The Washington Manual of Oncology, 3 Ed.

Principles and Practice of Radiation Oncology

Pawel Dyk • Clifford G. Robinson • Jeffrey D. Bradley • Joseph Roti Roti • Sasa Mutic

 I. INTRODUCTION. Optimal care of patients with malignant tumors is a multidisciplinary effort that often combines two or more of the classic disciplines: surgery, radiation therapy, and chemotherapy. Pathologists, radiologists, clinical laboratory physicians, and immunologists are integral members of the team that renders the correct diagnosis. Many professionals, including physicists, laboratory scientists, nurses, social workers, and others, are intimately involved in the care of the patient with cancer.

 Radiation oncology is a clinical and scientific discipline devoted to management of patients with cancer and other diseases through use of ionizing radiation, alone or in combination with other modalities, investigation of the biologic and physical basis of radiation therapy, and training of professionals in the field. The aim of radiation therapy is to deliver a precisely measured dose of radiation 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 competitive cost. In addition to curative efforts, radiation therapy plays a major role in the effective palliation or prevention of symptoms of cancer including improving pain and restoring luminal patency, skeletal integrity, and organ function with minimal morbidity.

 The radiation oncologist, like any other physician, must assess all conditions relative to the patient and the tumor under consideration for treatment, systematically review the need for diagnostic and staging procedures, and determine the best therapeutic strategy.

1. TYPES OF RADIATION USED IN RADIATION THERAPY. Many types of radiation are used for treatment of both benign and malignant diseases. The most common form of radiation is through the use of external beam photons or electrons. Photons are x-rays or γ-rays and may be considered as bundles of energy that deposit dose as they pass through matter. The term x-ray is used to describe radiation that is produced by machines, while γ-rays define radiation that is emitted from radioactive isotopes. Typical radiotherapy units used in modern-day x-ray therapy are linear accelerators with energies spanning 4 to 25 million volts or MV. The most common source of γ-rays for external beam radiotherapy has been ⁶⁰Co. Most radiotherapy facilities no longer use γ-rays because of their low energy profile, unfavorable dose distribution, and the need to replace and recalculate for decaying sources. An exception is the Gamma Knife unit used for intracranial stereotactic radiosurgery, which houses 192 or 201 (depending on the version) ⁶⁰Co sources to deliver high doses of radiation to relatively small target volumes within the brain. A recently developed radiotherapy unit, the ViewRay system, uses ⁶⁰Co sources to deliver radiotherapy simultaneously with real-time magnetic resonance imaging (MRI).

 Electrons or β-particles can also be used to treat patients. Similar to the distinction between x-rays and γ-rays, the term electron is used to describe radiation produced by machines, while β-particles describe electrons emitted by radioactive isotopes. Electrons deposit their maximal energy slightly beyond the skin surface and have a sharp falloff beyond their range. Electrons are used mainly for treating skin or superficial tumors.

 Other sources of external beam radiation are protons and neutrons. Protons are charged particles that have the advantage of depositing dose at a constant rate over most of the beam, but depositing most of the dose at the end of their range, creating a Bragg peak. The advantage of protons over photons is that beyond the Bragg peak, protons fall off rapidly and avoid dose deposition beyond the target. This vastly limits radiation dose to normal tissues beyond the target, as well as the total amount of radiation (integral dose) delivered to the patient. Proton dose-deposition characteristics are useful in situations where limiting dose to surrounding organs is critical, such as treating within a previously irradiated field where the structures surrounding the target have received the maximum tolerated radiation dose. Protons also have unique advantages in the treatment of pediatric malignancies by avoiding the irradiation of developing organs and skeletal structures, and potentially decreasing the risk of radiation-induced malignancies by lowering the delivered integral dose. The use of protons is also being investigated in other cancer sites, such as esophagus and lung, where improved reduction in dose to multiple uninvolved adjacent organs (lung, heart, esophagus, etc.) may be possible compared with other photon-based treatment techniques like 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). Because of the cost, few radiotherapy facilities in the United States currently have proton units available for patient treatment. The recent development of relatively cheaper proton delivery systems may substantially increase the availability of protons across the United States, potentially expanding their application and use to other clinical tumor sites.

 Neutrons are uncharged heavy particles that are produced by a variety of mechanisms. They deposit large amounts of energy very close to their initial interaction sites with the nuclei of a treated medium. Experience with neutrons has been limited to a few centers because of the cost of producing and maintaining these radiotherapy units. An example of depth–dose characteristics for photons, electrons, protons, and neutrons is shown in Figure 4-1.

 Brachytherapy is an alternative method of irradiating targeted tissues. Brachy is translated from Greek, meaning short distance. In brachytherapy, sealed or unsealed radioactive sources are placed very close to or in contact with the targeted tissue. The absorbed dose falls off rapidly with increasing distance from the source (1/radius² for a point source and 1/radius for a line source); thus, higher doses can be delivered safely to the targeted tissue over a short time. Prescribed brachytherapy doses are generally delivered in days for low-dose rate (LDR) or minutes for high-dose rate (HDR). Brachytherapy sources can be placed temporarily, as in the use of ¹⁹²Ir for HDR applications in cervix cancer, or permanently, as in the use of ¹²⁵I in the treatment of prostate cancer. Some common applications of sealed brachytherapy include the treatment of prostate (both HDR and permanent LDR), breast (mainly HDR), soft tissue sarcoma (HDR), and cervix (both HDR and LDR) cancers. In selective cases, sealed brachytherapy sources may also be used intraluminally in the palliative setting to relieve malignant obstruction in a previously irradiated field, such as obstructing esophageal and endobronchial tumors. Unsealed sources are radioactive substances in soluble form that are administered through ­ingestion or injection. Examples include ¹³¹I ingested to treat thyroid cancer, ⁹⁰Y embedded resin or glass microspheres injected into the hepatic vasculature to treat metastatic or primary liver malignancies, and ²²³Ra delivered intravenously to treat metastatic prostate cancer to the bone.

Figure 4-1. Depth–dose curves for photons (x-rays), electrons, protons, and neutrons at energies used in radiation therapy.

 III. GOALS OF RADIATION THERAPY. The clinical use of radiation is a complex process that involves many professionals and a variety of interrelated functions. The aim of therapy should be defined at the beginning of the therapeutic intervention.

1. Curative. The patient has a probability of long-term survival after adequate therapy. Oncologists may be willing to risk both acute and chronic complications as a result of therapy in an attempt to eradicate the malignant disease.
2. Palliative. There is no hope that the patient will survive for extended periods; symptoms that produce discomfort or an impending condition that may impair the comfort or self-sufficiency of the patient require treatment.

In curative therapy, some side effects, even though undesirable, may be acceptable. However, in palliative treatment, no major side effects should be seen. In palliation of epithelial solid tumors causing complications due to mass effect or pain, relatively high doses of radiation (sometimes 75% to 80% of curative dose) are required to control the tumor for the survival period of the patient. There are some exceptions to high-dose palliative radiotherapy, including patients with lymphoma or multiple myeloma or for treatment of bleeding such as patients with cervical or endobronchial malignancies. Some disease conditions, such as low-grade lymphoma, are long-standing and incurable. These conditions also fall into the palliative category because one is generally willing to sacrifice some long-term tumor control to avoid the development of treatment-related complications.

 IV. BASIS FOR PRESCRIPTION OF RADIATION THERAPY

1. Evaluation of tumor extent (staging), including radiographic, radioisotopic, and other studies
2. Knowledge of the pathologic characteristics of the disease
3. Definition of goal of therapy (cure vs. palliation)
4. Selection of appropriate treatment modalities (irradiation alone or combined with surgery, chemotherapy, or both)
5. Determination of the optimal dose of irradiation and the volume to be treated, according to the anatomic location, histologic type, stage, potential regional nodal involvement, and other characteristics of the tumor, and the normal structures present in the region
6. Evaluation of the patient’s general condition, periodic assessment of tolerance to treatment, tumor response, and status of the normal tissues treated

In addition to coordinating the patient’s care with the surgical and medical oncology teams, the radiation oncologist must work closely with the physics, treatment planning, and dosimetry staff within the radiotherapy facility to ensure the greatest possible accuracy, practicality, and cost benefit in the design of treatment plans. The ultimate responsibility for treatment decisions and the technical execution of the therapy will always rest with the physician.

1. RADIOBIOLOGIC PRINCIPLES
2. Probability of tumor control. It is axiomatic in radiation therapy that higher doses of radiation produce better tumor control. Numerous dose–response curves for cell killing of a variety of tumors by single dose and multiple repeated-dose radiation have been published. For every increment of radiation dose, a certain fraction of cells will be killed. Therefore, the total number of surviving cells will be proportional to the initial number of tumor cells present and the fraction killed with each. As such, various total doses will yield different probabilities of tumor control, depending on the extent of the lesion (number of clonogenic cells present) and the sensitivity to radiation. Additional factors that affect the efficacy of radiation therapy include repair of radiation damage (to DNA), the presence of hypoxic cells and their reoxygenation, cell cycle checkpoints, and tumor cell repopulation rates.

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, may subsequently evolve into clinically apparent tumor. 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. Microscopic tumor,as at the surgical margin, should not be regarded as subclinical disease; cell aggregates of 10⁶/cc or greater are required for the pathologist to detect them. Therefore, these volumes must receive higher doses of radiation, in the range of 60 to 65 Gy in 6 to 7 weeks for epithelial tumors.

For clinically palpable tumors, doses of 60 (for T1) to 75 to 80 Gy or higher (for T4 tumors) are required (2 Gy/day, five fractions weekly). This dose range and tumor control probability (TCP) has been documented for squamous cell carcinoma and adenocarcinoma (Fletcher GH. Textbook of Radiotherapy. Philadelphia, PA: Lea & Febiger, 1980). Ideally, the radiation oncologist would have the ability to deliver doses in this range. However, these doses are often beyond the tolerance of normal tissues. Exceeding normal tissue tolerance may result in debilitating or life-threatening complications.

1. Effects of radiation on tissues and the linear–quadratic equation. Radiation causes cell death by inducing DNA double-strand breaks. The presence of DNA double-strand breaks in cells leads to lethal, sublethal, and potentially lethal damage. Lethal damage is a level of DNA damage that is too much for the cell to repair. Sublethal damage is defined as damage that can be repaired when a single dose of x-rays is divided into two or more fractions. Potentially lethal damage is defined as damage that can be repaired or fixed to lethal damage by modifying growth conditions (i.e., cell cycle progression) during or after a dose of x-rays. Sublethal damage repair (SLDR) and potentially lethal damage repair (PLDR) are important concepts in considering normal tissue repair. 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).

A variety of changes in tissues are induced by ionizing radiation, depending on the total dose, fractionation schedule (daily dose and time), and volume treated. For many tissues, the necessary dose to produce a particular sequela increases as the irradiated fraction of volume of the organ decreases.

Chronologically, the effects of irradiation have been subdivided into acute (first 6 months), subacute (second 6 months), or late, depending on the time at which they are observed. The gross manifestations depend on the kinetic properties of the cells (slow or rapid renewal) and the dose of radiation given. No correlation has been established between the incidence and severity of acute reactions and the same parameters for late effects (Karcher KH, Kogelnik HD, Reinartz G, eds. Progress in Radio-Oncology II. New York, NY: Raven Press, 1982:287).

Formulations based on dose–survival models have been proposed to describe the dependence of cell killing on radiation dose and fractionation. These models are very useful in evaluating the biologic equivalence of various doses and fractionation schedules. These assumptions are based on a linear–quadratic survival curve represented by the equation

lnS = αD + βD² for a single dose or lnS = α(nd) + β(nd)d (4.1)

for a fractionated dose, where n = number of fractions, d = dose/fraction, and nd = total dose. In this equation, 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, α represents the less reparable component of lethal radiation damage, that is, damage for which the lethality is not reduced by fractionating the radiation dose. Conversely, β represents damage that can be repaired (i.e., its lethality is reduced) when the radiation dose is fractionated. At low doses, the α (linear) component of cell killing predominates. At high doses, the β(quadratic) component of cell killing predominates. The dose at which the two components of cell killing are equal constitutes the α/β ratio.

In general, tissues reacting immediately to acute effects, like the skin and mucosa, have a high α/β ratio (between 8 and 15 Gy), whereas tissues involved in late effects, like the brain and spinal cord, have a low α/βratio (1 to 5 Gy). Therefore, 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 immediately responding tissues. Therefore, in hyperfractionated regimens, the tolerable dose would be increased more for late effects than for early 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 early effects. A biologically equivalent dose (BED) can be obtained by using the following equations, derived from the equation for cell survival after a fractionated dose:

BED = −ln S/α = nd[1 + d/(α/β)] = D[1 + d/(α/β)] (4.2)

To compare two treatment regimens (with some reservations), the following formula can be used:

Dx = Dr[(α/β + dx)/(α/β + dr)] (4.3)

in which Dr is the known total dose (reference dose), Dx is the new total dose (with different fractionation schedule), dr is the known dose per fraction (reference), and dx is the new dose per fraction.

The following is an example of 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 = 5 Gy.

Using the earlier equation

Dx = 50 Gy(5 + 2)/(5 + 4) = 38 Gy (4.4)

Answer: A dose of 50 Gy in 25 fractions provides the same BED as 39 Gy in 4-Gy ­fractions.

As the total dose to a particular tumor and surrounding normal tissues increases, both TCP and normal tissue complication probability (NTCP) increase. Both TCP and NTCP are sigmoidal in shape. The farther these two curves diverge, the more favorable the therapeutic ratio (Fig. 4-2). When the curves are close together, increases in irradiation dose will lead to exponential increases in NTCP. The TCP and NTCP curves can be separated by the use of biologic modifiers, radioprotectors, three-dimensional conformal irradiation, IMRT, or proton therapy. When the TCP and NTCP curves are well ­separated, higher doses of radiation therapy can be delivered more safely. Chemotherapy also modifies the TCP and NTCP curves, often by shifting both curves to the left. Therefore, with chemoradiation, lower doses of radiotherapy are required to produce a given TCP/NTCP. Biologic factors can also contribute to the TCP and NTCP. Defects in DNA repair will lower the dose for both curves unless the defect is unique to the tumor. In contrast, defective apoptotic pathways tend to increase radiation resistance.

Figure 4-2. The therapeutic ratio represents the relationship between two sigmoidal curves; the TCP and the NTCP curves. The further the two curves are separated, the higher the TCP and the lower the NTCP.

An acceptable complication rate for severe injury is 5% to 10% in most curative clinical situations. Moderate sequelae are noted in varying proportions depending on the dose and fractionation of radiation given and the volume irradiated of the specific organ at risk. In 2010, a seminal series of articles was published that provides clinicians with evidence-based dosimetric tools to guide radiation treatment planning in order to minimize normal tissue complications. This QUantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) is an evaluable source that describes dose and volume parameters that have been shown in the literature to be associated with organ-specific radiation toxicity. Table 4-1 is a QUANTEC summary of dose, volume, and outcome data for organs at risk treated with conventional fractionation (1.8 to 2 Gy per fraction) (Int J Radiat Oncol Biol Phys 2010;76(3):S10).

Combining irradiation with surgery or cytotoxic agents frequently modifies the tolerance of normal tissues and/or tumor response to a given dose of radiation, which may necessitate adjustments in treatment planning and dose prescription. For example, in curative radiation therapy for cancer of the esophagus, concurrent chemotherapy consisting of 5-fluorouracil (5-FU) and cisplatin and radiation therapy to 50 Gy result in improved local tumor control and similar esophagitis rates when compared with irradiation alone to doses of 64 Gy.

1. Dose–time factors. Dose–time considerations constitute a complex function that expresses the interdependence of total dose, time, and number of fractions in the production of a biologic effect within a given tissue volume.

Short overall treatment times are required for tumors with rapid proliferation, and more slowly proliferating tumors can be treated with longer overall treatment times. With regard to fractionation, five fractions per week, for example, are preferable to three fractions because it has been shown that there is approximately 10-fold less cell killing per week with the latter schedule (Fowler JR. Fractionation and therapeutic gain. In: Steel GG, Adams GE, Peckham MJ, eds. Biological Basis of Radiotherapy. Amsterdam: Elsevier Science, 1983:181).

In general, fractionation of the radiation dose will spare acute tissue reactions, as in the skin and mucosa, because of compensatory accelerated proliferation in the epithelium. Therefore, a prolonged course of therapy with small daily fractions will decrease early acute reactions. However, such a strategy will not reduce serious late damage to normal tissue because such effects are not proliferation-dependent. Worse, extensively prolonging the treatment time will allow the growth of rapidly proliferating tumors. Therefore, prolonged treatment schedules are undesirable.

Radiation treatments may be delivered by conventional fractionation, hypofractionation, hyperfractionation, or accelerated fractionation schedules. In the United States, conventional fractionation is defined as a daily fraction size of 1.8 to 2.0 Gy, and in the nonpalliative setting it is typically delivered 5 days per week over 5 to 8 weeks to a total dose of 45 to 80 Gy. The other fractionation schedules are defined by overall treatment duration and total dose of radiation as compared with conventional fractionation.

Hypofractionation refers to fraction sizes that are larger than conventionally fractionated radiation therapy, and are delivered once daily. Typically, a lower total dose is delivered and designed to achieve the same tumor control probability (TCP) as conventional fractionation. Common examples of hypofractionation in the United States are palliative therapy regimens of 30 Gy in 10 fractions over a 2-week period or 8 Gy in a single fraction. The difficulty with hypofractionation is the effect of the larger dose per fraction on normal tissues, specifically negating the normal tissue-sparing effects of fractionation. As a consequence, this leads to lower total dose threshold tolerances for toxicity in normal tissues compared with conventional fractionation, and thus, historically, the reluctance to increase the total dose delivered to a tumor that may be adjacent to sensitive structures (e.g., the spinal cord). Recent technological advancements in patient immobilization and image-guided radiation therapy (IGRT) have allowed for the safe delivery of large cumulative doses of highly hypofractionated radiation (e.g., 10 to 18 Gy per fraction) with subcentimeter accuracy and excellent clinical outcomes. Reported results of hypofractionated stereotactic body radiation therapy (SBRT) in the treatment of early stage non–small cell lung cancer have shown local–regional control rates, metastatic disease control rates, and cancer-specific survival similar to surgical management, with minimal normal tissue toxicity (JAMA2010;303(11):1070).

The basic rationale of hyperfractionation is that the use of small doses per fraction of 1.1 to 1.2 Gy allows higher total doses to be delivered over the same treatment duration as compared with conventional fractionation, but within the tolerance of late-responding tissues—late-responding tissues such as bowel, spinal cord, kidney, lung, and bladder have the same probability of complications with hyperfractionation. However, the patient will experience more acute reactions as a result of the larger total dose. The typical period between daily fractions is 6 hours to allow late tissue repair. An example of hyperfractionation is 69.6 Gy total dose delivered over a 6-week period in twice-daily fractions of 1.2 Gy for non–small cell lung cancer.

The basic rationale for accelerated fractionation is that a reduction in overall treatment time decreases the opportunity for tumor cell regeneration during treatment and therefore increases the TCP for a given total dose. Therefore, the fraction size is decreased, and the treatment duration is decreased as compared with conventional fractionation. An example of accelerated fractionation is the delivery of 45 Gy in 30 twice-daily fractions of 1.5 Gy separated by a minimum of 6 hours over a 3-week period in the treatment of small cell lung cancer.

1. Prolongation of overall treatment time, tumor control, and morbidity. Treatment interruptions result in a lower TCP for the same total dose received. The total dose of irradiation to produce a given TCP must be increased when fractionation is prolonged beyond 4 weeks because of repopulation of surviving cells, which may result in improved nutrition of those cells after early shrinkage of the tumor due to the initial radiation fractions. Taylor et al. (Radiother Oncol 1990;17:95) estimated a >1 Gy increment in isoeffect dose per day in 473 patients with squamous cell carcinoma of the head and neck treated with irradiation.

 VI. RADIATION TREATMENT PLANNING

1. Introduction to treatment planning. The International Commission on Radiation Units and Measurements (ICRU) Report No. 50, and more recently No. 62, define the volumes of interest in treatment planning (ICRU 50, Prescribing, Recording, Reporting, Photon Beam Therapy. Washington, DC: International Commission on Radiation Units and Measurements, 1994; ICRU 62, Prescribing, Recording, Reporting, Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda, MD: International Commission on Radiation Units and Measurements, 1999). The delineation of tumor and target volumes is a crucial step in radiation therapy planning. Gross tumor volume (GTV) is defined as all known gross disease, including involved regional lymph nodes, and is determined using physical examination findings and imaging tools, like computed tomography (CT) imaging, MRI, and/or positron emission tomography (PET). Clinical target volume (CTV) encompasses the GTV plus regions considered to harbor potential microscopic disease. The internal margin (IM) is a margin that accounts for variations in size, shape, and position of the CTV due to physiological processes, such as bladder filling/emptying and tumor movement during respiration, and is added to the CTV to constitute the internal target volume (ITV). The setup margin (SM) is a margin that accounts for day-to-day uncertainties in patient positioning and alignment of beams during treatment planning. The final volume, that is, the actual treated target, is called the planning target volume (PTV), and consists of the SM added to the ITV. In shorthand, PTV = (CTV + IM) + SM = ITV + SM. Additionally, organs and normal structures that surround the PTV are defined as organs at risk (OAR), and play a critical role in the planning phase and evaluation of a treatment plan. The planning organ at risk volume (PRV) is analogous to the PTV volume, and is defined as PRV = OAR + IM + SM.

Simulation is the process used to accurately identify the tumor volume(s) and OAR in order to determine the optimal configuration of radiation beam portals necessary to treat the tumor and avoid sensitive structures. Modern radiation therapy planning systems use CT scanning for simulation in which patients are placed in their planned treatment positions using various immobilization devices. Individual CT slices can be imaged several times during CT simulation to capture the movement of the GTV and OARs due to respiratory excursion and other physiological processes (also known as 4D-simulation). CT scan images are obtained of the area(s) of interest, and contours are delineated (GTV, CTV, ITV, PTV, OAR, and PRV) from the CT images at a computer workstation. The conventional simulator had been the workhorse of simulation in the past, consisting of a table and gantry with 360 degrees of rotation as well as fluoroscopy and diagnostic x-ray capability, but it has been replaced by CT simulation in the vast majority of treatment centers.

The goal of treatment planning is to adequately irradiate the PTV(s) while at the same time attempting to avoid surrounding OAR, thus minimizing acute and late toxicity. Various steps can be taken to decrease toxicity in normal tissues, including precise treatment planning and irradiation techniques, selectively decreasing the volume receiving higher doses, and maneuvers to exclude sensitive organs from the irradiated volume. With the emphasis on organ preservation (which is being applied to patients with tumors in the head and neck, breast, and rectosigmoid, and soft tissue sarcomas), treatment planning is critical to achieve a maximum therapeutic ratio.

1. Three-dimensional treatment planning and intensity modulated radiation ­therapy. The CT simulator allows more accurate definition of tumor volume and anatomy of critical normal structures, three-dimensional (3D) treatment planning to optimize dose distribution, and radiographic verification of volume treated, as is done with conventional simulators (Int J Radiat Oncol Biol Phys 1994;30:887). Advances in computer technology have augmented accurate and timely computation, display of 3D radiation dose distributions, and dose–volume histograms (DVHs). 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.

In addition, DVHs are extremely useful as a means of dose display, particularly in assessing several treatment plan dose distributions. They provide a graphic summary of the entire 3D dose matrix, showing the amount of target volume or critical structure receiving more than a specified dose level. Because they do not provide spatial dose information, they cannot replace the other methods of dose display such as room-view displays, but can only complement them. For example, the DVH may show the percentage PTV receiving the prescribed dose, but cannot locate the portion of the PTV receiving less than the prescribed dose. Treatment verification is another area in which 3D treatment-planning systems play an important role. Digitally reconstructed radiographs of sequential CT slice data are used to generate a simulation film that can be used to aid in portal localization and comparison with the treatment portal film for verifying treatment geometry.

Intensity modulated radiation therapy is an advanced form of 3D treatment planning and conformal therapy that optimizes the delivery of radiation to irregularly shaped volumes through a process of complex inverse treatment planning and dynamic delivery of radiation that results in modulated fluence (intensity) of photon beams. By varying the fluence across multiple treatment fields, the radiation dose can be modulated to conform to irregular shapes (i.e., concave) and to design a heterogeneous dose distribution. Several IMRT hardware and software packages are commercially available including rotational slice-by-slice, dynamic multileaf, static (step and shoot) multileaf, milled compensator, and helical tomotherapy and arc delivery systems. Central to intensity modulation is the development of multileaf collimators (MLCs) and the concept of inverse treatment planning. MLCs are a set of shielding vanes measuring 0.5 to 1 cm wide that are located in the head of the linear accelerator and shape the radiation portal. Each vane is controlled independently and can remain static (static MLC) or move across the treatment field during “beam on” time (dynamic MLC). To understand inverse treatment planning, one must first understand traditional forward treatment planning. Under forward treatment planning, the radiation oncologist draws the radiation portals, considers the dose distribution generated by those portals, and adjusts the portals according to the desired dose distribution. Forward planning is cumbersome. Inverse planning reverses that order. The radiation oncologist contours the desired target volumes and critical structures to be avoided and prescribes an ideal dose distribution. Inverse planning starts with the ideal dose distribution and finds, through mathematical optimization algorithms, the beam characteristics (fluence profiles) that produce the best approximation of the ideal dose. IMRT is in widespread clinical use, and has clear advantages for treatment of many cancer sites.

1. Image-guided radiation therapy and stereotactic radiation therapy. The increased sophistication in treatment planning and radiation delivery requires parallel precision in patient immobilization, as well as patient and tumor position verification. This requirement has led to the development and implementation of IGRT. IGRT consists of the ability to image the patient, or optimally the tumor or a tumor surrogate, on a daily basis before or even during treatment. The daily images taken before or during treatment are used for patient and tumor positioning, greatly reducing random and systematic errors in daily localization between and during fractions of delivered radiation. Examples of common imaging modalities used before treatment include ultrasonography, optical (light-based) devices, on-board kV fluoroscopy, x-ray, and cone-beam CT, and megavoltage computed tomographic (MVCT) imaging. Image guidance systems that have the ability to image during radiation treatment include the Cyberknife kV-x-ray tracking system, the Calypso beacon localization system, and, most recently, the ViewRay radiation delivery system with on-board real-time MRI.

Because IGRT leads to improvements in daily patient and tumor localization, it allows the radiation oncologist to decrease the size of the setup margin when creating a PTV. In consequence, the PTV that is being irradiated to a particular dose can be significantly reduced without sacrificing local tumor control, and also can minimize normal tissue toxicity by reducing the irradiated volume of the surrounding OAR (Int J Radiat Oncol Biol Phys2012;84(1):125). Additionally, there is evidence that the combination of IGRT and IMRT can further reduce complications compared with more conventional, non-IGRT, 3D treatment techniques (Radiat Oncol2014;9:44). IGRT also allows for treatment gating, where the radiation beam can be turned on and off during treatment as the radiation therapist and radiation oncologist visualize the tumor, or tumor surrogate, on a computer screen as it moves in and out of the target volume because of normal physiologic processes like respiratory motion or bladder and rectal filling and emptying. The benefit of gating is the possibility of further reductions in margin size and PTV volume(s).

Continued improvements in the geometric accuracy of radiation delivery, as well as the development of advanced treatment techniques that allow for excellent coverage of irregularly shaped targets with surrounding steep dose gradients, has led to the development of effective treatment strategies that safely deliver very large doses of radiation to targets in very close proximity to sensitive structures or previously irradiated fields.

An excellent example is the ever-expanding use of hypofractionated SBRT in the definitive and palliative treatment of many different cancers. SBRT was initially developed to treat intracranial lesions with large single doses of radiation and is known as stereotactic radiosurgery (SRS) in this setting. The SRS system with the longest experience involves a frame that is rigidly attached to the patient’s head using surgical screws and defines a three-dimensional coordinate system. The location of the lesion is defined within this coordinate system using different diagnostic imaging tools, like CT or MRI, with the frame in place. The patient is aligned on the treatment machine according to the location of the lesion within the coordinate system relative to the rigid frame rather than to anatomic surrogates. Using MRI-based localization techniques, the immobilization provided by the rigid stereotactic frame allows for the delivered radiation therapy to be accurate within 1 to 2 mm (Neurosurgery 2001;48(5):1092). The accuracy of the system allows for the safe delivery of large doses of radiation therapy near critical and sensitive structures, like the optic chiasm and optic nerves. It has been used mostly for the treatment of brain metastases, but also pituitary adenomas/carcinomas, meningiomas, and benign intracranial pathologies, such as arteriovenous malformations and trigeminal neuralgia. Examples of SRS delivery systems included linear accelerator–based cone or micro multileaf collimators systems, as well as the ⁶⁰Co Gamma-Knife radiosurgery system. Although very accurate, the invasiveness of the stereotactic frame has significantly limited its application to other tumor sites. Modern immobilization devices, such as the thermoplastic S-frame mask and the semi-rigid vacuum body fixation system, have achieved geographic accuracies similar to SRS rigid frames, both for intra- and extracranial targets (Int J Radiat Oncol Biol Phys2012;84(2):520). The addition of image guidance allows for further refinement in patient positioning, and may also provide inter- and intra-fraction localization of targets and OAR that may move day-to-day because of normal physiologic processes. Failing to account for this movement can potentially lead to a geographic miss during high-dose radiation delivery, and unexpected irradiation of an adjacent sensitive structure to unacceptable dose levels.

SBRT is the application of SRS techniques to tumors or tumor surrogates in the body, but with the treatment machine being aligned to the tumor or tumor surrogate itself using image guidance. Spine SBRT is an excellent example of a growing treatment modality that uses the aforementioned technological advancements to deliver very high doses of radiation to lesions only a few millimeters from the spinal cord—a relatively radiosensitive structure with consequences of neurologic toxicity that can be devastating. Institutional studies have shown excellent pain and local control rates approaching 90% at 1 to 2 years, with <5% incidence of any severe toxicity, and no incidence of severe spinal cord toxicity (J Neurosurg Spine 2007;7(2):151–160; Int J Radiat Oncol Biol Phys 2011;81(2):S131). In addition to the treatment of early stage lung cancers, brain lesions, and spinal metastases, SBRT has also been used to treat liver malignancies, with promising results (J Clin Oncol 2013;31(13):1631). Recent interest has focused on the use of SBRT and its excellent local control rates in the treatment of patients with limited metastatic burden, or oligometastatic disease, typically defined as the presence of 1 to 5 metastatic lesions. It is believed that these patients do not have widespread subclinical metastases, but disease confined to 1 to 5 areas, with possibility of cure, and thus deserving of aggressive local treatment (J Clin Oncol 1995;13(1):8–10). This is an active area of research, and clinical trials are forthcoming.

It is imperative to understand that SBRT is a highly sophisticated and complex treatment technique that requires advanced equipment, and a dedicated staff of highly trained, competent, and experienced radiation therapists, dosimetrists, physicists, and radiation oncologists to deliver the treatment effectively and safely.

 VII. COMBINATION OF THERAPEUTIC MODALITIES

1. 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 main disadvantage of preoperative irradiation is that it may interfere with normal healing of the tissues affected by the radiation. Such interference, however, is minimal when radiation doses are less than 45 to 50 Gy in 5 weeks.

The rationale for postoperative irradiation is based on the fact that it is possible to eliminate any residual tumor in the operative field by destroying subclinical or microscopic foci of tumor cells after the surgical procedure by eradicating adjacent subclinical foci of cancer (including lymph node metastases) and by delivering higher doses than can be achieved with preoperative irradiation, the greater dose being directed to the volume of high-risk or known residual disease.

The potential disadvantages of postoperative irradiation are related to the delay in initiation of radiation therapy until wound healing is completed. Theoretical and experimental evidence suggests that the radiation effect may be impaired by vascular changes produced in the tumor bed by surgery.

1. Irradiation and chemotherapy. Chemotherapy and radiation therapy are combined to obtain an additive or supra-additive effect (Halperin EC, Perez CA, Brady LW, eds. Radiation Oncology: Technology and Biology. Philadelphia, PA: WB Saunders, 1994:113). Enhancement describes any increase in effect greater than that observed with either chemotherapy or irradiation alone on the tumor or normal tissues. Calculation of the presence of additivity, supra-additivity, or sub-additivity is simple when dose–response curves for irradiation and chemotherapy are linear. When chemotherapeutic agents are used, the agents should not be cross-resistant, and each agent should be quantitatively equivalent to the other.

Chemotherapy alone or combined with irradiation may be used in several settings. 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. Frei (J Natl Cancer Inst1989;80:1088) proposed the term neoadjuvant chemotherapy when this modality is used in the initial treatment of patients with localized tumors, before surgery or irradiation.

Administration of chemotherapy before irradiation produces some cell killing and reduces the number of cells to be eliminated by the irradiation. Use of chemotherapy during radiation therapy has a strong rationale because it could interact with the local treatment (additive and even supra-additive action) and could also affect subclinical disease early in treatment. Nevertheless, the combination of modalities may enhance normal tissue toxicity.

1. Integrated multimodality cancer management. Combinations of two or all three of the classic modalities are frequently used to improve tumor control and patient survival. Steel and Peckham (Steel GC, Adams GE, Peckham MJ, eds. The Biological Basis of Radiotherapy. Amsterdam, The Netherlands: Elsevier Science, 1983:239) 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, as it enhances the quality of life and psychoemotional feelings of our patients with excellent tumor control and survival, as has been demonstrated in many tumors.

VIII. FOLLOW-UP. Continued support of the patient during therapy is mandatory, with at least one weekly evaluation by the radiation oncologist to assess the effects of treatment on the tumor and the side effects of therapy. Psychological and emotional reinforcement, medications, dietetic counseling, oral cavity care, and skin care instructions are integral parts of the management of these patients and should result in better therapeutic outcome.

 IX. QUALITY ASSURANCE. A comprehensive quality assurance program is critical in any radiation oncology center to ensure the best possible treatment for the individual patient and to establish and document all operating policies and procedures.

 Quality assurance procedures in radiation therapy will vary, depending on whether standard treatment or a clinical trial is carried out at single or multiple institutions. Particularly in multi-institutional studies, clear instructions and standardized parameters are needed in dosimetry procedures, treatment techniques, and treatment planning to be carried out by all participants. Many reports of the Patterns of Care Study demonstrate a definite correlation between the quality of the radiation therapy delivered at various types of institutions and the outcome of therapy.

 The director of the department appoints the Quality Assurance Committee, which meets regularly to review the following: results of review and audit process, physics quality assurance program report, outcome studies, mortality and morbidity conference, any case of “misadministration” or error in delivery of more than 10% of the intended dose, and any chart in which an incident report is filed. Additional details can be obtained from the American College of Radiology.

SUGGESTED READINGS

Halperin EC, Bardy LW, Perez CA, et al. Perez & Brady’s Principles and Practice of Radiation Oncology, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2013.

ICRU 50, Prescribing, Recording, Reporting, Photon Beam Therapy. Washington, DC: International Commission on Radiation Units and Measurements, 1994.

ICRU 62, Prescribing, Recording, Reporting, Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda, MD: International Commission on Radiation Units and Measurements, 1999.

Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303(11):1070–1076.