transition of propulsive force from the extracellular matrix to the cytoskeleton. Tumor cells exhibit amoeboid movement, which is characterized by pseudopod extension. For the protrusion and retraction of pseudopods, the network of intracellular polymerized cross-linked filaments must be disassembled and then reassembled.427
MANAGEMENT OF THE PATIENT WITH CANCER
The optimal care of cancer patients is a multidisciplinary effort that may combine two or more disciplines: surgery, radiation therapy, and chemotherapy. Many professionals, including physicians, physicists, laboratory scientists, nurses, rehabilitation staff, sociologists, and social workers, are intimately involved. Pathologists, radiologists, clinical laboratory physicians, and immunologists are integral members of the team that renders the correct diagnosis. Biology, biochemistry, and pharmacology have contributed greatly to the advancement of methods used to evaluate and treat cancer patients (e.g., biomarkers, cell kinetics indicators, oncogenes).
The radiation oncologist, like any other physician, must assess all conditions relative to the patient and the tumor under consideration for treatment and systematically review the need for diagnostic and staging procedures as well as the best therapeutic strategy. This has been well illustrated in a series of “decision trees” designed by the Patterns of Care Study Group for radiation therapy.224 In several instances, a clear relationship existed between compliance with guidelines for diagnostic or therapeutic procedures (best current management consensus) and therapy outcome, as defined by survival, recurrence patterns, or complications of treatment.
Emphasis on screening and early diagnosis of cancer, as well as improvements in therapeutic strategies, has had a significant positive impact on the survival of patients with cancer. In the United States, results of the Surveillance Epidemiology and End Results program have shown a small but steady improvement in survival for a variety of tumor sites. Relative survival of patients with cancer at various times after diagnosis has improved substantially since 1960.
Box 1.7
Antiangiogenesis Therapy of Cancer
Tumor vessels are fundamentally different from normal blood vessels insofar as they are usually irregular and disorganized. In vessels that are leaky, hemorrhagic, or torturous or in those containing poorly oxygenated blood that may flow backward and forward in the same vessel, tumor vasculature may provide an interesting therapeutic target. The general public and the scientific community have recently experienced a wave of considerable excitement associated with the possibility that antiangiogenesis agents may be employed clinically to disrupt tumor angiogenesis. This form of therapy may complement existing cancer treatments. Vascular endothelial growth factor (VEGF) is a key element in the stimulation of angiogenesis. VEGF binds to a receptor on endothelial cells (VEGFR), which stimulates tyrosine kinase activity, which in turn stimulates downstream signaling and activation of endothelial cells. The drugs in the therapeutic pipeline may be categorized as follows:
• Anti-VEGF agents: Some drugs prevent the binding of VEGF to its receptors. Bevacizumab (Avastin) is a monoclonal antibody that binds to VEGF, prevents it binding to VEGFR, and inhibits VEGFR activation. It is being utilized in the therapy of a variety of human malignancies.179
• Anti-VEGFR agents: Several receptors bind to VEGF: VEGFR1, VEGFR2, NRP-1, and NRP-2. VEGR2 is thought to mediate most of the angiogenic properties of VEGF and is expressed at high levels on the endothelial cells of tumor vasculature. Several monoclonal antibodies are under investigation in animal models to target the VEGF receptor.
• Receptor tyrosine kinase inhibitors: An antiangiogenesis strategy is to target the downstream activity of the binding of the VEGFR by inhibition of tyrosine kinase activity. The following drugs, now in human clinical trials, fall into this category: Cediranib or Recentin (AZD2171), Pazopanib, BIBF 1120, Sorafenib, and Sunitib (SU11248).
Combination of Therapeutic Modalities
Irradiation and Surgery
The rationale for preoperative radiation therapy relates to its potential ability to eradicate subclinical or microscopic disease beyond the margins of the surgical resection, to diminish tumor implantation by decreasing the number of viable cells within the operative field, to sterilize lymph node metastases outside the operative field, to decrease the potential for dissemination of clonogenic tumor cells that might produce distant metastases, and to increase the possibility of resectability. The disadvantages of preoperative irradiation are that it may interfere with normal healing of the tissues affected by the radiation, it delays surgery, and it may disrupt surgical staging of the tumor and/or the expression of histologic or immunohistochemical prognostic factors.
The rationale for postoperative irradiation is based on the fact that it is possible to eliminate subclinical foci of tumor cells in the tumor bed (including lymph node metastases). By delivering higher doses to the volume of high-risk or known residual disease than can be achieved with preoperative irradiation, a greater tumor control may be obtained. For example, improved survival rates have been reported in patients with head and neck tumors treated with combined therapy in comparison with surgery alone.151
The potential disadvantages of postoperative irradiation are related to the delay in initiation of radiation therapy until wound healing is completed. Theoretic and experimental evidence suggests that the radiation effect may be impaired by vascular changes produced in the tumor bed by surgery. Experimental data suggest that preoperative irradiation may be more effective than postoperative irradiation392 (Fig. 1.32).
Irradiation and Chemotherapy
Tumor or normal tissue enhancement describes any increase in effect greater than that observed with either chemotherapy or irradiation alone.358 Agents used in chemoirradiation include those with cytotoxic activity against the tumor, which may show additive, subadditive, or supra-additive effects, such as 5-fluorouracil or mitomycin-C in anal carcinoma; agents with minimal or no significant activity against a specific tumor, which may, however, enhance the irradiation effect; radiation hypoxic cell cytotoxins or bioreductive agents; and radioprotectors.
Chemotherapy alone or combined with irradiation may be used in several settings.438 Primary chemotherapy is used as part of the primary lesion treatment (even if later followed by other local therapy) and when the primary tumor response to the initial treatment is the key identifier of systemic effects. Adjuvant chemotherapy is used as an adjunct to other local modalities as part of the initial curative treatment. The term neoadjuvant chemotherapy is used when this modality is used in the initial treatment of patients with localized tumors, before surgery or irradiation.
FIGURE 1.32. A: A pattern of failure analysis is useful to improve treatment of malignancies. B: If the tumor after surgery and/or radiotherapy tends to relapse at the primary site within the volume treated, it would suggest that the local therapy is insufficiently intense. C: If, however, there is a local-regional tumor relapse, it would suggest that the initial surgery or radiotherapy field size is insufficient to cover microscopic extension of disease that has the potential to be controlled. A pattern of failure as shown in panel (C) is not, by itself, sufficient to make the case for extended field radiation. One must have a pattern of failure such as that which is seen in panel (C) and also be able to show that intervention with large field irradiation can alter that pattern in a favorable manner.
The effects of combined radiation therapy–chemotherapy can be independent, additive, or interactive. Chemotherapy and irradiation can be administered sequentially or concomitantly. Sequencing of treatment at the appropriate time is significantly related to the residual tumor cell burden at the point of introduction of each new treatment program.515
Administration of chemotherapy before irradiation may produce cell killing and reduce the number of cells to be eliminated by the irradiation. Use of chemotherapy concurrently with radiation therapy has a strong rationale because it could interact with the local treatment (additive and even supra-additive action) and also could affect subclinical disease early in treatment. However, the combination of modalities may enhance normal tissue toxicity. When agents with added toxicity are used, lower tumor control may result because the added morbidity requires lowering the doses of the effective agents or prolonging overall irradiation treatment time. When fatal toxicity from chemotherapy occurs, it prevents some dying patients from demonstrating tumor response that could have been observed had they survived. Overall patient survival may be compromised as well.
Biologic Considerations in Combinations of Chemotherapy and Irradiation
Many experimental animal studies have shown therapeutic benefit from a combination of irradiation and drugs, but most are phenomenologic. Therapeutic benefit requires differential properties on tumor and normal tissues, which may be exploited for therapeutic gain. These include genetic instability of tumors compared with normal tissues, differences in cell proliferation (particularly cell repopulation during fractionated radiation therapy), and environmental factors such as hypoxia and acidity (which usually are confined to tumors). There are variations in sensitivity or resistance to irradiation or drugs. The mechanisms for resistance to these agents may be shared in some tumors and different in other tumors. Resistance to anticancer drugs may have implications for resistance to radiation therapy; many drug mechanisms for resistance are multifactorial, such as in cisplatin, in which this phenomenon may be the result of decreased drug uptake, increased repair of DNA, increased expression of sulfhydryl compounds such as glutathione and metallothionein, and increased expression of glutathione-S-transferase. Combined treatment with radiation and drugs might result in an improved therapeutic index if mechanisms of resistance are independent.440
Oxygen, pH, and nutrient supply can play an important role in the combined effects of chemotherapy and irradiation on tumor cells.128 Hypoxic cells are less radiosensitive and chemosensitive to many drugs, and chronic hypoxia can alter cell-cycle age distribution and proliferation rate—both important modifiers of cellular response to ionizing radiation and drugs. In addition, chronic hypoxia can affect cellular ability to repair radiation- and drug-induced DNA damage. Bioreductive drugs such as mitomycin-C are activated to toxic species and affect solid animal tumors under hypoxic conditions. DNA repair, cell-cycle age distribution, and the activity and stability of some chemotherapeutic drugs may be pH dependent; thus, this factor plays a role in the sensitivity of cells to irradiation and cytotoxic agents.
Hypoxic conditions, which commonly exist in tumors, may lead to amplification of genes. Under hypoxic conditions hypoxia-inducible factor 1 (HIF-1) occur, levels rise and functional HIF-1 transcription factor complexes induce angiogenesis, erythrocytopoiesis, glycolysis, and glucose transport into cells—all techniques to allow the cell to survive hypoxia. HIF-1 induces the genes encoding vascular endothelial growth factor (VEGF), platelet-derived growth factor, and transforming growth factor.494 Some cytokines such as tumor necrosis factor-α or interleukin513 and growth factors such as platelet-derived and fibroblast growth factors are seen in malignant and normal human cells after irradiation.512 These cytokines and growth factors enhance the cytotoxic effects of irradiation and chemotherapy in tumor cells256 or offer radioprotection in normal cells.322
Possible molecular or cellular mechanisms of interaction of chemotherapy and irradiation include:
1. Modification of the slope of the dose–response curves, such as has been shown with actinomycin D, cisplatin, doxorubicin, mitomycin-C, 5-fluorouracil, and other agents.
2. Decreased accumulation or inhibition of repair of sublethal damage, as induced by actinomycin D, cisplatin, bleomycin, hydroxyurea, and nitrosoureas.76,246,408 Doxorubicin and other DNA intercalators decrease the shoulder widths but do not decrease the slope or suppress the repair of lethal damage in in vitro studies.121
3. Inhibition of repair of potentially lethal damage, as has been shown with actinomycin D, doxorubicin, and cisplatin.124,482
4. Perturbation of cell kinetics, for example, after treatment with hydroxyurea, which kills cells in the S phase, when cells may become partially synchronized and blocked at the G1/S phase of the cell cycle. If irradiation is delivered during this sensitive phase, as the cells subsequently emerge from the block, an enhanced cytotoxic effect may be expected.
5. Selective cytotoxicity and radiosensitization of hypoxic cells, which have been reported with mitomycin-C and cisplatin.252
6. Inhibition of cell repopulation.
7. Decrease in tumor bulk leading to improved blood supply, reoxygenation, and cell-cycle recruitment, resulting in increased radiosensitivity and chemosensitivity.
A possible danger in the administration of cytotoxic drugs before radiation therapy is accelerated cell proliferation or repopulation. Because some tumor regression is induced by the cytotoxic agent (drugs or irradiation), the distance between the tumor cells, and decreases in adjacent functional capillaries, this may induce tumor cell proliferation so that higher doses of irradiation would be required to produce a given tumor control. This may occur because, during radiation therapy, tumor cells surviving neoadjuvant chemotherapy may be stimulated to repopulate at a faster rate. Because of this effect, the initial advantage in cell killing by drugs is lost, and the survival curves for fractionated radiation therapy may come together or even cross over. As pointed out by Tannock,440 although this mechanism is hypothetical, it suggests caution in the use of induction chemotherapy and explains why an initial tumor response may not necessarily translate to a therapeutic advantage with combined-modality treatment given in this fashion. In the example in Figure 1.33, three courses of induction chemotherapy reduced tumor cell numbers from 1010 to 108 (from 10 g to about 0.1 g), which is considered a complete clinical tumor regression. Even a pathologic complete response has limited long-term implications; a complete pathologic regression is consistent with the presence of about 106 tumor cells per gram, a substantial biologic cell burden.
Integrated Multimodality Cancer Management and Organ Preservation
Combinations of two or all three of the classic modalities frequently are used to improve tumor control and patient survival. Steel and Peckham424 postulated the biologic basis of cancer therapy as spatial cooperation, in which an agent is active against tumor cells spatially missed by another agent, addition of antitumor effects by two or more agents, and nonoverlapping toxicity and protection of normal tissues. Large primary tumors or metastatic lymph nodes must be removed surgically or treated with definitive radiation therapy. Regional microextensions are eliminated effectively by irradiation without the anatomic and at times physiologic deficit produced by equivalent medical surgery. Chemotherapy is applied mainly to control disseminated subclinical disease, although it also has an effect on some larger tumors.
Organ preservation is being vigorously promoted because it enhances the quality of life and psychoemotional feelings of patients with excellent tumor control and survival. In some types and stages of head and neck tumors, breast cancer, gastrointestinal malignancies, genitourinary tumors, soft-tissue sarcomas, and pediatric tumors, studies have shown that less radical surgical procedures combined with chemotherapy and radiation therapy yield the same local tumor control at the primary site and survival as did radical procedures. Advances in reconstructive surgery have greatly improved our ability to repair defects of radical surgery.
FIGURE 1.33. Relationship between clinical remission and cure. A 10-g tumor containing 1010 cells is treated with three courses of chemotherapy, each of which kills 90% of the tumor cells present. After three courses, the number of viable tumor cells is <108 (<0.1 g) and the patient is judged to be in clinical and radiologic complete remission. Note that this is a small step toward tumor cure. Moreover, additional chemotherapy may not be helpful if drug-resistant cells have been selected after three courses of chemotherapy. (From Tannock IF. Combined modality treatment with radiotherapy and chemotherapy. Radiother Oncol 1989;16:83–101, with permission.)
TABLE 1.12 TRENDS IN 5-YEAR U.S. CANCER SURVIVAL RATES (%)
TABLE 1.13 ESTIMATED NEW U.S. CANCER CASES AND DEATHS, 2011
CANCER PREVENTION
Cancer is a largely preventable disease. Epidemiologic studies have identified the causative agents for a significant proportion of adult cancers (Tables 1.12 and 1.13). Approximately 30% to 35% of cases of cancer in the United States are associated with tobacco use. Another 30% to 35% of cases are associated with excessive dietary fat and obesity. Approximately 5% of cancer is related to alcohol use. Another 5% is associated with exposure to viral agents.119 Among the other causative factors of cancer, each responsible for a small percentage of malignancies, are occupational exposures, a family history of cancer, environmental pollution, ionizing and ultraviolet irradiation, prescription drugs, and medical procedures.
There are two general approaches to cancer prevention. They are referred to as primary prevention strategies and secondary prevention strategies. A primary preventive strategy may be invoked when there is an explicit and indisputable behavior that should be avoided or adopted because of its association with a predictable and certain reduction in cancer risk for an individual. A secondary prevention is distinguished from primary prevention in that it is an intervention focused on altering the natural history of a disease and thus avoiding disease-related adverse outcomes.97 The most commonly used secondary prevention strategy is broad-based or targeted population screening.
The principal primary prevention strategies are directed against cancers that have been associated with certain behaviors. They begin, first and foremost, with avoidance of tobacco. Tobacco use, either in the form of cigarette, pipe, or cigar smoking or the use of snuff or chewing tobacco, is strongly associated with carcinoma of the lung, larynx, pharynx, oral cavity, and esophagus. Tobacco also appears to be an important contributing factor in cancer of the pancreas, bladder, kidney, stomach, colon, and uterine cervix. In addition to its role in the etiology of cancer, tobacco also is associated with coronary heart disease, chronic lung disease, stroke, and other maladies. Tobacco is the single largest preventable cause of death in the Western world today.
In recent years, we have come to understand the role of excessive fat consumption and obesity in the etiology of cancer. Studies suggest a direct correlation between average dietary fat intake in various countries and the incidence of breast cancer. Classic studies have shown that the incidence of stomach cancer among the Japanese decreases when Japanese individuals migrate to Hawaii. Second-generation Japanese residents of Hawaii have an incidence of stomach cancer equivalent to that of the White population.297 Clearly, a more healthy diet could reduce the incidence of cancer.292
Excessive alcohol consumption also is associated with cancer. Alcohol consumption is particularly harmful among cigarette smokers. It appears that smoking acts as an initiator, producing injurious mutations, and alcohol acts as a promoter in cancer of the oral cavity, oropharynx, pharynx, larynx, and esophagus.
A variety of occupational exposures also are associated with specific cancers. These include cancer in asbestos miners and workers, various forms of cancer in workers in the chemical industry, cancers associated with pesticide exposure in agricultural workers, and radiation-associated cancers in uranium miners. An obvious preventive strategy is to minimize or eliminate such harmful exposures in the workplace.
In recent years, scientists have become increasingly aware of various genetic syndromes associated with the etiology of cancer. These include the multiple endocrine neoplasia syndromes and their association with medullary cancer of the thyroid, susceptibility genes that increase the risk of colon cancer, and the association of the BRCA1 and BRCA2 genes with carcinoma of the breast and ovary. For some of these genetic susceptibility traits, the best that the physician can offer is close follow-up. There are certain situations where the avoidance of a potentially lethal cancer may lead an individual to consider prophylactic surgery. For example, consider the problem of a woman who is treated for breast-conserving surgery followed by radiotherapy for breast cancer. She subsequently is found to have a deleterious mutation of BRCA1 or BRCA2. The patient has a risk of relapse in the treated breast, development of a tumor in the contralateral breast, and development of ovarian cancer. Is the patient best handled by close follow-up? Should bilateral mastectomies be offered?316 At present, the answer is unclear. In a study reported in 2002, investigators found that prophylactic salpingo-oophorectomy in women with BRCA1 and BRCA2 mutations significantly reduced their risk of not only ovarian cancer but also breast cancer.8,294 This effect, presumably, is the result of decreasing endogenous estrogen exposure in the setting of BRCA genes, rendering the breast susceptible to estrogen-induced DNA damage.54
An exciting development in cancer prevention is the successful clinical trial of a vaccine capable of reducing, by about 70%, the incidence of human papillomavirus (HPV)-associated cervical cancer. The U.S. Food and Drug Administration approved this vaccine for clinical use in summer 2006. This vaccine, along with the use of routine Pap testing, has the potential to make invasive cervical cancer an exceedingly rare event.
Cancer screening is the most frequently considered secondary preventive strategy. A cancer screening procedure should lead to the early detection of an asymptomatic or unrecognized disease by the application of simple, inexpensive tests or examinations in a targeted population. For cancer screening to be appropriate and successful, several criteria should be met. These include the following:
1. The cancer for which one is screening should have a substantial morbidity and/or mortality rate that warrants the screening procedure.
2. The cancer for which one is screening should have a sufficiently high prevalence in a detectable, preclinical state to warrant screening.
3. Once the cancer is detected by a screening procedure, there should be an effective treatment related to early detection. This criterion is quite important because there is little value in screening for an untreatable malignancy.
4. The screening test should have a high sensitivity and specificity.
5. The screening test should be of low cost such that the expense of screening a large population would be more than offset by the reduced cost to society of treating early rather than advanced malignancy.
6. Individuals screened should suffer little inconvenience and discomfort.
There is no perfect screening test. Those tests currently used generally meet most, but not all, of the aforementioned criteria.97,377
There are several examples of currently used screening tests. For breast cancer, these include self-examination, examination by a trained health practitioner, and mammography, augmented, when appropriate, by ultrasound and MRI. The value of these tests in various populations of women is currently highly disputed. In screening for colorectal cancer, the tools available to the clinician include testing for fecal occult blood, sigmoidoscopy, colonoscopy, and barium enema studies, and the developing field of virtual colonoscopy. There is a general consensus that screening for fecal occult blood and, in the appropriate aged population, screening colonoscopy are worthwhile. Among the most controversial areas for cancer screening is the role of screening in the detection of early prostate cancer. There was rapid general acceptance of the use of physical examination and prostate-specific antigen (PSA) testing to ascertain the presence of early prostate cancer. On further consideration, however, many investigators fear that we have, as a society, successfully identified large numbers of men who would never have been diagnosed with symptomatic prostate cancer in their remaining lifetime or required treatment. The appropriate role of screening for prostate cancer has generated as much controversy as the debate over mammography in breast cancer. A considerable amount of anxiety has been generated in asymptomatic men compulsively watching their PSA levels. By the fall of 2011, the U.S. oncology community was engaged in a very public debate over the recommendation of the U.S. Preventive Services Task Force to rescind a recommendation in favor of the widespread use of PSA for screening. The task force report, released in October 2011, advised that healthy men should no longer receive the PSA blood test to screen for prostate cancer because the test does not save lives overall and often leads to more tests and treatments that needlessly cause pain, impotence, and incontinence in many.
The draft recommendation was based on the results of five clinical trials and could substantially change the care given to men age 50 years and older. There are 44 million such men in the United States, and 33 million of them have already had a PSA test—sometimes without their knowledge—during routine physicals.
It is likely that, in the future, efforts will be expended to identify that subset of men with biologic markers suggesting that they might benefit from PSA screening and, if diagnosed, treatment compared to those who are “best left alone.”
Far less controversial, however, has been the use of the Pap test for early detection of carcinoma of the cervix. Where properly used, the test appears to have resulted in a decrease of mortality from this malignancy.
Cancer chemoprevention is defined as a pharmacologic intervention with specific nutrients or other chemicals intended to suppress or reverse carcinogenesis and to prevent the development of invasive cancer. Trials involving chemopreventive therapy require large numbers of individuals who are at high risk for malignancy because of family history, carcinogenic exposure, or the presence of a mutated gene. The ideal chemopreventive agent would have minimal side effects because it would be given to a considerable number of people, none of whom have cancer. Chemoprevention trials differ from other types of cancer prevention studies and from therapeutic studies in important ways. The participants are healthy volunteers, and one seeks to measure a reduction in morbidity and mortality in the long run. Chemoprevention trials are, by definition, large. There are strict enrollment criteria that reflect the group of interest. These studies are often long term and expensive. To date, the best-studied agents in human preventive trials are retinoids (the natural derivatives and synthetic analogs of vitamin A) and one member of the carotenoid class, β-carotene. A number of randomized cancer prevention trials involving carotenoids and retinoids have been completed. Some of these trials have reported chemopreventive effects for various retinoids and for β-carotene, particularly in oral premalignancy. Other trials have been negative or even have suggested cancer promotional effects by β-carotene.292
CLINICAL TRIALS
These studies have been classified as phase I (toxicity), phase II (dose/efficacy), and phase III (efficacy and toxicity of a new drug compared with an established standard). Randomized phase III clinical trials and meta-analyses are the two most accepted sources of scientific information in evidence-based medicine. These randomized clinical studies, with sometimes complicated treatment schemas, large numbers of patients, defined end points, and rigorous statistical testing, which are increasingly required by the U.S. Food and Drug Administration to document the efficacy and safety of new drugs (and, we would add, should be required for medical devices), are logistically difficult and expensive to conduct. Suit and others have suggested replacing them with trials in humanized experimental animals. RTOG has been a major contributor, along with any participating institutions, investigators, and associated staff, to clinical investigation centered on the application of ionizing radiations, alone or combined with surgery or cytotoxic agents, hormones, and so forth, to improve the management of patients with cancer.
It is the responsibility of practicing radiation oncologists in academic and community centers to be active contributors, with both scientific input and encouragement of their patients to participate in many of these trials.
RADIATION-INDUCED SECOND PRIMARY MALIGNANT TUMORS
Patients cured of cancer have a significant probability of developing other cancers. Many publications document the frequency of second malignant neoplasms, associated with radiation therapy, in cancer survivors.201 Several principles characterize radiation-induced cancers:
FIGURE 1.34. Dose–response curves for incidence of tumors in relation to dose and dose rate of high–linear energy transfer (LET) and low-LET irradiation. (From Upton AC. Biological aspects of radiation carcinogenesis. In: Boice JD, Fraumeni JF, eds. Radiation carcinogenesis: epidemiology and biological significance. New York: Raven, 1984:9.)
1. A wide variety of histologic types of cancers can be induced by radiation therapy. The current state of knowledge does not allow us to distinguish these tumors, morphologically, from “naturally” occurring cancers. In the future, it may be possible to identify specific genetic changes associated with radiation-induced malignancy. This future technology, termed molecular forensics, may, ultimately, affect our understanding of attributable risk of radiation-induced malignancies.20,51
2. The dose incidence curve for carcinogenesis generally rises more steeply with high-LET radiation doses than with low-LET doses, especially at low dose rates (Fig. 1.34).465 In a liver cancer model in mice, neutron irradiation produces a greater incidence of hepatomas than gamma irradiation.502 Low-LET radiation becomes less effective at carcinogenesis per cGy as the dose falls. High-LET radiation, however, does not.251
3. When one compares the frequency of second malignant neoplasms over time, it appears that orthovoltage radiation therapy is more likely to be carcinogenic than megavoltage therapy. This may be a dose-related phenomenon insofar as orthovoltage irradiation gives a higher dose to bone. It is also possible that the longer-term follow-up available for survivors of orthovoltage irradiation may, somewhat artifactually, lead to a higher reported incidence of tumors.210,292,362
4. The sensitivity of tissues to radiation-induced malignancies is not uniform. Current evidence indicates that the thyroid gland and the breast are sensitive to cancer induction at relatively low doses of radiation; lymphoid tissue, lung, and liver require moderate doses; and bone requires the highest dose. It also seems likely that the relationship between dose and response may vary according to the type of induced tumor. One can estimate the cancer risk from radiation either per unit dose measured in Gy or per unit dose equivalent measured in sievert. When one measures in sieverts, a quality factor (Q) is used to take account of the varying biologic effectiveness of the different forms of radiation. For example, for a conventional γ-ray or x-ray, Q = 1. For neutron irradiation, Q = 20. A review of the available literature indicates that the lifetime cancer mortality risk for a working population of both sexes is 0.008 per Sv for high doses and 0.004 per Sv for low doses.196 The cancer mortality risk for the general population after whole-body exposure is 0.0001 to 0.0004 per cGy per person.
5. One of the most puzzling aspects of radiation-induced cancer concerns the issue of the relation of low radiation dose to carcinogenesis. Most of the data we have concerns relatively high doses. Much of the public debate, however, concerns exposure to relatively low doses. Because we have few exact data regarding low doses, extrapolation is, for the most part, used to predict risk at low doses. This can be a particularly vexing problem in litigation where a plaintiff sues for an alleged radiation-induced malignancy following relatively low-dose exposure to radiation.
6. Any assessment of the radiation-dose–response curve for the production of second malignant neoplasms has to take into account the fact that neoplasms also can be induced by agents other than radiation. These include chemotherapy, environmental exposures, and hereditary disposition.
7. Because the risk of radiation-induced carcinogenesis is very small, a large denominator of radiated patients followed for a long period with thorough follow-up would be necessary to calculate risk with any reliability.
8. Latent periods for the production of radiation-induced tumor vary according to the type of induced tumor. One type of latency is exemplified by the risk of leukemia in survivors of the atomic bomb. This consisted of an early pulse of increased risk followed by a gradual decline to baseline levels. The second pattern of occurrence, more typical of solid tumors, is an increase in the relative risk of second malignant neoplasms over many years that remains constant over time thereafter. It is important to remember, therefore, that the duration of follow-up for any study population is very likely to influence the frequency of tumors seen.
9. Age is a critical factor in determining radiation risk. In children, second cancers would be more likely to occur in tissues undergoing rapid proliferation such as bone and thyroid tissue.
There are several classically cited episodes of human radiation carcinogenesis. These include:
1. Individuals who are treated with radiation for ankylosing spondylitis suffered from an increase in leukemia. Mortality from colon cancer, which is associated with spondylitis through a common association with ulcerative colitis, was increased in irradiated patients. Mortality for patients with cancers other than leukemia or colon cancer also rose.105
2. Diagnostic x-rays of the abdomen and pelvis taken of a pregnant woman to ascertain the size of the pelvic outlet before delivery are associated with an increased risk of malignancy in the offspring.
3. A large number of immigrants entered the State of Israel following its founding in 1948. X-ray epilation was used to treat tinea capitis. There was an increased incidence of brain and nervous system tumors (1.8 excess risk per 10,000 persons per year) in 10,834 children irradiated for tinea capitis compared with the same number of nonirradiated matched controls and 5,392 siblings. There were 12 malignant brain tumors in the irradiated patients versus five and one suspected in nonirradiated people. The average dose received was 4 Gy in 5 consecutive days. Irradiation doses of 1 to 2 Gy significantly increased the risk of neurologic tumors.382
4. The United States dropped atomic bombs on Hiroshima and Nagasaki in Japan in August 1945. Radiation-related risks among bomb survivors show that the incidence of leukemia rose. The increased risk appeared 1 to 3 years after the bombing and peaked at 6 to 7 years. In solid tumors, excess tumor risk was manifest only after exposed individuals reached the age at which the cancer was normally prone to develop.
5. Uranium miners suffered an increase of lung cancer as a result of inhalation of radon gas. Workers who painted luminous radium dials on watch faces developed bone sarcomas because of the habit of shaping the paintbrush in the mouth and ingesting bone-seeking radium.170
6. In the past, thorotrast was used as a contrast medium in diagnostic radiology. This material is a colloidal suspension of the α-emitter thorium dioxide. The compound was associated with the late development of angiosarcoma.
7. Canadian studies of women with tuberculosis who were fluoroscoped repeatedly for monitoring of an induced pneumothorax demonstrated an increased incidence of breast cancer.
8. The Chernobyl Nuclear Power Plant accident of April 26, 1986, appears to be associated with an increased risk of thyroid cancer in Belarus and Ukraine.
An important review of radiation-induced sarcomas was published by Cahan et al.71 in 1948. Cahan’s criteria, which were used to define a radiation-induced sarcoma, have wide applicability and are used, by some investigators, as the standard for demonstration of any alleged radiation-induced malignancy. The Cahan Criteria,71 modified from his original definition, are:
a. A radiation-induced malignancy must have arisen in an irradiated field.
b. A sufficient latent period, preferably longer than 4 years, must have elapsed between the initial irradiation and the alleged induced malignancy.
c. The treated tumor must have been biopsied. The alleged induced tumor must have been biopsied. The two tumors must be of different histologies.
d. The tissue in which the alleged induced tumor arose must have been normal (i.e., metabolically and genetically normal) prior to radiation exposure.
QUALITY AND SAFETY
Quality and safety have always been important topics in the radiotherapy community. The issue of patient safety for radiation therapy and diagnostic imaging has been pulled to the forefront by reports in the lay press and associated congressional hearings. A number of misadministrations described in a series of New York Times articles triggered increased interest in improved patient safety in radiation oncology.49,50 These articles have highlighted some of the risks inherent to advanced radiation therapy treatment-planning and delivery systems and techniques. Many new patient safety initiatives, meetings, and other efforts have been organized to address the need to continue to enhance the safety of patients undergoing radiation therapy.
As part of this effort, the American Society for Radiation Oncology (ASTRO) commissioned a series of “Safety White Papers” to help identify areas where improvements are necessary, so that patient safety is continually enhanced.14 The white papers have been written by small interdisciplinary teams, reviewed by groups of experts, and subjected to a public comment period. The first paper in this series, “Safety Considerations for Intensity Modulated Radiation Therapy: Executive Summary,” by Moran et al.,310 addressed safety and quality issues for IMRT. Other white papers to follow address stereotactic body radiation therapy, high–dose-rate brachytherapy, IGRT, and peer review in radiation oncology. It is planned that additional reports and updates will continue to follow as radiation therapy techniques and devices evolve. Safety issues for any of these complex technologies cannot be summarized briefly. Thus, the goals of the white papers are as follows: (a) to provide an overview of issues that should be addressed within a broad safety program for these kinds of treatments (e.g., IMRT) and (b) to make recommendations to the radiation oncology community that identify issues that require new approaches, new guidance, or other modifications of current safety and quality assurance methods. The intended audience is radiation oncology professionals, including radiation oncologists, physicists, therapists, dosimetrists, nurses, radiation oncology administrators, and vendors.
Safety and quality are different but related concepts. Safety generally relates to preventing errors that can have major therapeutic implications (e.g., treatment of the wrong patient, treatment with the wrong plan, incorrect placement of a block or wedge, failure to correctly transfer electronic data between the various computer systems). In contrast, quality often relates more to somewhat subjective issues such as ensuring that the defined volumes, doses, beams, and so forth are clinically appropriate, and that the treatment is delivered as prescribed within acceptable clinical tolerance limits. To reconcile these concepts, in May of 2011, ASTRO sponsored the Intersociety Council to review and update previously published guidelines concerning the role of radiation oncology in integrated cancer management. In this updated document, entitled “Safety Is No Accident,” every facet of patient evaluation, treatment planning, and treatment delivery were described with the specific goal of maximizing patient safety.231 The process of care, the roles and responsibilities of staff, staff training and maintenance of competency, requirements for facilities and equipment, and the management of quality assurance were formally recognized as inextricably linked to the provision of safe, efficient, and effective radiation therapy. These ASTRO initiatives have involved cooperation with other organizations, including the American Association of Physicists in Medicine (AAPM), the American Brachytherapy Society, the American College of Radiology (ACR), the American College of Radiation Oncology, the American Board of Radiology, the American Society of Radiation Technologists, and the Society of Radiation Oncology Administrators.
Modern radiation therapy is complex and rapidly evolving. The safe delivery of radiation therapy requires the concerted and coordinated efforts of many individuals with varied responsibilities. Thus, all team members need to work together to create a safe, high-quality, and efficient clinical environment and workflow.
THE PROCESS OF CARE IN RADIATION ONCOLOGY
The “process of care” in radiation oncology refers to a conceptual framework for ensuring the appropriateness, quality, and safety of all patients treated with radiation for therapy. Each of the aspects of the process of care in radiation oncology requires knowledge and training in the natural history of cancer and certain benign diseases, radiobiology, medical physics, and radiation safety that can only be achieved by board certification in radiation oncology (or equivalent training) to synthesize and integrate the necessary knowledge base to safely and completely deliver care. This high level of training and board certification apply as a recommendation for all of the specialists on the radiation oncology team. The medical therapeutic application of ionizing radiation is irreversible, may cause significant morbidity, and is potentially lethal. Use of ionizing radiation in medical treatment, therefore, requires direct or personal physician management, as the leader of the radiation oncology team, as well as input from various other essential coworkers.
The radiation oncology process of care can be separated into five categories:
• Patient evaluation
• Preparing for treatment
• Therapeutic simulation
• Treatment planning
• Pretreatment quality assurance (QA) and plan verification
• Radiation treatment delivery
• Radiation treatment management
• Follow-up care management
A course of radiation therapy is composed of a series of distinct activities of varying complexity and is a function of the individual patient situation. All components of care involve intense cognitive medical evaluation, interpretation, management, and decision making by the radiation oncologist and other members of the clinical team. Each time a procedure is approved and reported, its level of effort/complexity should be appropriately documented in the patient record.
The clinical team, led by the radiation oncologist, provides the medical services associated with the process of care. Other team members involved in the patient’s planning and treatment regimen include the medical physicist, dosimetrist, radiation therapist, and nursing staff. Many of the procedures within each phase of care will be carried to completion before the patient’s care is taken to the next phase. Others will occur and recur during the course of treatment, and they are by necessity repeated during treatment due to patient tolerance, changes in tumor size, need for boost fields or port size changes, or protection of normal tissue, or as required by other clinical circumstances (i.e., certain procedures may need to occur multiple times during the treatment course). Each phase of care involves medical evaluation, interpretation, management, and decision making by the radiation oncologist as well as other team members.
Patient Evaluation
Patient evaluation is a service provided by a physician at the request of another physician, the patient, or an appropriate source to either recommend care for a specific condition or problem or to determine whether to accept responsibility for ongoing management of the patient’s entire care or for the care of a specific condition or problem. The physician as part of this process will review the pertinent radiologic and pathologic studies, the patient’s complaints, and physical findings. This initial visit can also be used for patient counseling, coordinating care, and making recommendations about other aspects of oncologic management or staging.
Preparing for Treatment
The selection of a comfortable and appropriate patient position for treatment is an important part of the simulation processes. The selected position should consider the location of the target and anticipated orientation of the treatment beams. Appropriate immobilization devices provide comfort, support, and reproducibility. Immobilization of the patient in a comfortable position for treatment might involve the construction or selection of certain treatment devices for helping the patient remain in position during treatment. This step must consider the potential treatment-planning considerations so that the treatment aids do not restrict the treatment techniques.
Simulation is the process of determining critical information about the patient’s geometry, to permit safe and reproducible treatments on a megavoltage machine. Simulation for external-beam radiation treatment is always image based. Most simulation procedures have now shifted away from the direct use of the treatment beam to using x-rays in the diagnostic range of energies. In general, this part of the overall process of care determines the relationship between the position of the target or targets and the surrounding critical structures. When a simulator of conventional design is used that mimics the geometry of the treatment unit or when direct simulation is performed on the treatment machine, this relationship is often determined indirectly through observation of skeletal anatomy that can act as a surrogate for the target position. Modern conventional simulators, like the CT simulator, can include the ability to produce volumetric data in addition to 2D images.
The preparation for external-beam treatment can also depend on other imaging modalities that are directly or indirectly introduced in the simulation process. MRI, ultrasound, and/or PET are now available, and treatment-planning systems that include image registration capabilities allow combining of information from other imaging modalities with the standard CT dataset obtained during simulation in appropriate situations. It is now possible to produce image datasets that quantify the motion of structures and targets due to respiration, cardiac motion, and physiologic changes in the body.
For most brachytherapy, treatment preparation is similar to the procedure described earlier for EBRT. The simulation process is also image based. Multiple imaging modalities may be important for some brachytherapy procedures, and these studies can be obtained as part of the preplanning imaging process. For clinical situations where therapy is delivered by unencapsulated radionuclides, a separate and distinct treatment-planning process is necessary due to its multidisciplinary execution.2
Clinical treatment planning is a comprehensive, cognitive team effort performed under the direction of the radiation oncologist for each patient undergoing radiation treatment. The radiation oncologist is responsible for understanding the natural history of the patient’s disease, knowing the extent of the disease relative to the adjacent normal anatomic structure, and integrating the patient’s overall medical condition and associated comorbidities. A detailed understanding of the integration of chemotherapeutic and surgical treatment modalities with radiation therapy is also essential.
The skills of the trained and appropriately credentialed dosimetrist relate to the efficient and effective use of the complex treatment-planning system hardware and software. This individual must also understand the clinical aspects of radiation oncology in order to interact with the radiation oncologist during the planning process. The role of the medical physicist is to guarantee proper functioning of the hardware and software used for the planning process, consult with the radiation oncologist and dosimetrist, check the accuracy of the selected treatment plan, and perform measurements and other checks aimed at ensuring accurate delivery of the plan.
For either EBRT or brachytherapy, treatment planning starts with a complete, formally documented, and approved directive. Details including total dose to all targets and organs at risk (OARs), fractionation, treatment modality, energy, time constraints, and all other aspects of the radiation prescription in a written or electronic format must be provided by the radiation oncologist prior to the start of treatment planning. In some cases, this prescription can require modification based on the results of the treatment-planning process.
Clinical treatment planning for either EBRT or brachytherapy is an important step in preparing for radiation oncology treatment. This planning includes the following components: determining the disease-bearing areas based on the imaging studies and pathology information, identifying the type (brachytherapy, photon beam, particle beam, other) and method of radiation treatment delivery, specifying areas to be treated, and specifying the dose and dose fractionation. In developing the clinical treatment plan, the radiation oncologist may use information obtained from the patient’s clinical evaluation as well as any additional tests, studies, and procedures that are necessary to complete treatment planning. Studies ordered as part of clinical treatment planning may or may not be associated with studies necessary for staging the cancer and may be needed to obtain specific information to accomplish the clinical treatment plan. Review of imaging studies and lab tests must be performed to determine treatment volume and critical structures in close proximity to the treatment area.
At various steps in the treatment-planning process, the radiation oncologist is presented with one or more treatment plans for review and selection. This process is often iterative and requires additional treatment planning. The radiation oncologist is responsible for selecting and formally approving the plan to be used for treatment.
The quality assurance steps taken after completion of treatment planning and before the start of treatment are critical for guaranteeing patient safety. In the past, treatment verification consisted of field aperture imaging using radiographic film. These images are referred to as portal images or port films. With the introduction of IMRT, imaging of individual apertures is no longer practical. However, the traditional method of verifying the plan isocenter position using orthogonal imaging is often used for both 3DCRT and IMRT. For IMRT, this important QA technique is not considered to be sufficient to guarantee patient safety. In addition to this isocenter check procedure, for IMRT and other complex delivery techniques that use inverse treatment planning, patient-specific QA measurements are also required. In terms of clearly organizing the different steps in the process of care for radiation oncology, a blurring of the separation between the verification and treatment delivery occurs on the first day of treatment and whenever the treatment plan is changed.
Radiation Treatment Delivery
The physician is responsible for verification and documentation of the accuracy of treatment delivery as related to the initial treatment-planning and setup procedure. Image guidance (IGRT) may be performed to ensure accurate targeting of precise radiation beams. IGRT requires a target that is expected to move from day to day and can be reliably identified by the selected imaging modality. The physician is responsible for the supervision and review of these images and prescribing necessary positional shifts to ensure the therapy delivered conforms to the originally planned dosimetric constraints. Similarly, management of organ motion during treatment delivery is the responsibility of the treating physician.
Radiation Treatment Management
Radiation treatment management encompasses the radiation oncologist’s overall management of the course of treatment and care for the patient as well as checks and approvals provided by other members of the radiation therapy team that are necessary at various points in the process. For the radiation oncologist, radiation treatment management requires and includes a minimum of one examination of the patient for medical evaluation and management. The professional services furnished during treatment management typically include:
• Review of portal images;
• Review of dosimetry, dose delivery, and treatment parameters;
• Review of patient treatment setup; and
• Patient evaluation visit.
Not all of these elements of treatment management are required for all patients for each week of management (except for the patient evaluation visit) because the clinical course of care may differ due to variation in treatment modality and individual patient requirements. Examinations and evaluations may be required more often than once weekly.
Follow-Up Care
Continued follow-up care of patients who have completed radiation therapy is necessary to manage acute and chronic morbidity resulting from treatment as well as to monitor the patient for tumor recurrence.
THE RADIATION ONCOLOGY TEAM
The radiation oncology team ensures every patient undergoing radiation treatment receives the appropriate level of medical, emotional, and psychological care before, during, and after treatment, through a collaborative multidisciplinary approach.
The radiation oncology team consists of but is not limited to radiation oncologists, physicists, dosimetrists, oncology nurses, and radiation therapists. The process of care in radiation oncology involves close collaboration of a team of qualified professionals. On-site or by consultation services can be provided by nonphysician providers, including nurse practitioners, clinical nurse specialists, advanced practice nurses and physician assistants, dentists, clinical social workers, psychologists/psychiatrists, nutritionists, speech/swallowing therapists, physical therapists, occupational therapists, genetic counselors, integrative medicine specialists, and pastoral care providers.
Board certification is the primary consideration for establishing proper qualifications and training for any professional working in radiation oncology. The relevant professional societies will establish the eligibility requirements to sit for a board exam. This may include education and training requirements such as a clinical residency. In addition, in some jurisdictions, professionals must meet requirements for obtaining appropriate licensure.
The applications, technologies, and methods of radiation oncology continue to expand and develop. Lifelong learning is vital to ensure incorporation of new knowledge into clinical practice. Therefore, each member of the interdisciplinary radiation oncology team should participate in available Continuing Education (CE) and Maintenance of Certification (MOC) programs. Each facility should have a policy regarding orientation, competency, credentialing, and periodic competency evaluations of all team members.
TABLE 1.14 STAFFING LEVELS FOR RADIATION ONCOLOGIST, MEDICAL PHYSICIST, DOSIMETRIST, AND RADIATION THERAPY TECHNOLOGIST
FIGURE 1.35. The theoretical relation between the cost per patient and rate of use of a linear accelerator for cancer therapy. As the rate of use of a linear accelerator increases, the average cost (AC) of treatment per patient declines until all economies of scale have been achieved (point B). The average cost of a radiotherapy treatment will fall as long as any additional patients can be treated at a marginal cost (MC) lower than the AC. It is important to remember that point B represents only the minimized cost of operating the linear accelerator. If you add in costs such as the travel time for a patient to go a considerable distance to reach the linear accelerator, the lost time from work for the patient and anyone traveling with him or her, child care costs, and stress, then the total societal expenditure for a linear accelerator will not be minimized at point B. It will, instead, be reached at point A. We are, however, quite poor at accounting for costs such as travel, loss of work time, and stress, so it is difficult to determine point B and, in turn, the need for a new linear accelerator. If you wish to persuade a government regulatory agency to grant a certificate of need for a piece of radiotherapy equipment at a moderate distance from an existing facility, then you will have an economic incentive to inflate the importance of travel and inconvenience. In the United States, this behavior is increasing as institutions try to justify the need for linear accelerators, radiosurgery, and proton therapy units. The corporations that manufacture and market these units have a vested interest in contributing to this exaggeration of need. (Modified from Suit HD, Urie M. Proton beams in radiation therapy. J Natl Cancer Inst 1992;84:155–164.)
Staffing Requirements
Starting in 1986, the Intersociety Council for Radiation Oncology published a set of guidelines in a small pamphlet titled “Radiation Oncology in Integrated Cancer Management,” often referred to as the “Blue Book.”230 This subsequently has been updated several times, most recently in May of 2011. The document offers guidelines for staffing requirements and equipment utilization. The staffing needs of each facility are unique based on the patient mix and complexity of the services offered. The patient load, number of machines, and satellite clinics and affiliated treatment centers will influence the demand on management and clinical staff (Figs. 1.35 and 1.36) The minimum personnel requirements for a radiation oncology facility specify the need for one medical director (radiation oncologist), chief medical physicist, and department manager per program.231 Table 1.14 presents an estimate of the maximum number of patients treated per FTE per year.
MANAGEMENT AND QUALITY ASSURANCE IN RADIATION ONCOLOGY
Quality assurance in radiation oncology is a set of processes and procedures designed to improve the practice of radiation therapy by confirming that radiation therapy will be or was administered appropriately and safely and documented properly. The overall goal of a QA process is the delivery of high-quality radiation oncology treatment to all patients. Note that QA is an all-encompassing term that is often used to describe some or all of the different elements involved in quality management and a culture of safety.
A radiation oncology facility must satisfy numerous requirements:231
• A department must provide adequate clinic space, exam rooms and equipment, patient waiting and changing space, convenient patient parking, treatment rooms, simulation and imaging space, brachytherapy source preparation and storage space, dosimetry/treatment-planning rooms, office space for professional staff, and medical physics laboratory and equipment storage space. The extent of facilities should be appropriate for the volume of patients seen and treated.
• Treatment rooms (for linear accelerators or other treatment machines) must be carefully designed for radiation shielding, environmental conditions, adequate storage space for spare parts, testing and dosimetry equipment, and patient access and safety.
• There must be access to CT imaging for treatment planning.
• Rooms used for brachytherapy procedures require special attention to the specific radiation protection requirements associated with the particular brachytherapy modalities to be used. If the brachytherapy procedure load warrants it, a brachytherapy suite should be available, including patient waiting space, procedure rooms, recovery rooms, and brachytherapy source preparation and storage areas.
• Each department must have electronic access to the hospital or clinic information system and picture archiving and communication system (PACS).
Every radiation oncology program should be accredited by the ASTRO/ACR accreditation process.231 Accreditation will verify that crucial basic capabilities and procedures are performed that are generally recognized as necessary for high-quality radiotherapy. The following specific capabilities and methods for various aspects of the radiotherapy process are considered essential:231
• Calibration of treatment machines, CT and MRI scanners, treatment-planning systems, and brachytherapy sources is to be carefully accomplished according to the appropriate protocols described by scientific/professional organizations.
• A safety program designed to monitor patient safety, avoid radiation incidents, and prevent errors in the treatment process should be in place and subject to periodic review and update.
• A system for documenting radiotherapy treatment and other aspects of the patient’s medical care should be rigorous and be subject to periodic review and update.
• High-quality and comprehensive treatment planning, using 3D computerized treatment planning for dose calculations, imaging, and other aspects of the planning process.
• A comprehensive quality management program, including QA, quality control (QC), and other quality improvement tools.
• Radiation monitoring of simulators and treatment machines. A system to carefully control and monitor all radioactive sources in accordance with the requirements of regulatory agencies.
• A program for maintenance and repair of equipment.
• Staff training that is comprehensive, ongoing, and well documented.
• A well-developed process for continuous peer review. This should include a mechanism for peer review of the entire department and its procedures as well as for individual clinical care decisions.
• Access to medical oncology, surgical oncology, and other physician and nonphysician specialists involved in the multidisciplinary care and follow-up of the patient.
• Each department must implement careful and well-described policies and procedures for every aspect of patient care, for QA of the patient care process, for staff behavior, and for any issues that may impact the safety of patients and/or staff. Each specific treatment modality (e.g., IMRT, IGRT, stereotactic body radiation therapy [SBRT], etc.) should have detailed documentation of its treatment planning and delivery process including a description of the roles and responsibilities of each team member in that procedure, QA checklists, and a plan for continuous quality improvement and safety.
One of the most crucial activities in a quality radiation oncology department is the organized review and monitoring of all aspects of safety, errors, and outcome. Creating a “culture of safety” depends on guidance, direction, and financial support from the leadership of the institution and of the radiotherapy department, on individual effort by every member of the department, and on organized support for quality and safety at every level in the institution.
Each department should have a department-wide review committee that monitors specific quality metrics including near misses and errors in treatment, diagnosis, patient care, or other procedural problems that might lead to errors. This committee should organize the collection and analysis of such events, work to identify potential problems in devices or processes, and then try to mitigate these problems by modifying processes or adding new checks or actions to minimize the likelihood of further problems. Radiation oncology departments should hold regularly scheduled rounds to review patient morbidity and mortality, dose discrepancies, and any incident reports that involved an accident or injury to a patient. Morbidity and mortality include unusual or severe complications of treatment, unexpected deaths, or unplanned interruptions of treatment. Staff included should represent all the team members, including radiation oncologists, nurses, physicists, dosimetrists, therapists, and administrators.
FIGURE 1.36. The number of people served by each radiation therapy center by country. (From Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. Based on data from the International Atomic Energy Agency, Directory of Radiotherapy Centers, http://www-nawebiaea.org/nuhu/dirac/; Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat, World Population Prospects: The 2008 Revision, http://esa.un.org/unpp.)
Professional Performance Review of Radiation Oncologists and Physicists
Over the past several years, there has been increasing interest on the part of the general public and government agencies in requirements for greater oversight for physicians and other health care providers. In response to these concerns, the American Board of Medical Specialties has mandated that all medical specialties must develop MOC programs to replace current recertification initiatives. The American Board of Medical Specialties has defined four components of MOC: professional standing, lifelong learning and self-assessment, cognitive expertise, and practice quality improvement (PQI).11
ASTRO and AAPM offer several opportunities for radiation oncologists and physicists to satisfy the requirements of MOC. ASTRO and other professional organizations have developed online courses with self-assessment modules (SAMs) to satisfy the lifelong learning requirements and a special program called the Performance Assessment for the Advancement of Radiation Oncology Treatment (PAAROT)14 to satisfy the PQI requirements. AAPM offers similar initiatives for medical physicists.
One important aspect of these programs is the use of peer review to help individuals learn from other practitioners in the field. Peer review is relevant in a number of different aspects of clinical practice including overall review of the behavior of the practice, review of individual skills and methods, and review of physician clinical decisions that occur at weekly chart rounds. Peer review is a quality improvement tool that has application throughout the process of radiotherapy.245
Radiation oncology is a highly technical field that is dependent on many well-trained and highly skilled individuals. It is, therefore, advisable that all members of the team maintain the proper credentials as reflected in their skills and training through demonstrated competency on an annual basis. In some cases (e.g., therapists moving between different kinds of treatment machines), additional training or review sessions in the use of specific devices may be necessary more often than annually.311
Equipment and Device Quality Management
The delivery of radiation therapy relies on computer-controlled treatment machines, interconnected imaging, delivery and planning systems, and complex ancillary devices. Any new radiotherapy system should go through the following processes as it is prepared for clinical use:1–4
• Each system should be carefully specified before acquisition, purchase, or development, including design, expectations, capabilities, tolerances, hazards, necessary training, usability, and technical specifications.
• To prevent data communication errors and clinical efficiency issues, each system must be interoperable and connectable with other systems in the clinic.
• Acceptance testing must be performed to document that the new system satisfies the specifications. Often, the acceptance criteria and/or testing methods should be documented as part of the specification for the system.
• Clinical commissioning includes all the activities that must be performed to understand, document, characterize, and prove that a given system is ready to be used clinically. Standard operating procedures, training, and hazard analysis should be part of the commissioning process.
• Each new system, device, and process must be formally released for clinical use after clinical commissioning has been completed.
Clinical use of a device, system, or process must involve the creation and application of a safety- and quality-oriented program designed to ensure that the machine or device is functioning in accordance with accepted standards:1–4
• Quality management (QM) is defined as the overall program to organize the oversight of the use of any system or process in radiation oncology. The QM program should include hazard analysis, quality control, quality assurance, training and documentation, and ongoing quality improvement efforts.
• Hazard analysis is the active evaluation of the potential for failures that will cause incorrect results or harm to the patient and should be performed for any new system.
• QC checks on the data that are input into a decision or process and is designed to prevent the propagation of error.
• QA is the typical shorthand term for the entire QM program and addresses quality checks that confirm that a given process is reasonable and generates appropriate results. QA checks, along with QC, are essential parts of the QM process for most devices and systems, as they can check the output of potentially very complicated decisions or actions performed by the system.
• Training of staff in goals, methods, results, operation, and evaluation of the quality of the output is important for the proper use of any system.
Patient-Related Quality Management
Within the complex and many-step process with which radiotherapy patients are treated, patient-specific issues must be carefully and comprehensively analyzed, documented and verified. Each radiation oncology facility, regardless of its location or size, must appropriately manage and adhere to high-quality standards of practice for general medical issues,6 including:
• Drug allergies;
• Medication reconciliation;
• Do-not-resuscitate codes;
• Cleanliness and efforts to reduce infection; and
• Patient confidentiality and security of protected health information.
Modern oncology patient care very often involves multiple modalities and requires the review and discussion of experts in various oncology-related disciplines. It is critical that the management of most cancer be addressed by the appropriate mix of disciplines. Regular presentation of these cases to a multidisciplinary tumor board is the standard of care and should be performed for most cancer cases to determine the appropriate combination (and coordination) of therapies for each individual case.
The details of the patient care process in radiation oncology varies from institution to institution. However, maintenance of the safety and quality of the radiotherapy process for most patients requires that a number of procedures be performed.231 These include:
• A new patient conference that consists of a brief presentation of the details of each patient’s history and physical examination, disease status, and plan for therapy to the other physicians and staff involved in patient care is used as an initial peer review for the basic treatment decisions and plan.
• The physician must obtain a clear, accurate, and detailed description of the patient’s chief complaint and pertinent history in conjunction with an appropriate physical examination as part of the decision process for radiation therapy.
• Virtually all patients who receive radiation therapy should receive a CT- or MRI-based simulation.
• After the physician defines target volumes and other normal tissues (contouring), this should be peer reviewed and confirmed before treatment planning begins.
• After treatment planning is complete, the physician and members of the planning team should review the plan and verify that it satisfies the clinical requirements and prescription(s) from the physician and that it can be carried out accurately.
• On-treatment visits of the patient by the physician are essential for continuity of care and monitoring of tumor response and normal tissue toxicity. Typically, this occurs every five fractions, but some situations may require more frequent visits.
• Patient chart rounds are an important peer review procedure used involving weekly review of all patients under treatment by the radiotherapy team, including physicians, therapists, nurses, dosimetrists, and physicists.
• Follow-up visits are a critical component of care for the radiotherapy patient. The frequency of follow-up visits will vary in accordance with the type of cancer, stage, degree of tumor response, normal tissue reactions, and other factors.
• Documentation is required of all the relevant details of patient care. Maintenance and continuous improvement of the quality and accessibility of the treatment record are essential.
The overall performance status of the patient prior to treatment should be recorded. Assessment of tumor response and normal tissue toxicity should occur both during and after treatment. Clinical assessment of patient response is a valuable independent check on the success of the overall quality management system as unexpected outcomes may identify issues related to technique or equipment performance.
External-Beam Quality Assurance
Nearly all external-beam treatment requires the following steps, each of which must be carefully confirmed as part of the patient-specific QA process: determination of patient setup position and immobilization; cross-sectional imaging (CT simulation); creation of the anatomic model (contouring); specification of the treatment intent; creation of the planning directive and treatment prescription by the physician; computerized treatment planning and dose calculation; monitor unit calculation and/or IMRT leaf sequencing; plan and (electronic chart) preparation; plan evaluation; download to treatment management system (TMS); patient-specific QA as typically performed for IMRT, stereotactic radiosurgery [SRS], or SBRT; patient setup and delivery; plan verification checks; plan adaptation and modifications; chart checks; and more. The details associated with these processes have been described in a series of guideline reports.3,4,208,317
Brachytherapy Quality Assurance
The QA process for brachytherapy is similar to that of external beam and involves several components that must be confirmed as part of the patient-specific QA management: treatment planning; treatment delivery systems; applicator commissioning and periodic checks; cross-sectional imaging (CT simulation); specification of the treatment intent, planning directive, and treatment prescription by the physician; plan preparation; plan evaluation; download to TMS; plan verification checks; plan modifications; and chart checks. The details of these processes have been described in a series of guideline reports.145,317,318,447,477,478,524
LEGAL PRINCIPLES CONCERNING MALPRACTICE IN RADIATION ONCOLOGY
A plaintiff initiates a radiation oncology malpractice lawsuit by filing papers with the court claiming that he or she was harmed by the radiation oncologist and is entitled to legal redress. The claim of malpractice must be set out in the plaintiff’s prima facie case. This will include a statement of the facts and legal theories that establish that the plaintiff believes he or she is legally entitled to enforceable claims against the physician.
There are four essential elements to a prima facie case of medical malpractice. They are the establishment of duty, breach, causation, and damages. To demonstrate medical malpractice, a plaintiff–patient must show that the radiation oncologist had a duty to provide nonnegligent care to the patient, that the provider breached that duty by providing negligent care, and that this breech caused the patient injury or damage.376
To establish a duty, the plaintiff must have facts that demonstrate a legal relationship between the radiation oncologist and the patient. It is a basic rule of Anglo-American law that there is no duty to another person unless there is a legally recognized relationship with that person. The plaintiff–patient must demonstrate the existence of a physician–patient relationship.376
To establish a breach, the patient–plaintiff must demonstrate facts that illustrate the radiation oncologist breached the legal duties implied in the physician–patient relationship or duties that would be generally imposed on members of society. The plaintiff must establish that the appropriate standard of care was violated. Although, in theory, the establishment of the standard of care and the breach of that standard are legally separate, in reality, unless there is a factual question about what the radiation oncologist actually did, the proof of the standard of care also would demonstrate the defendant’s breach. Most commonly, in law, the definition of standard of care is how similarly qualified radiation oncologists would have managed the patient’s care under the same or similar circumstances. In most medical malpractice cases, both the standard of care and the breach are established through the testimony of expert witnesses.269
Negligence is defined as “the omission to do something which a reasonable man guided by those ordinary considerations which ordinarily regulate human affairs would do, or the doing of something which a reasonable and prudent man would not do.” The person who brings a malpractice claim is asserting that he or she is owed some duty by the defendant physician and that the violation of that duty by the physician must have caused injury. The court will make a determination concerning the propriety or impropriety of the defendant physician’s performance on the basis of “the reasonable man” had he or she been in the same situation as the individual being judged. Negligence may derive from the physician’s lack of training or experience. It may also result from the physician’s carelessness or inadvertence.48
To understand the concept of an expert witness, we must consider the legal doctrines of the school of practice, the locality rule, and the concept of the qualifications of an expert. The legal doctrine of the school of practice is designed to deal with the historic problem of the competing interests of physicians. Physicians generally do not want to testify against their colleagues, but they often are tempted to try to run their competitors out of business. Allopathic physicians were happy to label homeopathic physicians as quacks, and many medical doctors would be happy to dispute the competence of a chiropractor. To deal with the problem, the courts use the legal doctrine of the school of practice in which they refuse to allow physician experts to question a different school based on philosophic or psychologic beliefs.376 The school of practice rule now generally is used to differentiate physicians in the self-designated specialties (we use the term self-designated because few state licensing boards recognize specialties or limit physicians’ rights to practice the specialties in which they have been trained).
The locality rule refers to the concept that a physician’s competence should be determined by comparison with other physicians in the community or in similar neighboring communities.376 However, with the development of national standards for the practice of radiation oncology, there is no justification for rules that shelter substandard medical decision making by using an excuse that it is the norm for a given community. A radiation oncologist, for example, could not be held at fault for failing to treat a patient with an unusual or exotic technology if that technology were not available in his or her local community. However, physicians are required to inform the patients of the limitations of the available facilities and recommend prompt transfer if indicated. Failure to refer patients when a provider lacks the experience to appropriately treat may create malpractice liability. Furthermore, if a radiation oncologist does not give a patient information about the potential result associated with not seeing a subspecialist able to use a specific technology, then the initial radiation oncologist may be held liable. Physicians must recognize when a particular medical problem is beyond their capacity for diagnosis or treatment. They are responsible for obtaining timely and adequate consultations when indicated and for referring the patient to an appropriate specialist or facility whenever the requirements for the appropriate or specialized care cannot be satisfied at the available facilities. The continued expansion of knowledge in radiation oncology and the increasingly specialized training of physicians make it essential that the radiation oncologist be able to recognize any limitations in his or her capabilities or ability to treat a given patient with what is perceived to be standard of care. Failure to obtain an appropriate consultation or make an appropriate referral may denote negligence.17,18,261
Qualified experts sometimes disagree as to the standard of care. When alternative schools of thought exist, the physician defendant is entitled to be judged by the tenants of the school he or she follows. In such states, this is called the minority practice doctrine. With this doctrine, also called the respectable minority rule, the physician may show that although the course of therapy followed was not the same as other practitioners would have followed, it was one that was accepted by a respectable minority group of practitioners.376
A problem that is increasingly facing physicians in the United States has been the pressure radiation oncologists face from health maintenance organizations (HMOs) and insurance companies to conform their proposed care to a predetermined regimen. Despite legislative initiatives to hold managed care organizations accountable, the radiation oncologist will, for the most part, carry a significant portion of the risk of liability in cases where the patient asserts that he or she was unable to obtain the most accurate and appropriate diagnostic and therapeutic measures. It is essential that the radiation oncologist come to his or her own conclusions about the standard of care irrespective of any pressures applied by an HMO or an insurance company. In litigation, the radiation oncologist’s best defense against a claim of malpractice is if he or she can demonstrate action only in the interest of the patient, regardless of any financial consideration or bureaucratic restraint imposed by an insurance company, an HMO, or any other financial consideration. If a conflict arises between the radiation oncologist’s recommendations for the best course of treatment and the level of care authorized by the HMO, the physician must give the best care to the patient even if it means he or she will not ultimately be compensated.225
Radiation oncologists will, on occasion, be called on to serve as expert witnesses in malpractice cases. Physicians, trained to give opinions, may find the give and take of the court room off-putting. For an expert witness, the foremost qualifications are effective presentation and teaching ability. The radiation oncologist, serving as an expert witness, must educate the attorneys, judge, and jury. Once there is a perception of understanding, the radiation oncologist may be able to convince the judge and jury that they can make an independent decision that his or her testimony is correct.
Both the plaintiff’s attorney and the defense attorney will retain expert witnesses who will be persuaded to “take sides.” The expert witness will be asked to swear, under oath, what influence the radiation dose, volume, or technique had on the risk of an ill effect of radiation therapy on normal tissue or alleged failure to control the tumor. This expert witness system troubles many physicians who feel that they can bring a dispassionate and scientific view to such cases and come to a reasonable conclusion about whether or not malpractice occurred outside the process of litigation.225 Whatever the wishes of the physician, a trial is an adversarial process. The physician is best advised, therefore, to state his or her opinion about the case frankly and not attempt to predict or handicap how a trial will turn out. The physician should do his or her best to provide an opinion and then step aside to let a system, in which he or she has little expertise, run its course in the hands of the attorneys and judge. Although often frustrating and distressing, the physicians will find themselves out of their league if they attempt to act as attorney or judge.
Each physician must make a determination as to whether he or she feels comfortable participating in the legal process as an expert witness. Some radiation oncologists accept employment as expert witnesses in both plaintiffs’ actions and in defense. Some only choose to participate as expert witnesses for the defendant physicians or simply wash their hands of the matter and will have nothing to do with the process. The lure of money is strong and serving as an expert witness can be quite lucrative. Each physician must, however, determine for him- or herself whether the financial compensation for serving as an expert witness outweighs the considerable effort and troubling aspects of the process.
It is important that radiation oncologists understand that the concept in malpractice law of res ipsa loquitur,376 roughly translated as “the thing speaks for itself,” is used to deal with cases in which the actual negligent act may not be proved, but it is clear that the injury was caused by negligence. In law, this doctrine was first recognized in the case of a man who was injured when a barrel rolled out of a second-story window of a warehouse. The defense attorney argued that the plaintiff did not know what events preceded the barrel rolling out of the window and, therefore, it could not be proven that an employee of the warehouse was negligent. The plaintiff, however, countered that barrels do not normally fall out of second-story warehouse windows. The simple fact that the barrel fell from the window and caused an injury “spoke for itself” and demonstrated that someone must have been negligent.
In medical malpractice law, res ipsa loquitur is used to shift the burden of proof to the defendant’s position regarding causation. Res ipsa loquitur can be invoked if the patient suffers an injury that is not an expected complication of medical care, the injury does not normally occur unless someone has been negligent, and the defendant was responsible for the patient’s well-being at the time of the injury. Examples in which this concept has been invoked include the dislocation of a patient’s shoulder while aligning it for a chest x-ray, knocking out a patient’s tooth while the patient was under anesthesia for a tonsillectomy, nerve injury due to a hypodermic injection, leaving a sponge in the abdomen during an operation, or fracturing a patient’s jaw while extracting a tooth.376
An intentional tort is an action that can result in harm to the plaintiff. The classic intentional tort in medical malpractice law is forcing unwanted medical care on a patient. Even if care clearly would benefit a patient, if that care were refused and the radiation oncologist had no state mandate to force care on the patient, but did so anyway, the patient might sue for intentional tort. The most common intentional tort is battery. The legal standard for a battery is “an intentional unconsented touching.”269
Battery is not the same, in law, as assault. Assault is the act of putting a person in fear of bodily harm. Most battery claims against physicians are based on real attacks. However, battery claims also can be created by the circumstances of the medical treatment. The legal standard of care is that male health care providers do not examine female patients without a female attendant present. Although the standard frequently is ignored, it should not be. An attorney representing a plaintiff–patient may attempt to demonstrate that allowing an unattended examination of a female patient by a male radiation oncologist is concrete evidence that, at the very least, the physician has very poor judgment.
Of particular concern to radiation oncologists, in the realm of malpractice, is the concept of loss of chance. This usually is evoked in circumstances where physicians failed to diagnose a terminal illness. The loss of chance stems from the failure to diagnose in time for the patient to have a chance of cure. Not all states recognize this standard. In those states that do, however, the patient must show that the loss of chance is statistically significant.376
It is generally viewed that any patient injured by exposure to a defective x-ray machine will be compensated as a matter of law.48 If, however, the radiation oncologists did not know or could not have reasonably been expected to know that a machine was defective, they will generally not be held liable if they used the machine properly.19 Radiation oncologists are bound by the usual standards of skill, knowledge, and appropriate diligence that apply to the specialists within the field.
If a patient is hypersensitive to radiation therapy, and in the absence of any reasonable way to predict this, the radiation oncologist will not be expected to predict or prevent it.21,390,503 There is, however, the possibility that the plaintiff’s attorney will invoke res ipsa loquitur in certain circumstances.96 For example, in a patient who received radiation therapy for a benign condition and suffered a severe radiation cutaneous reaction that required bilateral amputation, the radiation oncologist was found to be negligent.480 In the employment of diagnostic radiation, minimal exposure is involved, and it is not expected that a skin reaction will be produced. Thus, if a skin reaction does ensue, many courts would infer negligence.28 If a part of the body is unintentionally irradiated and injured, liability will generally follow. For example, a patient who is undergoing radiation therapy to the head and neck was compensated when he suffered severe injury to the arms.290 A patient given radiation therapy to the ear suffered reaction of the head, face, and neck. Liability was also imposed.142 It is reasonable to expect that patients give informed consent for radiation therapy and will accept a certain risk of ill effects. This does not mean that the patient assumes a risk of negligent care.188,223
In a case where a patient with carcinoma of the rectum was given radiation therapy at a dose above that recognized as proper and suffered severe ill effects, the radiation oncologist offered a defense that such dosage had been given in accordance with the recommendation of a recently delivered scientific paper. The court rejected this claim. In the court’s view, this was not a generally accepted course or program of therapy, and the patient’s specific consent to the variance in therapy had not been obtained.7
One must be particularly cautious in dealing with a woman of childbearing age concerning the possibility of pregnancy before exposing her to radiation therapy. Because the fetus might be injured, producing birth defects or necessitating an abortion, the patient has a right to refuse or at least should be given the full chance of providing informed consent.392
One must also be wary of injury through other forms of negligence involving radiation therapy. Injuries of this type include allowing the patient to fall, unstrapped, off the couch of a linear accelerator as it is being moved into the correct position, being struck by a fluoroscopic screen or other equipment from a treatment machine or a simulator, being shocked or burned, or being permitted to come in contact with high-tension electrical wires.
There are some data concerning the types of malpractice claims brought in radiation oncology. From 1975 through 1994, a total of 18,860 malpractice suits were brought in Cook County, Illinois, naming at least one codefendant physician; 8% named a radiation oncologist as one of the defendants. The number of suits directed against radiation oncologists fell sharply in Cook County after 1982. At that time allegations that thyroid cancer in adults developed from tonsillar irradiation administered in childhood for benign disease halted when such suits proved unsuccessful. The most common complaints initiating radiation oncology suits in recent years relate to:
a. Alleged complications of radiation therapy;
b. Alleged administration of radiation therapy for inappropriate indications, and
c. Alleged inappropriate withholding of radiation therapy.43
An interesting survey of 107 radiation oncology lawsuits conducted by the Fletcher Society found that 59% of the plaintiff patients were female. The four most common organ sites involved in the suits were gynecologic (17%), breast (16%), head and neck (14%), and urologic (12%). The actuarial probability of a radiation oncologist remaining free of a lawsuit after 30 years in practice was 35%.403
The National Association for Insurance Commissioners conducted an extensive study of medical liability claims and insurance indemnity. It was published yearly between 1977 and 1980. The final report was based on data collected from over 70,000 medical liability claims arising from over 62,000 alleged injuries or incidences that were closed with payments to the plaintiffs by insurers. These data show that 4% of paid claims were related to external-beam radiation therapy.319
Brachytherapy as the origin of a malpractice action poses particular problems for the radiation oncologist. Brachytherapy procedures are relatively rare. Therefore, expertise is often limited and the individual experience of the practicing radiation oncologist may be minimal. The existence of postimplant films, which document the location of the radioactive material, can be used to challenge the quality of the implant procedure. Brachytherapy complications can take years to occur and, because brachytherapy is often employed in treatment of carcinoma of the prostate, cervix, and uterus, the development of fistulas in long-term survivors can be the cause of a malpractice action.
Radiation oncologists conduct their practice with the assistance of others: physicists, dosimetrists, nurses, and therapists. It is necessary, therefore, for radiation oncologists to understand vicarious liability. In general, employers are responsible for the actions of their employees. This is called respondent superior—also called the master–servant relationship.284 The fundamental issue that determines whether a person is legally treated as an employee is the extent to which the person hiring the worker may control the details of that work. Nurses, physician assistants, radiation therapists, and other physician extenders are professionals, but in most states in which they are licensed, they generally have a limited license. The extent to which they make medical decisions is determined by state law, but they usually must work under the supervision of a practicing physician. The physician’s license, however, is unlimited. The physician, for example, may perform nursing tasks without violating nursing practice laws. Injury caused by extenders may, ultimately, lead to a malpractice claim against the physician. Physician liability for the actions of hospital employees is particularly problematic for radiation oncologists. Many radiation oncologists practice in hospital-based clinics. In general, the doctrine of the borrowed-servant or the captain of the ship doctrine states that all actions of hospital employees are attributable to the patient’s attending physician. Under such a doctrine, the radiation oncologist may be found liable for the actions of a nurse, dosimetrist, or radiation therapist who the physician can neither hire, fire, nor otherwise directly control.269
When radiation oncologists are directors of clinical services, they also should be aware of the fact that they may be vicariously liable for the behavior of employees if they tolerate inappropriate activity or do not properly screen employees for dangerous tendencies. If, for example, a therapist has assaulted persons in the past and the radiation oncologist was negligent in discovering this, the radiation oncologist could be held liable under the theory of negligent hiring. The radiation oncologist also could be held liable for negligent retention if there were complaints about the behavior of the therapist and the physician failed to act on them.376
The captain of the ship doctrine means that physicians may have responsibility for the mistakes of their radiation therapists, dosimetrists, physicists, nurses, and fellow practicing physicians allegedly under their supervision or control. It is, therefore, incumbent upon the responsible radiation oncologist to take care in staff selection, training, and supervision. There is a risk in delegating such matters to an office manager. Ultimately, the physician must maintain an active role in ascertaining that he or she can fully trust the person selected to assist in all aspects of patient care. This means that the radiation oncologist must protect against allegations of sexual misconduct or abuse, alcohol or drug impairment, or mental illness potentially affecting patient care; because the physician is ultimately liable for the care given to a patient, the radiation oncologist must play an active role in ongoing training and professional development of his or her staff.
If an accident or allegation of misconduct occurs, the radiation oncologist must have a thorough, efficient, and adequate means of investigation of the matter and, if necessary, discipline or dismissal. Adequate employment records must be maintained.225
One of the most vexing problems now facing the practicing radiation oncologist is the matter of substance and alcohol abuse in the workplace and potential criminal records of employees. Some practices are instituting mandatory pre-employment screening for alcohol and drug abuse and criminal background checks. These issues, however, are extremely complicated, and it is not yet clear which drugs should be tested for, when the testing should occur, who should be evaluated for a potential criminal background, which positive criminal background checks merit a decision not to employ an individual or to dismiss the person, under what circumstances a person can be felt to have paid his or her debt to society in a way that allows the individual to practice in a health care environment, and to what extent a radiation oncologist can be held liable for failure to exercise due caution in this process. Obtaining sound advice from an expert in personnel relations and legal counsel is advisable.43
It is well recognized that no radiation oncologist can be available at all times and in all circumstances. A physician may arrange, during his or her absence for vacation or ill health, for practice coverage by another physician. When one radiation oncologist “covers” for another, there are risks to patient safety, and possible susceptibility to malpractice claims, if clinical care “falls through the cracks.” To minimize the risk of malpractice claims, the following guidelines should be followed:
• When you are away from your practice, you should select a covering radiation oncologist who possesses knowledge and skill at least equal to yours.
• Inform and obtain consent from those patients who will be affected.
• Apprise your covering physician of any important clinical information pertaining to patients he or she will see in your absence.
• The covering physician is expected to do more than just “fill in.” He or she must apply the same degree of medical skill and care as the regular radiation oncologist.
• When the regular radiation oncologist returns, he or she should receive a report of any noteworthy patient care events, laboratory tests or diagnostic imaging results that deserve follow-up, and any other “loose-ends.”37
It cannot be overemphasized that well-maintained medical records are crucial to a satisfactory legal defense in malpractice claims in radiation oncology. In law, the concept of spoliation refers to the destruction of evidence of significance or a meaningful alteration of a document. In medical malpractice cases, this would refer to the absence or disappearance of medical records. One radiation oncologist wisely counseled: now and then pick up an old chart, see if you can trace all of your steps in making decisions and executing treatments. Would this chart be sufficient to defend yourself against a malpractice claim?403
The Nature of Grievances and Malpractice Claims in Radiation Oncology
Dissatisfied patients might ignore their physician’s advice or seek a new physician. Assertive patients may confront their physician. It is also commonplace for patients to discuss their complaints about physicians with friends and relatives.
In Anglo-American law and custom, patients whose dissatisfaction prompts formal action have several options. These include bringing a malpractice claim and seeking redress in courts. Other options include filing a complaint with a government medical board; filing a complaint with the “patient relations office” of a hospital or group practice; directing a complaint to a hospital’s chief of medical staff or credentials office; or submitting a grievance to the local, state, district, or national medical society. Why some dissatisfied patients do nothing and others take formal action is not well studied. The general nature of patient grievances against physicians, however, has been evaluated by several authors.198 Complaints fall into several broad categories:
• Alleged failure of physicians to fulfill the patient’s expectations for examination and treatment (i.e., inadequate therapy, failure to obtain informed consent prior to a procedure, inadequate physical examination, or lack of prompt attention following hospitalization);
• Alleged failure to make a prompt diagnosis;
• Alleged rude or discourteous behavior;
• Alleged unacceptable practice behavior, such as producing excessive pain or practicing outside an area of expertise;
• Alleged inappropriate behavior related to billings and collections;
• Alleged physician’s use of alcohol or drugs;
• Alleged sexual misconduct;
• Alleged errors in prescribing; and
• Alleged insurance fraud.
Formal complaints, including malpractice suits, represent only the tip of the iceberg of patient dissatisfaction. Patients far more often deal with their dissatisfaction by complaining to family and friends or switching doctors than by submitting a written complaint. A study by the Harvard Medical Practice Study Group, for example, found that <2% of patients who had adverse events because of medical malpractice ever filed malpractice claims.277 Patients pursued medical malpractice claims for a variety of reasons. The four most common include an attempt to hold the offending caregiver accountable, to seek a more complete or satisfying explanation for the adverse event, to stop similar events from occurring to other patients, and to obtain financial compensation476 (Boxes 1.8 and 1.9).
A disagreement between a patient and his or her radiation oncologist may cause the patient to have diminished trust in the physician, to be dissatisfied with the clinical results, to change physicians or health plans, to file a complaint, or to undertake litigation. For physicians, however, disagreements with patients may result in frustration, anger, a feeling of loss of control, and career dissatisfaction.
Box 1.8
Systematic Radiation Therapy Overdose and Underdose: Recent Events in the United Kingdom
It was discovered in 1998 at Exeter that 207 patients were given a radiation dose >25% than that generally deemed appropriate for the treatment of breast cancer. Some patients had more marked radiation reactions than appropriate. When this became known, adverse publicity appeared in the press. At Stafford ~1,000 patients received ~25% underdosing over a 20-year period. An investigation concluded that in ~500 patients there was a real possibility that underdosage may have affected the outcome of treatment and, in a small number of patients, produced a cancer recurrence higher rate than that expected.22,255
The causes of these two incidents were analyzed in great detail and may have been related to inadequate medical physics staffing. A Royal College of Radiologists survey showed that radiation oncologists in many U.K. radiotherapy departments were seeing ≥600 new patients per year as compared to the usual 250 to 300 patients seen in France, Germany, and the United States.
Box 1.9
The RAGE Campaign
In 1991, a group of women formed an organization in the United Kingdom called RAGE (Radiation in Action Group Exposure). Their campaign began when a patient developed serious brachial plexus damage following surgery and radiotherapy for breast cancer. The patient wrote a letter to several newspapers describing these events and criticizing the medical and legal processes. This produced an outpouring of concern from other patients who claimed to have suffered from the same side effects. RAGE called for significant changes in the use of radiotherapy for the treatment of breast cancer.373 The group successfully applied to the legal aid board for funds to undertake research toward a group legal action and, in 1995, constituted a group of plaintiffs in a malpractice case. Publicity associated with the litigation prompted the Royal College of Radiology to establish a multidisciplinary working party that made recommendations to ensure that patients with symptoms that might be due to radiation-associated brachial plexus injury had access to a network of health care professionals and cancer centers with the necessary skills for diagnosis, functional assessment, and treatment. The case highlighted the risks of high-dose-per-fraction radiation therapy used in the 1970s and 1980s. When the case eventually came to judgment, Justice Ebsworth concluded that there was no negligence and costs were directed against the plaintiffs. The justice commented that “it was unfortunate that litigation in terms of medical negligence was felt to be the only mechanism available,” particularly in view of the fact that the cost of litigation exceeded £4 million. The case is instructive on several grounds:
1. The ill effects of radiation therapy may take a long time to become manifest.
2. Communication with patients concerning the causes and treatment of an injury is crucial.
3. The cost of litigation is quite high, and one would certainly hope that in the future society can derive alternative mechanisms to costly malpractice actions to allow patients to understand how and why injuries occur.22,117,255
Box 1.10
The New York Times Investigates Radiation Therapy
Radiation therapy practice was severely shaken when The New York Times published an article on June 21, 2009, titled “At V.A. Hospital, a Rogue Cancer Unit” and a second article on January 23, 2010, titled “Radiation Offers New Cures, and Ways to Do Harm.” Both articles were authored by Walt Bogdanich.49,50
The first article described allegations that the prostate brachytherapy program at the Philadelphia V.A. Medical Center was “a rogue cancer unit at the hospital, one that operated with virtually no outside scrutiny and botched 92 of 116 cancer treatments over a span of more than six years—and then kept quiet about it….” The article described allegations of repetitive misplacement of prostate brachytherapy seeds, the changing of treatment plans to cover up the alleged errors, lack of peer review and quality assurance procedures, and the development of severe complications in patients.
The second article focused on the death of a 43-year-old man who had been irradiated at St. Vincent’s Hospital in Manhattan for a tongue carcinoma and a 32-year-old female breast cancer patient treated at the State University of New York Downstate Medical Center. In the former case, the multileaf collimator was left fully open during intensity-modulated radiation therapy. In the latter case, a wedge was left out of the linear accelerator. Both patients were significantly overdosed and the tongue cancer patient died of radiation injuries. Bogdanich explores the causes of the errors: possible software malfunctions, human error, and lack of quality assurance and safety check procedures. Furthermore, the reporter raised the serious question of whether or not governmental oversight was sufficient to ensure the safety of clinical radiation therapy.
The articles made the safety of radiation therapy a national concern and have produced considerable soul searching in the medical physics and clinical radiation therapy communities. Efforts are under way at many levels to understand what can go wrong in radiation therapy, what can be done to prevent these errors, how much can be done to engineer procedures to prevent machine and human error, and what types of oversight are necessary to minimize error. We must never forget the Hippocratic admonishment primo non nocere: “First do no harm.”
It is important to document your explanation of the risks and benefits of radiation therapy and to obtain the patient’s written authorization to proceed, with a full understanding of those risks. In discussing any procedure or treatment with the patient or his or her guardian, the radiation oncologist should endeavor to explain all of the risks in sufficient detail to permit the patient to make a well-educated decision. Written informed consent should be obtained. But simply having the patient sign a standard form is not the end of the matter. The forms need to be easily understood and written in clear language. It is unwise for a physician to adopt standard printed forms without giving them proper scrutiny. Radiation oncologists must also be sure that the consent form is properly filled out. If, for example, there are blanks for explanations of particular risks involved for the procedure, they should be properly filled in.225
It is essential that radiation oncologists use fundamental communication skills to avoid grievances and malpractice claims, understand the patient’s worries and concerns, express empathy, actively discuss care options, negotiate differences of opinion, and allow time for adequate conversation. The challenge for radiation oncologists is to recognize patients’ unfulfilled expectations and to engage patients in a discussion with the goal of identifying and avoiding dissatisfaction while building a trusting therapeutic relationship (Box 1.10).
Health Insurance Portability and Accountability Act
Since the Health Insurance Portability and Accountability Act of 1996 (HIPAA) has come fully into effect, considerable changes have occurred in the area of health care fraud and abuse. HIPAA created new criminal offenses and brought civil remedies while strengthening existing ones. More important for the practicing radiation oncologist, however, HIPAA is part of a larger political initiative in which health care fraud and abuse became a top law enforcement priority. Large numbers of civil investigations have been brought regarding alleged abuses of Medicare and Medicaid. Many physicians and organizations have been excluded from federally funded health care programs, and there have been criminal convictions and collection of large amounts of money in criminal fines.
RISK MANAGEMENT IN RADIATION ONCOLOGY
In an era of increasing litigation and, unfortunately, a growth in adversarial situations between physicians and patients, it is critical for the radiation oncologist and staff to make every effort to decrease professional liability risks.
The origins of medical malpractice suits include:242
• Medical accidents that may not be adequately understood by the patient or explained by the treating physician.
• Less than successful or unexpected adverse results of treatment.
• Poor results from previous treatment elsewhere and ill-advised comments by other physicians or health care personnel.
• Rejection of a plan of therapy without appropriate documentation that the physician has advised the patient of the consequences of declining treatment. Some physicians document this discussion in the chart and send a certified letter advising the patient of the consequences of rejection of treatment.
• Complaint of experimentation when the patient has not been appropriately informed of the nature of the therapy to be administered.
• An angry patient who may find this a way to vent anger or frustration about any events surrounding treatment, including lack of communication, discourteous treatment by the physician or staff, or the amount of the medical bill.
The best prevention against a lawsuit is good rapport with the patient and relatives, effective communication and QA programs in all activities related to patient management, and clear and accurate documentation of all procedures, discussions, and events that take place before, during, and after treatment.
After appropriate clinical assessment, the histologic diagnosis of the patient must be confirmed at the treating institution; this often includes review of outside pathologic slides. Rationale of therapy and any changes in treatment plan should be duly explained and documented in the record. All procedures performed on the patient should be recorded in the chart, including details of daily treatments, such as use of special treatment aids (i.e., bright blocks, testicular shields, eye shields, immobilization devices), and any problems related to equipment operation. All treatment parameters and calculations should be accurately recorded and verified by a physicist or dosimetrist, in addition to the radiation oncologist. We should remember that, as professional liability attorneys say, “If it is not recorded on the chart, we may assume it never happened.”
The physician and staff may help in their own professional liability defense in case a lawsuit occurs. It is extremely important for the physician to understand and, at an appropriate time, identify early warning signs of an impending malpractice suit. The physician should promptly contact his or her attorney, risk management office, and insurance carrier.
The physician should prepare an incident report in anticipation of potential litigation, describing the potential liability, including dates when events took place and actors and witnesses to be identified by name, affiliation, and status. Incident reports are confidential information between the physician and the attorney, risk manager, or insurance carrier. The report should be prepared while the facts are still fresh so that documentation will be optimal.
Clear and well-kept records with notes documenting every discussion and procedure that is performed on the patient should help in case of a lawsuit. A full discussion with the patient and relatives regarding planned therapy, particularly side effects of irradiation, and a well-documented informed consent form are valuable in risk management.
TABLE 1.15 POSSIBLE SPECIFIC SEQUELAE OF THERAPY DISCUSSED IN INFORMED CONSENT
Informed Consent
The need to obtain informed consent for treatment is based on the patient’s right to self-determination and the fiduciary relationship between the patient and physician.375 The law requires that the treating physician adequately apprise every patient of the nature of the disease requiring treatment, recommended course of therapy and details regarding it, alternative treatments available, benefits of recommended treatment, and all minor and major risks (acute and late effects) associated with the recommended therapy (Table 1.15). If the plan of therapy is modified, this should be discussed with the patient, and, if warranted, a second informed consent may be required. It is advisable to discuss the informed consent contents in the presence of a witness and have that person sign an informed consent form or the chart verifying that the information was discussed with the patient.
Informed consent is a process, not a form. A consent form documents and codifies the process but does not substitute for clear and appropriate provision of information to the patient with adequate time for questions, answers, and free discussion and exchange. Ultimately, the competent adult patient or a legal representative must agree to the treatment and give approval. For unemancipated minors or legally incompetent adults, informed consent must be signed by the parents, adult brothers or sisters, or a responsible near relative or legal guardian. For incompetent adults, spouses may be allowed by the state to sign. Emancipated minors may provide their own consent. It is extremely important for the radiation oncologist and the staff to spend as much time as is needed to ensure that the patient and, if necessary, relatives understand all aspects of the radiation therapy, particularly the specific description of the various potential deleterious effects of this modality. Many physicians indicate which situations may require surgery to treat a complication and, specifically, when a gastrostomy, colostomy, ileal bladder, or other organ-substituting operation may be necessary to correct sequelae of therapy.
The radiation oncologist is always balancing a full disclosure of risks and options without overwhelming the patient with data and causing distress. It is reasonable to expect the patient to come away from a meeting with the treating radiation oncologist with a general realistic hope regarding the proposed course of treatment and honest understanding of the side effects, and a sense of trust for the physician and the organization.225 Good documentation is crucial and, if a malpractice action were to occur, liability may hinge on who said what to whom at what point of the treatment process. Absent or lost records will reflect extremely poorly on the radiation oncologist.225
It must be stressed that in dealing with children or mentally incompetent adults, a thorough discussion of the plan of therapy and sequelae should be held with the parents, relatives, or legal guardian of the patient. Also, they must sign the informed consent.
Although, in case of a lawsuit, having a properly executed informed consent form in the record is helpful, more important is the incontrovertible documentation in the chart of the pertinent discussion held with the patient. Table 1.15 describes many of the specific sequelae in several anatomic sites that should be included in the informed consent. Radiation oncologists also should be aware of court decisions that place a greater burden on the physician to disclose statistical life-expectancy information to critically ill patients as part of the informed consent and as an affirmation of patient-centered decision making (regarding treatment) in the context of a physician–patient relationship based on trust.16
FIGURE 1.37. New developments in biotechnology will permit an analysis of how the genome or proteome of a tumor changes with treatment. This may allow researchers to identify novel therapeutic targets or find predictors of treatment outcome. The interaction between ionizing radiation and a biologic system may be thought of as a molecular event. Before, during, and after radiation, gene expression profiles using microarrays may be generated. (From Coleman CN. Radiation oncology–linking technology and biology in the treatment of cancer. Acta Oncol 2002;41:6–13.)
SMART RADIATION ONCOLOGY IS COMING
Sequencing of the human genome is now complete. There are now vigorous efforts under way to catalog specific genes and to identify the protein makeup of cells—disciplines called genomics and proteomics.
What do genomics and proteomics mean for the future of radiation oncology? Engaging in predictions is a highly risky endeavor. We think it is reasonable, however, to expect the development of a new, more individualized, smarter radiation oncology.
First, we think that there will continue to be a movement away from anatomic staging of cancer toward molecular staging. When cancer staging was first developed, it was based on whether tumors could be labeled “operable” or “inoperable.” Our discipline then moved toward anatomic staging, in which an assessment of the status of the tumor was made by inspection and palpation. Typical examples of this were the Jewett system for prostate cancer or the League of Nations system for cervical cancer. Staging now has developed into a system based on physical examination, radiographic studies, and, in some cases, pathologic assessment. The most widely used system includes an assessment of tumor status (T), nodal status (N), and the presence or absence of distant metastasis (M).
There is a trend toward a more molecular-based staging of cancer in which one assesses the genetic component of an individual tumor as a predictor of outcome and as a guide toward treatment. We see evidence of this trend in the use of hormone receptors, DNA ploidy, presence or absence of n-myc, presence or absence of H-erb-2B, and study of subtypes of gene rearrangements in the staging of leukemias and solid tumors. With more detailed molecular staging, one will be able to more finely tailor therapy to the specific needs of the patient.500
There will be an increasing trend toward the use of genomics and proteomics to prospectively identify high-risk patients for development of cancer. There are many cancers that have an obvious genetic basis. Population screening tests based on the presence or absence of a gene could change significantly the stage distribution of malignancies the clinician faces.145 It is hoped that screening will allow us to identify earlier cases that would be more amenable to treatment. It certainly will be preferable to have a clear-cut genetic test for the early detection of colorectal cancer, for example, rather than the cumbersome, uncomfortable, and relatively expensive use of colonoscopy.
Developments in genetics and proteomics are highly likely to modify the clinician’s use of drugs and radiation (Fig. 1.37). In many situations physicians treat individuals as a statistically average person. Medications are prescribed because they are thought, on average, to bring about a certain effect in the average patient and have a known risk of side effects. It would be preferable to understand the genetic profile of the individual patient and to more precisely predict whether he or she will respond to a drug and whether he or she would be more or less likely to have side effects from the medication. Genomics offers the possibility of developing a personalized medicine in which one would match medication-prescribing practices to the specific DNA profile of an individual patient. This evolving discipline is called pharmacogenomics.
Predictive assays for tumor control and the risk of normal tissue complications are under active investigation. Among the hypotheses being explored are the possible correlation of gene activity promoting or inhibiting apoptosis with tumor response to radiation, the correlation of the presence or absence of tumor markers for hypoxia with the chance of local tumor control with radiation, whether skin fibroblast radiosensitivity correlates with normal tissue complication risk from radiotherapy, the possible association of transforming growth factor β-1 polymorphisms with the risk of radiation-induced normal tissue damage, the possible correlation between in vitro chromosomal radiosensitivity of lymphocytes and normal tissue damage following external-beam radiotherapy, the pretreatment predictive power of microarray technology for gene expression in tumors, and protein expression profiling (proteomics) of tumors and normal tissue. These latter two technologies, because of their ability to measure many genes or proteins quickly, may allow the clinician of the future to obtain profiles of the tumor before, during, and after treatment; predict outcome; and, perhaps, tailor treatment according to the molecular response of the tumor.26,102,190,265,266,379
Finally, we may hope to understand the fine tuning of the individual patient’s and his or her tumor’s genome to influence or direct (epigenetics) therapy. Overproduction of oncogenes or inadequate production of tumor-suppressor genes might be genetically modified to place tumors in remission. Such activities are, almost certainly, far off in the future and will be enormously complex. One biotechnology executive artfully characterized the problem, as it regards the p53 tumor-suppressor gene, as follows:
This is a gene that produces a tumor suppressor protein… If it is under expressed [the cell] becomes cancerous. So when your p53 is lowered, the whole intelligence network of the cell is altered, and that’s where cancer begins.
However, researchers now have identified that if p53 is too high, that same gene produces osteoporosis, wrinkled skin, and shriveled organs—results that are linked to premature aging and a number of other diseases. A healthy human being, then, has an exact regulation of the p53 gene. There appears only to be a fine line between premature old age and cancer. It’s obviously a very important gene, but we don’t know much about how it works yet.499
One of the evolving areas in external-beam radiotherapy will, undoubtedly, be the attempt to develop dose painting or biologically based optimization. These techniques strive to marry diagnostic imaging, which identifies the tumor location, with metabolic imaging to show tumor activity (PET and PET/CT), along with calculations of tumor control probability, normal tissue complication probability, and uncomplicated tumor control probability. The software packages for these techniques strive to conform the radiation dose not only to the anatomic location of the tumor but also to the most metabolically active areas of the tumor while, at the same time, minimizing the dose to those areas of normal tissue most likely to produce complications.379
A new, smart form of radiation oncology offers enormous promise to the practicing clinician. An exciting age of medicine is before us. Obviously, developments in biotechnology pose formidable ethical problems that will vex the clinician. How much will be known about each individual patient’s genetic makeup? How will that information be shared with the patient’s family, insurance company, and employer? What protection will be built into a system in which enormous amounts of very private information will exist in electronic form? We must make sure that ethics and law keep up with scientific progress.
Radiation oncologists must enrich training programs with more exposure to basic science investigation and nurture research that will provide new directions for the personalized applications of radiation therapy to the treatment of malignant neoplasias in specific patients.
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