Ramesh Rengan, Indrin J. Chetty, Roy Decker, Corey J. Langer, William P. O’Meara, and Benjamin Movsas
EPIDEMIOLOGY
Throughout the world, lung cancer accounts for 13% (1.6 million) of the total cases of cancer and 18% (1.4 million) of the cancer-related deaths based on 2008 estimates.1 Among males, lung cancer is the most commonly diagnosed cancer and leading cause of cancer death. Among females worldwide, it is the fourth most commonly diagnosed cancer and the second leading cause of cancer death.
In the United States, lung cancer is the second most common cancer and the most common cause of cancer-related death in both men and women. The American Cancer Society estimates 156,940 people in the United States died of lung cancer in 2011, including 85,600 men and 71,340 women.2 More people in the United States die of lung cancer than from breast, prostate, and colorectal cancer combined. The overall 5-year survival rate for lung cancer is approximately 16%.3
The overall incidence and mortality rate for lung cancer rose steadily from the 1930s until peaking in the early 1990s. The incidence and mortality rates for men began to drop around 1990, and the latest analysis demonstrates a drop in the incidence and mortality rates for women for the first time.4 The lag in the trend of lung cancer rates in women compared with men reflects historical differences in cigarette smoking between the sexes; cigarette smoking in women peaked about 20 years later than in men. Gender and racial disparities exist in the incidence and mortality for lung cancer with rates highest in men, particularly those who are African American.2,5 In terms of socioeconomics, lung cancer demonstrates the largest disparity of all cancers, with the death rate in men five times higher for the least educated than for the most educated.2
Although the lung cancer numbers in the general population are startling, the main risk of lung cancer is based on exposures to carcinogens; most lung cancer cases are attributable to cigarette smoking. Voluntary or involuntary cigarette exposure accounts for 80% to 90% of all cases of lung cancer.6 Since the 1964 landmark report by U.S. Surgeon General citing smoking as a causal agent for the development of lung cancer,7 the prevalence of smoking in the United States has declined significantly. More recently, exposure to secondhand smoke has been considered a risk for lung cancer with up to a 30% increase in risk from secondhand smoke exposure associated with living with a smoker.8 Indoor radon exposure is now considered the second leading cause of lung cancer in the United States.9 Other known risk factors for lung cancer include exposure to occupational and environmental carcinogens such as asbestos, arsenic, and polycyclic aromatic hydrocarbons.10–13
ANATOMY
In the past, a simplified and relatively superficial understanding of thoracic anatomy provided an acceptable framework for the radiation oncologist to design treatment fields in lung cancer patients utilizing conventional techniques with the carina and bony structures as landmarks. As the field of thoracic radiation oncology has moved toward more conformal therapy, however, a more detailed understanding of thoracic anatomy is essential for proper target delineation and treatment design.
The lungs are situated on each side of the mediastinum, which contains the heart, trachea, esophagus, and great vessels. The lungs are conical in shape with an apex projecting upward into the neck for approximately 2 to 3 cm above the clavicle, a base sitting on the diaphragm, a costal surface along the chest wall, and a mediastinal surface that is molded to the heart and other mediastinal structures. Visceral pleura cover the lungs, and parietal pleura cover the inside of the chest cavity. The lungs are freely suspended but are rooted to the mediastinum by the structures emerging from the hilum.
The lungs are divided into distinct lobes—three lobes to the right lung and two to the left. The right lung is divided into the upper, middle, and lower lobes by the oblique (major) and horizontal (minor) fissures. The oblique fissure runs forward and downward from approximately the level of the fifth thoracic vertebral body to the diaphragm, dividing the lungs into upper and lower lobes. The horizontal fissure separates the right middle from the right upper lobe, fanning out forward and laterally from the hilum. The middle lobe is thus a small, triangular lobe bounded by the horizontal and oblique fissures and actually rests on the diaphragm. The left lung is divided by only the oblique fissure into two lobes—the upper and lower lobes. The lingula, located in the left upper lobe, is homologous to the right middle lobe and also touches the diaphragm.
The bronchopulmonary segment is the functional unit of the lung and is defined by the segmental bronchi. The trachea bifurcates at the carina, which lies at the junction between the manubrium and body of the sternum, into the right and left main bronchi. Each main bronchus divides into lobar bronchi, each supplying a lobe of the lung. Although the lingula is located in the left upper lobe, the lingular bronchus is considered by many a lobar bronchus. Each lobar bronchus divides into smaller bronchi that form the bronchopulmonary segments. These segments are pyramidal in shape, with an apex toward the lung root and a base at the pleural surface. Structures entering each bronchopulmonary segment (i.e., bronchus and artery) tend to lie centrally. Structures leaving the segment (i.e., veins and lymphatics) lie in the periphery of the segment within the connective tissue that separates the segments.14Segmental bronchi divide into bronchioles, continue to branch, and eventually form the alveoli, where blood-gas exchange occurs.
The main lymphatic drainage for each bronchopulmonary segment follows the vasculature and airways toward the hilum, where it ultimately drains into the mediastinum. However, the rich network of lymphatics within the thorax leads to complex variability in drainage patterns.15
For nearly half a century, lymph node maps have been used in lung cancer to describe the clinical and pathologic extent of lymph node involvement.16 Two such maps—the Naruke lymph node map17 and the Mountain/Dresler map18—have been used the most. Recently, however, the International Association for the Study of Lung Cancer (IASLC) proposed a new lymph node map that reconciles differences among currently used maps and provides precise anatomic definitions for all lymph node stations.16 The IASLC lymph node map has been endorsed by the American Joint Committee on Cancer (AJCC) and incorporated into the seventh edition of its staging manual. Figure 51.1 shows the IASLC lymph node map, which designates 14 levels of intrapulmonary, hilar, and mediastinal lymph nodes stations. The IASLC also compartmentalized the stations into zones that appear to have prognostic implications and are already utilized in common clinical practice.
FIGURE 51.1. The International Association for the Study of Lung Cancer lymph node map for lung cancer staging. (From Lababede O, Meziane M, Rice T. Seventh edition of the Cancer Staging Manual and stage grouping of lung cancer. Chest 2011;139(1):183–189, with permission.)
CLINICAL PRESENTATION AND PATTERNS OF SPREAD
Lung cancer spreads locally by direct extension of the primary tumor, regionally via involvement of the lymphatics, and distantly via invasion into vascular channels leading to hematogenous spread. In a recent Surveillance Epidemiology and End Results (SEER) analysis involving all lung cancer histologies, 15% of all cases of lung cancer were localized to the primary site at initial diagnosis; 22% had regional lymph node spread, and 56% distant metastasis; and the remaining 7% were stage unknown.19 In non–small cell lung cancer (NSCLC), half the patients present with localized or locally advanced disease and half with advanced disease. In small cell lung cancer (SCLC), 20% to 30% present with locally advanced disease, and 70% to 80% present with advanced disease. Table 51.1 shows the site of metastasis based on histologic type.20 Signs and symptoms of lung cancer directly reflect the patient’s local, regional, or distant pattern of spread.
FIGURE 51.2. The American Joint Committee on Cancer released the seventh edition of its lung cancer TNM staging system in 2009. The T classification can be defined by evaluating the size first (upper left), then upgrading the classification (if necessary) based on the other criteria of primary tumor invasion/extent (A, B, and C). The criteria of extent should not be used to assign a lower classification. The lower diagram can be used to define the N and M classification and to determine the corresponding stage. Note that N1, N2, N3, and the separate tumor nodule of M1a were depicted in the lower illustration based on a right-sided tumor (T). For left lung tumors, a mirror image of these descriptors should be used. Additionally, the endobronchial extension and local invasion (A and B of the extent criteria) were shown in the upper illustration based on a left-sided tumor to simplify the drawing. (From Lababede O, Meziane M, Rice T. Seventh edition of the Cancer Staging Manual and stage grouping of lung cancer. Chest 2011;139(1):183–189, with permission.)
TABLE 51.1 SITE OF METASTASIS CORRELATED WITH HISTOLOGIC SUBTYPE IN LUNG CANCER: NECROPSY FINDINGS IN CARCINOMA OF THE BRONCHUS IN 255 PATIENTS WITH METASTASES TO 431 SITES
Intrathoracic Spread
The intrathoracic spread of lung cancer involves direct extension of the primary tumor or lymphatic spread to regional lymph nodes involving the hilum or mediastinum. There is a wide range of symptoms owing to the intrathoracic effects of lung cancer; the most common include cough, dyspnea, hemoptysis, and chest pain.
The central etiology for many symptoms is owing to a growing tumor involving the airway. Cough is present in 50% to 75% of lung cancer patients at presentation and occurs most frequently in patients with squamous cell and small cell carcinomas because of their tendency to involve central airways.21,22 As central airway involvement progresses, wheezing may develop. Additionally, tumor eroding into a blood vessel or bleeding from the neovasculature supplying the tumor may lead to hemoptysis, which is a presenting symptom in approximately 25% of patients.23 If tumor blocks airflow through a portion of the lung, shortness of breath may develop and is identified at presentation in approximately 25% of cases.21,24 Dyspnea may also be due to the development of atelectasis, postobstructive pneumonia, or a pleural or pericardial effusion.
Chest pain is present in approximately 20% of patients presenting with lung cancer.21,24 Pain may be attributed to direct extension to the mediastinum, parietal pleura, or chest wall. Pleuritic pain may also be the result of obstructive pneumonitis or a pulmonary embolus related to a hypercoagulable state. Pleural involvement can also manifest as pleural thickening or pleural effusion. During the course of lung cancer, 10% to 15% of all cases will eventually develop a malignant pleural effusion.25
Direct extension of a central primary tumor or mediastinal lymph node involvement may lead to nerve involvement. Involvement of the recurrent laryngeal nerve along its course under the arch of the aorta can result in hoarseness. Irritation of the phrenic nerve may initially produce hiccups, and progressive damage can produce unilateral paralysis of the diaphragm with shortness of breath.
Obstruction of the superior vena cava (SVC) from primary tumor or mediastinal lymphadenopathy causes symptoms that commonly include a sensation of fullness in the head and dyspnea. Physical findings include jugular venous distension and occasionally swelling of the face and arms. SVC syndrome is more common in patients with SCLC than NSCLC. The pathophysiology and treatment options for the management of patients with SVC syndrome are discussed in more detail later.
Primary tumors arising within the superior sulcus may produce the classic Pancoast’s syndrome manifested by shoulder pain, Horner’s syndrome, and brachial plexopathy. Pancoast’s syndrome is most commonly caused by NSCLC and only rarely by SCLC. The treatment of patients with superior sulcus tumors (SSTs) will be discussed later.
Distant Extrathoracic Spread
Once vascular or lymphatic invasion occurs, metastatic dissemination to distant sites is common. Contralateral lung, liver, bone, adrenals, and brain are the most frequent sites of distant disease; however, lung cancer can spread to any part of the body (Table 51.1).
Asymptomatic liver metastases may be detected at presentation by liver enzyme abnormalities or on staging workup imaging. Among patients with otherwise resectable NSCLC in the chest, computed tomography (CT) evidence of liver metastasis has been identified in approximately 3% of cases.26 Positron emission tomography (PET) or integrated PET-CT identifies unsuspected metastases in the liver or adrenal glands in about 4% of patients.27,28 Autopsy studies have identified hepatic metastases in >50% of patients with either NSCLC or SCLC.29,30
Pain in the back, chest, or extremity and elevated levels of serum alkaline phosphatase are usually present in patients with bone metastasis. The serum calcium may be elevated owing to extensive bone disease, although the majority of patients with elevated calcium have paraneoplastic parathyroid hormone (PTH)-like syndrome. Approximately 20% of patients with NSCLC and 30% to 40% of patients with SCLC have bone metastases at presentation.31,32 An osteolytic radiographic appearance is more frequent than an osteoblastic one, although a mixed picture is common. The most common sites of involvement are the vertebral bodies.
The adrenal glands are a frequent site of metastasis; however, such metastases are only rarely symptomatic. Concern about adrenal metastasis usually occurs when a unilateral mass is found by staging CT in a patient with a known or suspected lung cancer. Most adrenal masses detected on staging scans are benign, as illustrated by a series of 330 patients with operable NSCLC in which 32 (10%) had an isolated adrenal mass.33 Only 8 of these 32 patients (25%) had a malignancy. Conversely, a negative imaging study does not exclude adrenal metastases. A study of patients with SCLC found that 17% of adrenal biopsies showed metastatic involvement despite having a normal CT scan.34The lack of specificity of an initial CT scan in identifying an adrenal mass creates a special problem in patients with an otherwise resectable lung cancer. In this situation, PET may be particularly useful in distinguishing a benign from malignant adrenal mass.35 Other procedures that may be useful in excluding a metastasis include magnetic resonance imaging (MRI) consistent with a benign adenoma or a negative needle biopsy. Involvement of the adrenal glands is more frequent in patients with widely disseminated disease. In autopsy series, adrenal metastases were identified in about 40% of patients with lung cancer.30 Patients with an isolated adrenal metastasis but otherwise limited thoracic disease seem to have a much better prognosis than other stage IV disease and may be considered for aggressive definitive management.36,37
Symptoms from brain metastasis include headache, vomiting, visual field loss, hemiparesis, cranial nerve deficit, and seizures. In patients with NSCLC, the frequency of brain metastasis is greatest with adenocarcinoma and least with squamous cell carcinoma. The risk of brain metastasis increases with larger primary tumor size and regional node involvement.38 In patients with SCLC, metastasis to brain is present in approximately 20% to 30% of patients at presentation.39 Without prophylactic irradiation, relapse in the brain occurs in about one-half of patients within 2 years.40 An autopsy series of SCLC patients disclosed central nervous system (CNS) metastases in 80% of cases.41
Paraneoplastic Syndromes
A paraneoplastic syndrome is a disease or symptom that is the consequence of cancer cells in the body but is not attributable to the local presence of tumor. These phenomena are thought to be mediated by humoral factors secreted by tumor cells or by an immune response against the tumor. Treating the cancer, if successful, usually resolves the syndrome. Some of the more common paraneoplastic syndromes are described next.
Cushing Syndrome
Ectopic production of adrenocorticotropic hormone (ACTH) can cause Cushing’s syndrome. Patients typically present with muscle weakness, weight loss, hypertension, hirsutism, and osteoporosis. Hypokalemic alkalosis and hyperglycemia are usually present. Cushing’s syndrome is relatively common in patients with SCLC and with carcinoid tumors of the lung. SCLC patients with Cushing’s syndrome appear to have a worse prognosis than those without Cushing’s syndrome.42–44
Syndrome of Inappropriate Antidiuretic
Hormone Secretion
The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is frequently caused by SCLC and results in hyponatremia. Approximately 10% of patients who have SCLC exhibit SIADH, and SCLC accounts for approximately 75% of all SIADH.45,46 Symptoms include headache, muscle cramps, anorexia, and decreased urine output. If left untreated, cerebral edema can develop, leading to mental status changes, coma, seizures, and respiratory arrest. Besides treating the underlying cancer, demeclocycline is the agent of choice.
Hypercalcemia
Hypercalcemia in patients with lung cancer may be attributable to the secretion of a parathyroid hormone–related protein (PTHrP), calcitriol, or other cytokines, including osteoclast activating factors. In one study of 1,149 consecutive lung cancers, 6% of patients had hypercalcemia.47 Among those with hypercalcemia, squamous cell carcinoma, adenocarcinoma, and SCLC were responsible in 51%, 22%, and 15% of cases, respectively. Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, lethargy, polyuria, polydipsia, and dehydration. Renal failure, confusion, and coma are late manifestations.
Lambert-Eaton Myasthenic Syndrome
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by muscle weakness of the limbs that improves with repeated testing, in contrast to myasthenia gravis, which worsens with repetition. Proximal muscles are predominantly affected, and patients complain of difficulty climbing stairs and rising from a sitting position. Approximately 3% of patients with SCLC exhibit LEMS, and SCLC accounts for approximately 60% of all LEMS.48 The neurologic symptoms of LEMS precede the diagnosis of SCLC in >80% of cases, often by months or years.
Hypertrophic Osteoarthropathy
Hypertrophic pulmonary osteoarthropathy (HPO), most frequently associated with adenocarcinoma, is defined by clubbing and periosteal proliferation of the tubular bones. HPO is further characterized by a symmetrical, painful arthropathy that usually involves the ankles, knees, wrists, and elbows. A radiograph of the long bones shows characteristic periosteal new bone formation. A bone scan or PET typically demonstrates diffuse uptake by the long bones. In a series of 111 lung cancer patients, clubbing was present in 29%.49
SCREENING, DIAGNOSTIC STAGING, AND WORKUP
Screening for Lung Cancer
Given the high mortality rate of lung cancer and that the majority of patients are diagnosed at a late stage, lung cancer researchers have theorized that identifying lung cancer at an earlier stage might improve outcomes. Thus, lung cancer has been considered as a candidate for cancer screening. Early screening trials involving chest x-rays and/or sputum failed to demonstrate a survival benefit.50–52 The role of screening has recently been reinvestigated with the advent of spiral CT scans. Early pilot trials of spiral CT in lung cancer screening looked promising with an increase in the identification of stage I detectable cancer. A subsequent international observational trial using spiral CT screening in a cohort of 31,000 high-risk individuals corroborated the findings, showing that annual spiral CT screening could detect lung cancer at an early, potentially more curable stage, suggesting that the stage I disease detection rate and 10-year survival rate could both exceed 80%.53 With a possible mortality benefit theorized but not yet proven, some researchers countered that the use of spiral CT screening might not significantly reduce the mortality risk for lung cancer.54 This set the groundwork for the landmark National Lung Screening Trial (NLST). From August 2002 through April 2004, 53,454 current or former heavy smokers at 33 U.S. medical centers were randomly assigned to three annual screenings with either low-dose CT (26,722 participants) or standard chest x-ray (26,732). Eligible participants were between 55 and 74 years of age with a history of cigarette smoking of at least 30 pack-years and, if former smokers, had quit within the previous 15 years. Persons who had previously received a diagnosis of lung cancer, had undergone chest CT within 18 months before enrollment, had hemoptysis, or had an unexplained weight loss >6.8 kg (15 lb) in the preceding year were excluded. The findings revealed that participants who received low-dose helical CT scans had a 20% relative reduction in risk of death caused by lung cancer compared with the control radiography group (p = .004). Additionally, the all-cause mortality was reduced in the CT screening group by 6.7% when compared with the control group (p = .02). This is the first randomized trial to demonstrate a reduction in all-cause mortality with screening.55 This demonstrates that the benefits to screening outweigh the potential risk from biopsy and further diagnostic intervention in patients who had a false-positive screen. Although this is clearly a landmark study, it is unclear at this time whether this trial alone will lead to a paradigm shift in screening for lung cancer with CT. A key issue relates to the cost-benefit ratio of lung cancer screening with low-dose CT. Several similar randomized CT screening trials are under way.56–60
Diagnostic Staging and Workup
When a patient presents with suspected lung cancer, testing is indicated to confirm the diagnosis, identify the histologic type, and determine the disease stage, all in an effort to guide management decisions. The process begins with a thorough history and physical examination to identify signs or symptoms suggestive of locally extensive or metastatic disease, assess pulmonary health status, identify significant comorbidities, and assess overall health status. Each impacts the therapeutic options in a more comprehensive manner than stage alone. A detailed history should also elicit tobacco use and past exposure to environmental carcinogens. Weight loss >5% from baseline has direct prognostic implications for survival in lung cancer.61–63
Physical examination of the chest may detect signs of partial or complete obstruction of the airways, pneumonia, or pleural effusion. Examination of the neck can reveal evidence of supraclavicular lymphadenopathy. Abdominal examination may detect hepatomegaly. Neurologic examination can detect signs of brain metastasis.
Laboratory studies include complete blood count, liver function tests, and serum electrolytes including calcium. Renal function tests should be performed to assess whether the patient can tolerate intravenous contrast for CT examination or subsequent platinum-based therapy. Liver function test abnormalities could be owing to liver metastasis. Elevation of alkaline phosphatase could be owing to liver or bone metastasis. Calcium elevation could be owing to bone metastasis or paraneoplastic syndrome. Anemia could be owing to metastatic disease.
Radiologic Examinations
Chest X-Ray
Chest x-ray is the initial imaging modality for evaluating a patient with suspected lung cancer. The current x-ray should be compared to prior ones, if available, to determine if a lesion is new, enlarging, or stable.
Computed Tomography
All patients with suspected lung cancer, with or without an abnormal chest x-ray, should undergo a contrast-enhanced CT scan of the chest and upper abdomen to include the entire liver and adrenal glands. Intravenous contrast helps to distinguish vascular structures from mediastinal structures. This not only adds detail to the imaging characteristics of the primary tumor but is also critical to accurately identify suspicious lymph nodes in the mediastinum. CT assessment can establish T-stage by determining tumor size, presence of separate tumor nodules, presence of atelectasis or postobstructive pneumonia, invasion of adjacent structures, and proximal extent of the tumor.
Lymph node enlargement on CT presumes lymph node metastasis in the context of newly diagnosed lung cancer. Most normal mediastinal lymph nodes measure <1 cm, although normal subcarinal lymph nodes can reach a diameter of 1.5 cm. In a patient with known lung cancer, a lymph node is considered suspicious if it measures >1 cm in diameter on its short axis. Unfortunately, many subcentimeter regional lymph nodes may still harbor metastasis. In one study involving pathologic staging, up to 44% of nodes with metastatic deposits were <1 cm in diameter, and 18% of patients with pathologically involved mediastinal nodes did not have any nodes >1 cm.64
Positron Emission Tomography or Positron Emission
Tomography–Computed Tomography
PET scanning has become standard in the staging workup of lung cancer patients. Although the primary tumor characteristics are usually clearly staged with a CT scan, PET can help distinguish atelectasis from tumor in certain cases.65 The largest benefit provided by PET is the identification of suspicious lymph nodes or distant metastasis not seen on CT scan. Kalff et al.66 prospectively evaluated the utility of PET in patients with lung cancer, performing a PET scan on 105 consecutive clinically staged patients with a diagnosis of NSCLC. They found that PET correctly upstaged 26% of patients to palliative from curative intent therapy and appropriately downstaged 10 of 16 patients initially designated for palliative therapy.66 Additionally, PET can detect malignant disease in lymph nodes of normal size, overcoming one of the major limitations of CT.67–69 Integrated PET-CT scanners fuse images obtained in tandem from PET and CT, thus providing both anatomic and metabolic information simultaneously. This is superior to CT or PET alone70,71–72 and can detect malignancy in tumors as small as 0.5 cm.
Although PET has dramatically improved the noninvasive staging of lung cancer patients, it does have some key limitations. On meta-analysis, the sensitivity and specificity of CT for mediastinal nodal metastasis were estimated to be approximately 59% and 79%, respectively, and the sensitivity and specificity of PET were approximately 81% and 90%, respectively.69 This same meta-analysis also found a difference in the accuracy of PET based on the CT size of a lymph node with a sensitivity of 91% for enlarged mediastinal nodes and 75% for nonenlarged nodes.69 Because false positives and false negatives are observed with PET, tissue sampling should be pursued to confirm the presence or absence of regional lymph node involvement before a treatment decision is made. A positive PET should not be considered proof of lymph node metastasis, especially if such a conclusion would otherwise exclude surgery.
With highly conformal radiation therapy for lung cancer becoming commonplace, PET is now being used to aid radiation oncologists in the target delineation process for involved-field radiotherapy (IFRT).73,74 Registration of PET with the planning CT scan at the contouring stage has been shown to enhance the accuracy of defining gross tumor volumes (GTVs).75 The clinician must be mindful that target volumes based solely on 18F-fluorodeoxyglucose (FDG)-PET positivity have their limitations, with the most notable being a false-negative rate of approximately 25% in mediastinal lymph nodes <1 cm in size.69 Additionally, the optimal windowing algorithm for the purposes of contouring remains to be determined. Depending on the algorithm employed, the volume that is contoured can vary significantly.76 When benchmarked against the true pathologic volume, at present the CT-derived contour appears to be more accurate than that derived from FDG-PET regardless of the algorithm employed.77 Efforts are under way to improve on the accuracy of current PET scanning, and one approach is through the exploration of novel tracers. Standard PET scanning focuses on glucose metabolism with FDG as the radionuclide. Other PET tracers currently being explored for interrogation of distinct components of tumor biology include 18F-fluoromisonidazole (FMISO) and 2-(2-nitro-(1)H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) for tumor hypoxia; 18F-fluorothymidine (FLT) for tumor proliferation; and 11C-methionine and 11C-tyrosine for amino acid metabolism.78,79 In addition to potentially improving the accuracy of target delineation, integrating the functional information from these novel tracers into the treatment planning process provides an opportunity for dose escalation to areas of radioresistance.79
Special Diagnostic Procedures
Sputum Cytology
Sputum cytology is a rapid, relatively inexpensive but underused means to establish a tissue diagnosis in an individual with a suspected pulmonary carcinoma. Previous reports have indicated that the sensitivity of sputum cytology is 65% in the setting of established cancers.80 Three specimens increase the diagnostic yield. Sputum samples are considered representative if alveolar macrophages and bronchial epithelial cells are present. The diagnostic yield of sputum cytology is enhanced with centrally located, intraluminal cancers such as squamous cell carcinoma.
Percutaneous Fine Needle Aspiration
CT-guided fine needle aspiration (FNA) is an excellent method for establishing a tissue diagnosis from a suspicious peripheral pulmonary nodule that cannot be reached by bronchoscopy. The risk of a pneumothorax from this procedure is 25%. However, most of these are small, asymptomatic, and resolve without intervention; only approximately 5% require a chest tube. The overall diagnostic yield is 80%.81 Indeterminate biopsies must be interpreted with caution. FNA cannot rule out malignancy unless another benign diagnosis can clearly be established. Abnormalities involving bone, liver, and adrenal glands can also be confirmed by CT-guided FNA. Frequently, biopsy of one of these suspected metastatic sites simultaneously establishes tissue diagnosis and stage of the disease. Increasingly, as we enter the modern era of molecularly guided therapy, core biopsies are displacing FNAs. This increases the risk but also increases the yield.
Bronchoscopy
Fiberoptic bronchoscopy enables visualization of the tracheobronchial tree to the second or third segmental divisions. Cytologic brushings or biopsy forceps specimens can be obtained from identified lesions. Even when no visible lesion is identified, the bronchus draining the area of suspicion can be lavaged for cytologic analysis. With the use of fiberoptic bronchoscopy combined with special CT imaging techniques, even more peripheral lesions can be reached.82 The diagnostic yield of fiberoptic bronchoscopy is directly related to the ability of the operator to navigate the scope to the lesion of interest; this can be challenging for peripheral lesions. The superDimension/Bronchus system is a real-time guidance system designed to guide the bronchoscope to specified locations within the bronchial tree. Using this approach, a virtual map of the bronchial tree is generated from a high-resolution CT scan of the chest, enabling the physician to monitor the location of the bronchoscope in real time through feedback from a positional sensor attached to the tip of the bronchoscope. There is evidence that this approach may significantly improve the diagnostic yield for peripheral lesions.82
Endoscopic Fine Needle Aspiration
Fiberoptic endoscopy techniques can also be combined with ultrasound to evaluate mediastinal and hilar lymph nodes. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) involves FNA sampling of ultrasound-suspicious lymph nodes, especially those located in the paratracheal (lymph node levels 2 and 4), subcarinal (level 7), or hilar lymph node stations (level 10).83 A prospective study comparing EBUS-TBNA with PET-CT scans revealed an accuracy of 98% and a sensitivity and specificity of 92% and 100%, respectively.84 An esophageal approach known as transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) can perform the same function, especially the sampling of mediastinal nodes that are posterior or inferior, such as the retrotracheal (lymph node station 3p), subcarinal (level 7), paraesophageal (level 8), and pulmonary ligament lymph nodes (level 9).85,86
Thoracentesis
Most pleural effusions in lung cancer patients are owing to tumor and should be evaluated with thoracentesis. In general, a diagnosis of cancer can be established in 70% to 80% of malignant effusions by thoracentesis.87 Even if cytology fails to identify cancer cells, repeat thoracenteses improve the diagnostic yield. If on multiple taps the fluid is consistently bloody or exudative, it should be considered malignant. Light’s criteria88 can be used to help classify an effusion as exudative or transudative. As an alternative to repeat thoracentesis, thoracoscopy can be used to simultaneously collect pleural fluid for cytology, visualize the pleural space and biopsy suspicious lesions if present, and perform lymph node biopsies if indicated.
Mediastinoscopy and Mediastinotomy
Mediastinoscopy remains the most accurate technique to assess upper and lower paratracheal (lymph node stations 2 and 4), prevascular (station 3a), retrotracheal (station 3p), subcarinal (station 7), and hilar lymph nodes (station 7) in lung cancer patients. Lymph nodes within the aortopulmonary window (lymph node station 5) and along the ascending aorta (station 6) are not accessible by standard mediastinoscopy techniques; however, they can be evaluated by anterior mediastinotomy (also known as the Chamberlain procedure) or video-assisted thoracoscopic techniques. Although considered the gold standard, mediastinoscopy does have a false-negative rate of approximately 10%.89Furthermore, the role of mediastinoscopy for lung cancer has evolved recently. Less invasive techniques such as EBUS-TBNA or EUS-FNA are frequently utilized instead to sample lymph nodes found to be clinically suspicious on imaging.90 Mediastinoscopy should still be considered in situations where less invasive techniques are nondiagnostic. It is reasonable to forgo invasive staging of the mediastinum in patients with clinical stage I peripheral disease, particularly those with PET-positive primary tumors but no mediastinal uptake and no obviously enlarged nodes on CT. Patients with more locally advanced disease being considered for surgery should undergo mediastinoscopy to rule out N3 disease and to identify those with N2 disease for whom induction therapy should be considered prior to surgery.
Thoracoscopy
Video-assisted thoracoscopy is frequently used for the diagnosis, staging, and resection of lung cancer. Peripheral nodules can be identified and excised using video-assisted, minimally invasive techniques. As discussed previously, this technique is also extremely valuable for evaluation of suspected pleural disease when thoracentesis has been nondiagnostic. Thoracoscopy can also be used to reach mediastinal nodes not accessible by standard mediastinoscopy, EBUS-TBNA, or EUS-FNA techniques.
TABLE 51.2 AJCC STAGING OF LUNG CANCERA
TABLE 51.3 STAGE GROUPING: TNM SUBSETS
STAGING
The current seventh edition of the AJCC Cancer Staging Manual represents a major change in the developmental process of the staging system. The IASLC established a Lung Cancer Staging Project in 1998 to bring together larger databases available worldwide. The IASLC lung cancer database is comprised of 81,015 cases available for analysis from 46 sources in more than 19 countries, diagnosed between 1990 and 2000, and treated by all therapeutic modalities.91,92 The results of this project were accepted by the AJCC as the primary source for revisions of the lung cancer staging system in the seventh edition of their staging manual. Definitions of TNM for the seventh edition of the manual are shown in Table 51.2; the stage groupings are shown in Table 51.3. A reference chart can be found in Figure 51.2. This new staging system more accurately expresses the prognostic significance of both the T and N stages in lung cancer outcome.
Given all of the various ways to assess lymph node status, accuracy in determining the nodal stage is essential.93 In accordance with IASLC recommendations adopted by the AJCC, when pathologic staging of lymph nodes is pursued, sampling of paratracheal (stations 2R and 4R), subcarinal (station 7), hilar (station 10R), and interlobar lymph nodes (station 11R) should be obtained for right-sided tumors, and aortopulmonary window (station 5), ascending aorta (station 6), subcarinal (station 7), hilar (station 10L), and interlobar (station 11L) lymph nodes for all left-sided tumors. Pulmonary ligament lymph nodes (station 9) should also be evaluated for lower lobe tumors. At least six lymph nodes (three from the mediastinum and three from the hilar region) should be examined. If all resected lymph nodes are negative but the number recommended is not met, the patient is still classified as pN0 in the AJCC staging system.3 For the radiation oncologist, proper staging of nodal disease has taken on increased importance as advances in conformal radiotherapy have resulted in elective mediastinal nodal irradiation being replaced by IFRT.94
FIGURE 51.3. Patterns of failure. Sites of locoregional recurrence after surgical resection of 26 right upper lobe, 6 right lower lobe, 20 left upper lobe, and 7 left lower lobe tumors. A distinction is made between isolated recurrences (patients with a single recurrent site: open stars) and nonisolated recurrences (filled stars). (From Kelsey CR, Light KL, Marks LB. Patterns of failure after resection of NSCLC. Int J Radiat Oncol Biol Phys 2006;65(4):1097–1105, with permission from Elsevier.)
TABLE 51.4 HISTOLOGIC CLASSIFICATION OF LUNG CANCER IN RESECTED SPECIMENS
PATHOLOGIC CLASSIFICATION
The pathologic classification of lung cancer is undergoing significant transformation, driven primarily by recent therapeutic advancements in the management of advanced disease and the movement toward minimally invasive tissue acquisition procedures. The primary charge of the pathologist in the past had been to distinguish between non–small cell carcinoma and small cell carcinoma of the lung. However, since 2000, there are now important therapeutic implications for each of the four major classifications of lung cancer: (a) squamous cell carcinoma, (b) adenocarcinoma of the lung, (c) small cell carcinoma, and (d) large cell carcinoma. Histology—for the first time—is an important determinant in the selection of systemic therapy for advanced NSCLC. Bevacizumab, a monoclonal antibody targeting VEGF, resulted in grade 4 and 5 pulmonary hemorrhage in patients with squamous cell histology; however, this agent in combination with standard chemotherapy has yielded a statistically significant survival advantage in patients with nonsquamous histology.95,96 An association between nonsquamous histology (including adenocarcinoma and large cell carcinoma) and improved survival has been observed with pemetrexed in combination with platinum-based chemotherapy.97,98 Adenocarcinoma histology is often associated with the presence of epidermal growth factor receptor (EGFR) mutations that confer heightened sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy and with echinoderm microtubule associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK) translocations that confer sensitivity to the MET/ALK inhibitor crizotinib.99–102,103 All of these changes are being incorporated into the pathologic classification scheme for lung and have resulted in modifications to the 2004 World Health Organization (WHO) classification scheme for resected specimens104 (Table 51.4). Additional changes that include the classification of specimens obtained from minimally invasive procedures are reviewed extensively elsewhere.105,106
PROGNOSTIC AND PREDICTIVE FACTORS
The recent advancements in our understanding of tumor biology have underscored the fact that lung cancer is a heterogeneous cluster of illnesses rather than simply a dual (small cell, non–small cell) disease entity. Given the varied clinical outcomes and significant toxicity of treatment, there is an underlying need for robust prognostic and predictive factors in this disease. Prognostic factors, such as TNM stage, are those that predict clinical outcome independent of therapy, and predictive factors are those that predict response to a particular therapeutic regimen. In general, a discussion of prognostic and predictive factors is divided into two categories: tumor-related factors and patient-related factors. In the near future, these factors may be incorporated into a comprehensive approach to tailor therapy not simply by TNM stage but individualized to the patient and the biology of the patient’s tumor.
Tumor-Related Prognostic and Predictive Factors
The past decade has seen significant advances in our understanding of tumor-related prognostic and predictive factors. Excision repair cross-complementation group 1 (ERCC-1)—a key enzyme involved in the pathway that repairs DNA adducts formed with cisplatin—has been identified to be both a positive prognostic factor for survival (ERCC-1 positivity predicts for improved survival after surgical resection) and a negative predictive factor for response to cisplatin-based chemotherapy (low levels of ERCC-1 predicts for response to cisplatin).107 Activating mutations in the EGFR have been demonstrated to be predictive for response to therapy with EGFR inhibitors, such as gefitinib.108 Thymidylate synthase (TS), which is an important enzyme in DNA biosynthesis and one of the target enzymes for antifolate drugs, has been proposed as a predictive factor for response to therapy in NSCLC patients receiving pemetrexed, a multitargeted antifolate approved for first-line therapy in combination with cisplatin in advanced lung cancer patients with nonsquamous histology. High levels of TS have been shown in vitro and in vivo to correlate with resistance to pemetrexed, and TS gene expression has been shown to be significantly higher in squamous cell carcinomas than in nonsquamous tumors.109–111
Patient-Related Prognostic and Predictive Factors
Given the significant metabolic toll that lung cancer takes on patients, several patient-related factors have been identified as powerful prognostic indicators of clinical outcome. Performance status, as quantified by either the Karnofsky scale or the Eastern Cooperative Oncology Group (ECOG) scale, and weight loss in the 6 months preceding diagnosis have been shown in large trials to be among the factors most predictive of survival (along with TNM stage).112 Additionally, age, gender, and marital status have been shown to be prognostic for survival in a number of studies.113 More recently, Movsas et al.114 reported that baseline quality of life (QOL), as quantified by validated instruments, superseded performance status, age, gender, and other classic prognostic indicators for survival in a prospectively collected data set in patients enrolled on a Radiation Therapy Oncology Group (RTOG) clinical trial, suggesting that QOL may be one of the most important predictors of long-term survival.114
GENERAL MANAGEMENT: NON–SMALL CELL LUNG CANCER
The management of NSCLC presents a formidable challenge. Oncologists must not only account for the stage and extent of disease spread at the time of diagnosis but also must carefully weigh the impact of baseline pulmonary functional status and comorbidities on the patient’s ability to tolerate treatment. NSCLC is an aggressive tumor of a vital organ that is poorly functioning at baseline in the majority of patients. Therefore, the final therapeutic approach must be tailored to the individual. The treatment principles presented in this section should be viewed as guidelines and not as a cookbook for the management of this disease.
In general, the standard of care for patients with stage I and stage II disease is complete surgical resection with the possible addition of adjuvant chemotherapy. For stage III patients, a significant amount of controversy exists regarding optimal management. For select patients with stage IIIA disease at diagnosis who are candidates for surgical resection, neoadjuvant chemotherapy or chemoradiotherapy is often used. For patients with unresectable stage III disease, the standard approach is concurrent chemoradiotherapy for fit patients or sequential chemotherapy and radiotherapy for patients who cannot tolerate concurrent treatment. Approximately 50% of patients present with evidence of hematogenous dissemination at the time of diagnosis.115 For stage IV patients without significant local presenting symptoms or need for urgent radiation, systemic chemotherapy is the standard initial treatment approach. For stage IV patients with significant local presenting symptoms requiring urgent radiotherapy, such as SVC obstruction, hemoptysis, or cord compression, palliative radiotherapy followed by systemic chemotherapy is the preferred treatment approach. For patients with stage IV disease, owing to the poor prognosis, a detailed discussion of the goals of care with consideration of early referral to hospice should be part of the initial treatment approach. Recent evidence suggests that early introduction of palliative care into the standard treatment paradigm in this setting not only improves QOL and reduces inappropriate hospitalization at the end of life but may also improve survival.116
Resectable Tumors
Preoperative Assessment
Patient selection is critical when an operative approach is being considered for the management of NSCLC. This includes an assessment by the pulmonologist and operating surgeon of the clinical extent of disease, the predicted postresection pulmonary reserve of the patient, and preoperative cardiac clearance for the intended surgical procedure. Although there are no strict guidelines for operability, traditionally patients are considered to be suitable for pneumonectomy if their predicted postoperative forced expiratory volume in 1 second (FEV1) is >1.2 L.117 Additional contraindications to pneumonectomy are hypercarbia and cor pulmonale.118,119 Patients are usually referred for preoperative pulmonary function testing, including spirometry, diffusion capacity, and arterial blood gases. Imaging studies include ventilation-perfusion imaging to determine the regional variance in pulmonary function, including the potential loss of functional lung tissue within the planned area of excision.
Stage I and Stage II Non–Small Cell Lung Cancer
The standard of care for a patient with stage I or II lung cancer is surgical resection through either a lobectomy or pneumonectomy with mediastinal lymph node dissection. The Lung Cancer Study Group performed a randomized trial of lobectomy versus limited surgical resection (either through a wedge resection or through segmentectomy) in patients with T1N0 or T2N0 NSCLC. This trial randomized 276 patients to either lobectomy or limited resection and found a 17% risk of local recurrence with limited resection versus 6% with lobectomy (p = .008). This observation was associated with a trend toward an increase in all-cause and cancer-specific risk of death in patients randomized to the limited resection (30% and 50% increased risk, respectively [p = .09], for both). Additionally, the report did not demonstrate any late functional advantages or decreased perioperative morbidity with limited resection.120 This study firmly established lobectomy as the standard of care for early-stage lung cancer. The 5-year survival with lobectomy or pneumonectomy with mediastinal nodal dissection is approximately 60% for pN0 disease and 40% in pN1 disease.121
In a series from Memorial Sloan-Kettering Cancer Center, Martini et al.122 documented a survival with lobectomy or pneumonectomy with complete mediastinal nodal dissection of 82% in T1N0 tumors at 5 years and 74% at 10 years, and 68% at 5 years and 60% at 10 years for patients with T2N0 tumors (p <.0004). They reported a decreased 5- and 10-year survival rate of 59% and 32%, respectively, in 38 patients who did not undergo lymph node dissection. Additionally, they observed poorer 5- and 10-year survival with wedge resection or segmentectomy of 59% and 35%, respectively, compared with 77% and 70% for patients who underwent lobectomy, corroborating the findings of the Lung Cancer Study Group report. The authors additionally documented second primary cancers in 206 of 598 (34%) patients; 70 of these were lung cancers (34% of second primary cancers). Martini et al.122concluded that “(1) Systematic lymph node dissection is necessary to ensure that the disease is accurately staged; (2) lesser resections (wedge/segment) result in high recurrence rates and reduced survival regardless of histologic type; and (3) second primary lung cancers are prevalent in long-term survivors.” However, some controversy remains regarding their assertions in the role of mediastinal lymph node dissection in early-stage NSCLC as well as the contention that a sublobar resection is a “compromised” surgical procedure. The American College of Surgeons Oncology Group (ACOSOG) Z0030 trial was a randomized trial of 1,111 patients with N0 or N1 (less than hilar) early-stage NSCLC to either mediastinal lymph node sampling or complete lymphadenectomy during pulmonary resection. The 5-year disease-free survival was 69% in the mediastinal lymph node sampling group and 68% in the mediastinal lymph node dissection group (p = .92). There was no difference in local (p = .52), regional (p = .10), or distant (p = .76) recurrence between the two groups, suggesting that complete lymphadenectomy does not improve survival in patients with early-stage NSCLC.123 There have been several recent series comparing sublobar resection in appropriately selected early-stage NSCLC with lobectomy, showing comparable oncologic outcomes with the more limited resection. Okada et al.124 performed a retrospective multi-institutional comparison of 567 patients undergoing either a sublobar (N = 305) or a lobar (N = 262) resection for cT1N0M0 (tumor size <2 cm) disease. With a median follow-up >5 years, they reported a 5-year overall survival (OS) of 89.6% for the sublobar resection group and 89.1% for the lobar resection group. The recurrence rate with sublobar resection was not inferior to those obtained with lobar resection, and postoperative lung function was significantly better in patients who underwent sublobar resection.124 Two currently active prospective randomized trials are examining the role of sublobar resection in early-stage disease: the Cancer and Leukemia Group B (CALGB) 140503, a randomized trial of sublobar resection versus lobectomy in small, peripheral early-stage operable NSCLC, and ACOSOG Z4032, a prospective randomized trial of sublobar resection with or without brachytherapy for high-risk early-stage NSCLC. These trials will delineate the role of sublobar resection in the management of early-stage NSCLC.
Stage III Non–Small Cell Lung Cancer
Considerable controversy exists regarding the role of surgery in stage III NSCLC. In the 1960s and 1970s, patients with documented N2 disease were generally regarded as incurable and referred for nonoperative approaches. In 1981, Martini et al.125 reported the outcome of 80 patients with documented N2 disease who underwent complete surgical resection and mediastinal lymph node dissection. Most patients also received postoperative mediastinal irradiation. Survival was 47% at 3 years and 38% at 4 years, with better survival associated with adenocarcinoma histology. Additionally, patients who had small primary tumors and nonbulky mediastinal nodes (i.e., no evidence of mediastinal enlargement on preoperative chest x-ray) had better survival. This study suggested a potential role for surgical resection in select patients with N2 disease.125 Martini et al.126 extended this observation in a second report in an expanded cohort of 1,598 patients who underwent surgical resection, 706 of whom had mediastinal nodal involvement. Of these, 151 patients underwent complete surgical resection with mediastinal node dissection. They reported an OS rate of 74% at 1 year, 43% at 3 years, and 29% at 5 years. Survival in patients with clinical stage I or II (pathologic N2) was favorable at 50% at 3 years. Survival in patients with obvious clinical N2 disease was extremely poor at 8% at 3 years. Martini et al.126 stated: “Very few patients with gross mediastinal nodal involvement benefit from resection. We believe that this group of patients should not be considered for thoracotomy unless innovative forms of treatment can be offered.”
Based, in part, on these and similar results with surgical resection alone in stage III disease, neoadjuvant approaches—either preoperative chemotherapy or chemoradiotherapy—were explored in an attempt to facilitate surgical resection. However, significant controversy still exists regarding the role of surgical resection in stage III disease. Van Meerbeeck et al.127 reported the results of a European Organisation for Research and Treatment of Cancer (EORTC) phase III randomized trial of surgical resection versus radiotherapy after induction chemotherapy in patients with pathologically proven N2 disease. In this study, 579 eligible patients were enrolled and received three cycles of cisplatin-based induction chemotherapy. The 332 patients who responded to induction chemotherapy were then randomized to surgery (167 patients) or radiotherapy (165 patients). Median and 5-year OS for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.84 to 1.35). Rates of progression-free survival (PFS) were also similar in both groups. The authors concluded that radiotherapy is the preferred approach in these patients owing to lower rates of treatment-related morbidity and mortality.127
TABLE 51.5 SURGERY ALONE VERSUS NEOADJUVANT CHEMOTHERAPY FOLLOWED BY SURGERY IN STAGE III NON–SMALL CELL LUNG CANCER
Neoadjuvant (Induction) Therapy
Preoperative Chemotherapy
The primary rationale for induction chemotherapy is similar to the rationale for preoperative radiotherapy: to facilitate complete surgical resection of disease. Additionally, induction chemotherapy may potentially sterilize micrometastatic disease beyond the thorax. In 1988, Martini et al.128 reported on a series of 41 patients with bulky mediastinal nodal involvement, so-called clinical N2 disease, who had evidence of mediastinal nodal enlargement on chest x-ray. Patients received two or three cycles of high-dose cisplatin with vindesine or vinblastine, with or without mitomycin C. Thirty-one (73%) patients had a major radiographic response, 28 patients underwent thoracotomy, and 21 patients (75%) had complete resection of the disease. Eight patients had a pathologic complete response, with an additional 4 patients having “limited microscopic foci of either residual primary or nodal disease.” The 3-year survival was 34% for all patients and 54% for those who had complete resection with a median follow-up of 44 months.128 These promising early results prompted several randomized trials comparing preoperative chemotherapy versus surgical resection alone in stage III NSCLC (Table 51.5). Pass et al.129 reported the results of a small trial randomizing 27 patients with histologically confirmed N2 disease to preoperative etoposide and cisplatin (EP) followed by surgical resection versus immediate surgical resection with postoperative mediastinal radiation. The initial report showed a trend toward increased survival time for the patients who received preoperative chemotherapy (median, 28.7 months) versus the immediate surgery group (median, 15.6 months) (p = .095). Two separate randomized trials were reported in 1994, both of which were terminated early after enrollment of only 60 patients. Roth et al.130 randomized 60 patients with resectable, pathologically confirmed IIIA NSCLC between 1987 and 1993 to receive either six cycles of perioperative chemotherapy (cyclophosphamide, EP) and surgery (28 patients) or immediate surgery alone (32 patients). Patients who had a pathologically confirmed tumor response after three cycles of preoperative chemotherapy received three additional cycles of postoperative chemotherapy for a total of six cycles. Patients randomized to perioperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had immediate surgical resection (P <.008). The estimated 2- and 3-year survival rates were 60% and 56% for the perioperative chemotherapy patients and 25% and 15% for those who had surgery alone. The trial was terminated early because of the magnitude of the treatment benefit for perioperative chemotherapy after an unplanned interim analysis.130
Similarly, Rosell et al.131 randomized 60 patients with pathologically confirmed IIIA NSCLC to either immediate surgical resection or three cycles of mitomycin C, ifosfamide, and cisplatin (MIP) chemotherapy followed by surgical resection. All patients received postoperative mediastinal irradiation. The median survival was 26 months in the patients treated with chemotherapy plus surgery, compared with 8 months in the patients treated with surgery alone (P <.001).131 The updated 3- and 5-year survival rates for the preoperative chemotherapy arm were 20% and 17%, respectively, compared to 5% and 0%, respectively, for the surgery arm. Additionally, Rosell et al.132 observed a survival plateau in the preoperative chemotherapy group and interpreted this to imply that preoperative chemotherapy altered the natural progression of stage III disease. Depierre et al.133 reported the results of the largest randomized trial examining the role of preoperative chemotherapy in 2002. In this study, 355 patients with stage I through stage IIIA (with the exception of T1N0) were randomized to immediate surgical resection versus two cycles of mitomycin, ifosfamide, and cisplatin and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy. The median survival was 26 months in the immediate surgery arm versus 37 months with preoperative chemotherapy (p = .15, not significant [NS]). On subgroup analysis, however, a survival benefit was observed in patients with N0 or N1 disease (relative risk [RR] 0.68; p = .027), whereas there was no observed benefit to preoperative chemotherapy in the 122 patients with N2 disease (52 patients in the immediate surgery arm, 70 patients in the preoperative chemotherapy arm; RR = 1.04; p = .85). Betticher et al.134 reported the results of a multicenter phase II trial of preoperative chemotherapy in 90 patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC. Patients received three cycles of docetaxel and cisplatin, with subsequent surgical resection. The pathologic complete response rate was 19% in patients undergoing tumor resection. Interestingly, 31% of patients achieved mediastinal and hilar nodal clearance (downstaged to ypN0) with this regimen. The median survival for these patients was not reached with a median follow-up of 32 months.134 In an updated report after 5 years of follow-up, the median survival still had not been reached for these patients.135 Although the data are somewhat divergent, most would recommend preoperative chemotherapy if surgical resection is planned in potentially resectable stage IIIA (pN2) disease.
Preoperative Chemoradiotherapy
Local control rates in stage III disease with chemoradiotherapy alone are inadequate. Le Chevalier et al.136 observed that the histologic 1-year local control rate was only 15% for patients with unresectable NSCLC treated to 65 Gy. A relationship has been shown between local failure and the subsequent appearance of distant metastases.137 Furthermore, improved local control in stage III NSCLC has been shown to result in a significant improvement in OS.138 The rationale for preoperative chemoradiotherapy is that surgical resection after chemoradiotherapy will optimize local control, thereby improving clinical outcomes in locally advanced disease. A phase II trial by the Southwest Oncology Group (SWOG) of induction chemoradiotherapy followed by surgical resection in 126 patients with stage IIIA/IIIB disease showed a promising 3-year survival of 26%.139 An exploratory analysis of the 27 patients with N3 disease revealed the 2-year survival rate to be 35% for the subgroup with supraclavicular nodes and 0% for the group with contralateral mediastinal nodes. Motivated by these results, an intergroup randomized phase III trial was initiated to determine the value of adding surgery to chemoradiotherapy in stage III disease with a primary end point of OS. Patients with stage T1-3 pN2 M0 NSCLC were randomly assigned to concurrent induction platin-based chemotherapy plus radiotherapy (45 Gy). If no progression, patients either underwent resection or continued radiotherapy to 61 Gy.140 A total of 202 patients were randomized to surgery and 194 to concurrent chemoradiotherapy. The median OS was 23.6 months in the trimodality arm and 22.2 months in the bimodality group (p = 0.24). For those with pN0 status at thoracotomy, the median OS was 34.4 months. PFS was better in the trimodality arm, median 12.8 months (5.3 to 42.2 months) versus 10.5 months (p = .017). An unplanned, exploratory analysis suggested that patients who underwent lobectomy in the trimodality arm had improved survival compared to matched patients receiving chemoradiotherapy; however, this result is hypothesis-generating only. One of the most important findings from this trial was the significant toxicity of right-sided pneumonectomy after induction chemoradiotherapy. Among the 29 patients who underwent a right pneumonectomy, there were 11 postoperative deaths (38%).141 Overall, this trial did not demonstrate a survival benefit for the addition of surgery to chemoradiotherapy in patients with stage IIIA NSCLC. In conclusion, the role of neoadjuvant chemoradiotherapy in stage III NSCLC remains unclear. Using a multidisciplinary approach, this strategy should be carefully tailored to the individual patient, accounting for his or her performance status, pulmonary function, extent of disease, extent of surgical resection required, and experience of the clinical team.
Adjuvant Therapy
Postoperative Radiotherapy
Locoregional recurrence after resection of NSCLC is common, occurring in approximately 20% of patients with stage I disease142,143 and in up to 50% of patients with stage III disease.135,144,145 The predominant pattern of intrathoracic failure after surgical resection is along the surgical stump or in the mediastinal nodes (Fig. 51.3). Concern over locoregional failure led to the idea that PORT in completely resected stages II and IIIA NSCLC might be beneficial because of evidence that it reduced local recurrence.146 However, the role of PORT was called into question in 1998 when the Medical Research Council published a meta-analysis of nine randomized controlled trials assessing the effect of PORT after resection.147 The PORT meta-analysis included information on 2,128 patients and 1,368 deaths. PORT was associated with a decrease in survival for patients with pN1 disease. Given the theoretical benefit of radiotherapy on local control, the detriment in survival was attributed to excessive radiotherapy-induced morbidity exceeding any benefit. There was no survival difference for pN2 patients. This analysis has been criticized for many reasons. Twenty-five percent of the patients were pN0 who did not need adjuvant therapy. There was no quality control in the radiotherapy arms, and it was felt to be inferior to modern standards; many of the patients were treated to large volumes using older Cobalt-60 equipment to fields designed under fluoroscopy. A subsequent SEER analysis provided insight to counter some of the findings from the PORT meta-analysis. In this study, over 7,400 patients with stage II/III resected NSCLC were evaluated. PORT showed an improved 5-year OS for pN2 patients (27 vs. 20%) but reduced OS for pN0 and pN1 patients.148
Additional support for the use of PORT in the modern era can be found in the Adjuvant Navelbine International Trialist Association (ANITA) trial.149 This trial randomized 840 patients at stage IB through stage IIIA between 1994 and 2000 to adjuvant chemotherapy or observation. The use of radiotherapy was not randomized; however, each center decided whether to use PORT before initiation of the study. Radiotherapy doses ranged from 45 to 60 Gy in 2 Gy fractions and were given after completion of chemotherapy. In patients with pN1 disease, PORT had an improved survival in the observation arm (median survival 25.9 vs. 50.2 months) but a detrimental effect in the chemotherapy group (median survival 93.6 months and 46.6 months). In contrast, in patients with pN2 disease, survival was improved both in the chemotherapy (median survival 23.8 vs. 47.4 months) and observation arm (median survival 12.7 vs. 22.7 months). The retrospective evaluation of the ANITA trial supports the findings from the SEER analysis that PORT may confer a benefit in pN2 NSCLC. The Lung Adjuvant Radiotherapy trial (Lung-ART) is an intergroup collaborative effort in Europe, randomizing patients with completely resected locally advanced NSCLC with mediastinal nodal involvement to observation or PORT to 54Gy. Adjuvant chemotherapy is allowed on the control arm, and pre- and/or postoperative chemotherapy is allowed on the radiotherapy arm. The trial is ongoing, and results are not yet available.
FIGURE 51.4. Stereotactic body radiation therapy (SBRT) in stage I non–small cell lung carcinoma (NSCLC). The patient was diagnosed as having T1N0M0 right upper lobe NSCLC and was treated with SBRT. A: Pretreatment tumor volume. B: Treatment plan with dose color-wash C: CT showing response 6 weeks after treatment.
Postoperative Chemotherapy
Historically, there was little evidence to support the routine use of adjuvant chemotherapy in completely resected lung cancer patients. However, benefits to chemotherapy began to emerge from clinical trials, as doubt was cast on the role for PORT. In 1995, the Non–Small Cell Lung Cancer Collaborative Group150 published a meta-analysis that showed mixed results based on the class of chemotherapeutic regimen utilized. There was decreased survival with alkylating agents, no change in survival with fluorouracil (5-FU)-based regimens, and a trend toward improved survival by 5% with cisplatin-based chemotherapy.150 This benefit was not statistically significant (p = .08); however, this publication led to numerous prospective, randomized trials investigating the role of platinum-based adjuvant chemotherapy in NSCLC.
The International Adjuvant Lung Cancer Trial (IALT) reported a statistically significant survival benefit with cisplatin-based adjuvant therapy in patients with completely resected stage I, II, or III NSCLC.151 In this trial, 1,867 patients were randomized to cisplatin-based adjuvant chemotherapy or observation. With a median follow-up duration of 56 months, patients receiving chemotherapy had a statistically significant higher survival rate (44.5% vs. 40.4% at 5 years) and disease-free survival rate (39.4% vs. 34.3% at 5 years) compared with observation. However, after 7.5 years of follow-up, there were more deaths in the chemotherapy group, and the benefit of chemotherapy decreased over time (p = .10).152
The National Cancer Institute of Canada JBR.10 trial tested effectiveness of adjuvant vinorelbine plus cisplatin versus observation in 482 patients with completely resected stage IB and II NSCLC.153 Adjuvant chemotherapy significantly prolonged OS (94 vs. 73 months) and relapse-free survival (not reached in chemo arm vs. 46.7 months) compared to observation alone. Like the IALT trial, some of the benefit diminished with longer follow-up; however, unlike IALT, the survival difference remained statistically significant. After 9 years of follow-up, adjuvant chemotherapy was found beneficial for stage II (median survival 6.8 vs. 3.6 years), although not for stage IB patients.154
In the ANITA trial, 840 patients with stage IB through stage IIIA NSCLC were randomized to adjuvant vinorelbine plus cisplatin or to observation.155 Median and 5-year OS with chemotherapy improved compared with observation. On subset analysis, this benefit was limited to node-positive patients (stage II through stage IIIA). The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis showed similar results by pooling data from five large randomized trials enrolling 4,584 patients to examine the role of cisplatin-based adjuvant chemotherapy in completely resected patients. They demonstrated a statistically significant 5.4% absolute survival benefit favoring adjuvant cisplatin.156
Postoperative Chemoradiotherapy
With the positive early results from adjuvant chemotherapy trials and prior to the publication of the PORT meta-analysis, a few groups began to explore the role of chemoradiotherapy in the postoperative setting.
One of the first multi-institutional randomized trials to investigate postoperative chemoradiotherapy was led by the ECOG. The ECOG 3590 trial randomized 488 patients with stage II through IIIA NSCLC and negative margins after surgery to either radiotherapy alone or radiotherapy plus four cycles of EP chemotherapy. Radiotherapy in both arms consisted of 50.4 Gy in 28 daily fractions. There was no difference in local recurrence or survival between the two arms.157
Before the results of ECOG 3590 were published, the RTOG embarked on a phase II combined modality study using a newer chemotherapy regimen consisting of carboplatin and paclitaxel. RTOG 9705 included 88 patients with stage II and IIIA NSCLC after surgery who received PORT with concurrent carboplatin and paclitaxel. Radiotherapy consisted of 50.4 Gy in 28 fractions with a boost of 10.8 Gy in extranodal extension or T3 lesions. The radiotherapy was administered during cycles 1 and 2. At a median follow-up of 56.7 months, median OS time was 56.3 months, with 1-, 2-, and 3-year survival rates of 86%, 70%, and 61%, respectively. The 1-, 2-, and 3- year PFS rates were 70%, 57%, and 50%, respectively. Toxicities were acceptable. When compared to previously reported studies, the RTOG concluded that these results might portend an improvement in OS and PFS with postoperative chemoradiotherapy in resected NSCLC patients.158 Promising findings were also noted in a similar study design at Fox Chase Cancer Center,132 supporting the concept that concurrent chemoradiotherapy should be formally investigated with a modern chemotherapy regimen in node-positive patients in the postoperative setting.
Summary
Adjuvant chemotherapy is accepted as standard of care for patients with node-positive (stages IIA, IIB, and IIIA) NSCLC. PORT might be beneficial in stage IIIA but is not indicated in completely resected stage I and stage II NSCLC. In practice, a patient who clinically appears to have early-stage NSCLC undergoes a gross total resection with pathology-confirmed clear margins but is unexpectedly found to have pN2 disease should receive adjuvant chemotherapy first (because of the known survival benefit) and may subsequently be considered for PORT (because of the reported local control benefit) on completion of chemotherapy.
The role of postoperative therapy for NSCLC patients at high risk for local recurrence has not been clearly established. If a patient who is clinically felt to have early-stage NSCLC undergoes surgery that results in a positive microscopic margin or residual macroscopic disease, the radiation therapy should start earlier, as local recurrence is the most common cause of failure in this group of patients.159 Chemoradiotherapy should be considered in this setting if the patient is medically fit.158,160,161
INOPERABLE TUMORS
Stage I/II Non–Small Cell Lung Cancer
The standard of care for a patient with operable early-stage lung cancer remains lobectomy or pneumonectomy with mediastinal lymph node dissection. However, a significant percentage of these patients cannot tolerate invasive procedures because of the comorbidities prevalent in patients with lung cancer, such as chronic obstructive pulmonary disease and poor cardiovascular health. Historically, the standard therapeutic approach for these patients has been conventionally fractionated definitive radiotherapy alone, with daily fractions delivered over a period of 6 to 8 weeks.162 More recently, a hypofractionated approach with delivery of a small number of large fractions over a short period of time has gained acceptance. This approach has most commonly been referred to as stereotactic body radiation therapy (SBRT), although recently there has been a move to rename this approach stereotactic ablative radiotherapy (SABR) to emphasize its distinct radiobiology.163
TABLE 51.6 OUTCOME BY RADIATION THERAPY DOSE AND TREATMENT VOLUME FOR PATIENTS WITH EARLY-STAGE NON–SMALL CELL LUNG CANCER
Conventionally Fractionated External-Beam Radiotherapy
The RTOG performed a multi-institutional dose escalation study for inoperable NSCLC using three-dimensional conformal radiotherapy (3D-CRT). Patients with small, early-stage tumors were escalated to doses as high as 83.8Gy with acceptable toxicity. The 1-year local control rate for patients treated to this dose was 76%.164 Hayman et al.165 performed an adaptive dose escalation trial allowing safe delivery of doses up to 102.9 Gy to small peripheral tumors.165 However, the OS rates for patients with medically inoperable early-stage NSCLC remain poor when compared to surgery. The 5-year survival for patients treated with definitive radiotherapy range from 10% to 30% and are approximately one-half that reported in surgical series166–169 (Table 51.6). Several possible explanations exist for this disparity in outcomes, including the poorer overall health of the medically inoperable patient and the fact that most of these patients are clinically, rather than surgically, staged. An additional limitation is the maximum dose that can be delivered to the tumor through conventionally fractionated external-beam radiotherapy (EBRT) utilizing currently available techniques. Based on fundamental radiobiologic principles, Fletcher170 predicted that using conventional fraction sizes of 1.8 to 2 Gy, doses of 100 Gy or higher might be required for the sterilization of most NSCLC tumors. These doses are not routinely achievable with conventionally fractionated radiotherapy in the medically inoperable patient without excessive toxicity.
FIGURE 51.5. A 51-year-old former smoker presented with right shoulder pain and right-sided Horner’s syndrome and was found to have an adenocarcinoma in the right superior sulcus. A: Coronal view with gross tumor volume (GTV) contoured. B: An axial view with GTV contoured. A 4-cm tumor is seen invading the mediastinum with displacement of the trachea. He underwent a staging evaluation including mediastinoscopy and was staged as T4N0M0. C: Sagittal view with GTV contoured showing vertebral body impingement. The patient was treated with radiotherapy with concurrent cisplatin and etoposide to 50 Gy and underwent resection with negative margins.
Stereotactic Body Radiotherapy
SBRT refers to the delivery of large doses of radiation to a small treatment volume, usually employing multiple beams, using a small number of fractions (usually five fractions or less). It has been known for quite some time that this approach is remarkably effective at tumor sterilization, presumably due to greater radiobiologic efficacy.171 This treatment approach was initially put to clinical use over a half-century ago by a Swedish neurosurgeon, Lars Leksell, for the treatment of intracranial metastases.172 However, unlike the cranial vault, the lung is a highly mobile structure. Thus, application of SBRT in lung cancer was impractical until advanced imaging treatment delivery techniques were developed (Fig. 51.4).
A phase I dose escalation trial enrolled patients with T1–2 N0 NSCLC, stratified into three dose escalation groups based on T-stage and size (T1, T2 <5 cm, and T2 5–7 cm). This trial reported a maximally tolerated dose for T2 tumors >5 cm of 22 Gy × 3 and was not reached at 20 Gy × 3 for T1 tumors or at 22 Gy × 3 for T2 tumors <5 cm.173 There was a loose association between total delivered dose and likelihood of local failure, with 9 of 10 local failures observed in patients treated to the lower dose levels (<16 Gy × 3). Based on these results, this group moved forward with a phase II trial, utilizing the dose levels identified in the phase I trial. They were able to duplicate the excellent local control results in this expanded cohort of 70 patients. With a median follow-up of 17.5 months, the local control rate was 95%. However, with such large fraction sizes (of approximately 20 Gy), the group also identified an association between tumor location and toxicity, with severe toxicity occurring at a median of 10.5 months in 17% of those patients with peripheral lesions versus 46% with central lesions.174 Preliminary data from other institutions suggest that early, central lesions can be treated safely and effectively using a lower dose per fraction (e.g., 7 to 12 Gy).175 To this end, the RTOG has recently opened a phase I dose escalation trial for patients with centrally located, medically inoperable stage I NSCLC.
Several other institutions have published their experience applying SBRT to early (primarily peripheral) lung cancer with a variety of dose fractionation and prescription schemes (Table 51.7). The initial data appear promising with 80% to 100% local control, 40% to 100% 2- to 3-year survival, and 0% to 4% grade 3 toxicity, although in general the median follow-up for these studies is relatively short.176–182 Timmerman et al.174 reported the results of RTOG 0236, a phase II trial of SBRT in medically inoperable patients with T1 or T2 tumors treated to 54 Gy in three 18-Gy fractions. In this study, 59 patients were enrolled, with 55 patients having evaluable disease. At a median follow-up of 34 months, they reported a 3-year primary tumor control rate of 97.6% and a 3-year primary tumor and involved lobe (local) control rate of 90.6%. Two patients experienced regional failure; the locoregional control rate was 87.2%. Eleven patients experienced distant recurrence with a 3-year rate of distant failure of 22.1%. The rates for disease-free survival and OS at 3 years were 48.3% and 55.8%, respectively. The median OS was 48.1 months. Protocol-specific treatment-related grade 3 adverse events were reported in 7 patients; grade 4 adverse events were reported in 2 patients. No grade 5 adverse events were reported. The RTOG (RTOG 0618) initiated a phase II study of SBRT in operable patients with early-stage NSCLC, and, together with the ACOSOG, a randomized trial of SBRT versus sublobar resection for high-risk early-stage NSCLC. SBRT, with its advantage of patient convenience and promising local control results, has largely replaced conventionally fractionated radiotherapy as the standard approach in the medically inoperable patient.
TABLE 51.7 OUTCOME FOR PATIENTS WITH EARLY-STAGE NON–SMALL CELL LUNG CANCER RECEIVING STEREOTACTIC BODY RADIATION THERAPY
Stage III Non–Small Cell Lung Cancer
Definitive Radiotherapy
The majority of patients with inoperable locally advanced NSCLC will receive definitive thoracic radiotherapy as a part of their treatment strategy. The rationale for definitive radiotherapy in patients with inoperable NSCLC is to provide intrathoracic control of disease. Kubota et al.183 performed a prospective randomized trial in 63 patients with stage III NSCLC comparing chemotherapy alone to chemotherapy plus thoracic radiotherapy. The survival rate in the thoracic radiotherapy group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the chemotherapy-alone group. The investigators concluded that thoracic radiotherapy “significantly increases the number of long-term survivors as compared with chemotherapy alone and that radiotherapy to bulky disease in the thorax is an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.” At present, definitive thoracic radiotherapy is part of the standard therapeutic approach for patients with unresectable locally advanced NSCLC. However, because of high local failure rates and the significant toxicity associated with this treatment, the optimal dose, treatment volume, and optimal integration scheme with chemotherapy remain to be defined.
Dose and Fractionation with Radiotherapy Alone
The RTOG launched a prospective randomized trial in 1973 to determine the most effective dose and fractionation schedule in patients with inoperable NSCLC. In the initial report of RTOG 7301, 365 patients with T1-3, N0-2, M0 unresectable NSCLC were randomized to one of four treatment regimens: 40 Gy given in a split course of 20 Gy in five fractions in 1 week, a 2-week rest, and then an additional 20 Gy in 1 week; or 40 Gy, 50 Gy, or 60 Gy given in 2 Gy per fraction continuous course 5 days per week. The split-course group had the poorest survival: 10% at 2 years.184 The incidence of tumor recurrence in the irradiated volume was 58% for the patients receiving 40 Gy continuous course, 53% for those treated with 40 Gy split course, 49% with 50 Gy continuous irradiation, and 35% in the patients receiving 60 Gy.185 There were no differences in 5-year survival rates between the four arms. However, based on the differences in local tumor control and short-term survival, this study established 60 Gy as the standard of care.
Motivated by these results, the RTOG moved to explore methods of escalating radiation dose while maintaining the therapeutic ratio through altered fractionation schedules or improved treatment delivery techniques. RTOG 8311 was a randomized phase I/II trial that delivered thoracic radiation at a dose of 1.2 Gy with twice daily fractions escalating from a starting point of 60.0 Gy to 79.2 Gy. A total of 848 patients were enrolled and analyzed for outcome. No significant differences in the risks of acute or late effects in normal tissues were found in the five arms. In a subset analysis of good performance status patients (stage III, Karnofsky performance scale [KPS] ≥70, <6% weight loss), there was a dose response identified for survival with 69.6 Gy yielding improved survival over the lower-dose arms (p = .02). There were no differences in survival among the three high-dose arms; therefore, 69.6 Gy became the standard altered fractionation regimen for subsequent RTOG trials.186
The development of 3D-CRT in the early 1990s allowed the radiation oncologist to increase the dose distribution to the tumor while restricting the dose to surrounding critical normal structures.187 This approach had immediate applications in the treatment of NSCLC, and preliminary data suggested that 3D-CRT might allow for safe escalation of dose to the tumor bed.188 However, it is unclear whether this approach to dose escalation can be broadly applied to all lung cancer patients. Bradley et al.189 examined 207 patients with inoperable NSCLC and demonstrated by multivariate analysis that GTV was strongly predictive of overall and cause-specific survival, suggesting that large-volume disease might require escalated doses of radiotherapy, if feasible without significantly increased toxicity risk.189 Rengan et al.190 examined the value of dose escalation in patients with large-volume stage III disease and found that even in patients with large tumor volumes, local failure rates were significantly reduced when treated to ≥64 Gy. Taken together, these data suggest that dose escalation can be achieved safely in locally advanced NSCLC via novel fractionation or treatment delivery approaches.
Volume of Radiation with Definitive Radiotherapy:
Involved-Field Versus Elective Nodal Irradiation in Inoperable Stage III Non–Small Cell Lung Cancer
In the era of two-dimensional (2D) radiation therapy for NSCLC, it was customary to include the elective nodal basin in the radiation portals for any patient receiving curative intent radiotherapy, regardless of stage. There is ample evidence that the elective nodal basins can be safely omitted in stage I NSCLC, as there is low risk of nodal failure after IFRT either with conventionally fractionated radiotherapy or SBRT in this setting in patients who have undergone modern clinical staging.191,192 The rationale for IFRT in locally advanced disease is to allow for safe dose escalation. Although there are limited data to suggest that escalating radiation dose could improve local control and that this approach would be feasible in locally advanced NSCLC, this increased dose is associated with an increased risk of radiation toxicity when larger treatment volumes are employed.190 One technique for facilitating dose escalation while maintaining the therapeutic ratio is to utilize IFRT; this approach has been widely adopted. However, there is clear evidence to suggest that the untreated nodal basin may harbor occult disease. Surgical studies report that 10% to 35% of patients with clinically node negative NSCLC have evidence of occult mediastinal metastasis on lymph node dissection.193 Additionally, although 18FDG-PET/CT has become an indispensible tool for noninvasive staging of the mediastinum, studies have shown that FDG-PET may carry up to a 25% false-negative rate in lymph nodes <1 cm in the short axis.69 Therefore, some have argued that while IFRT may allow for dose escalation, this may come at the expense of clinical outcome in this disease.194
Motivated by this concern, several studies have examined the rate of elective nodal failure in patients treated with IFRT and have shown this to be a relatively rare event.195 In a study of 524 inoperable patients treated with IFRT, Rosenzweig et al.196 reported a 2-year elective nodal control rate of 92.4%. Kepka et al.197 studied 207 unresectable patients, staged without 18FDG-PET and treated with elective nodal irradiation (ENI). This study reported a 2-year elective nodal control rate of 88%. In a separate study, Kepka et al.198 performed a comparative analysis of IFRT, limited ENI, and extended ENI and reported that substantial incidental radiation dose was delivered to the elective nodal basins even with IFRT; the median dose delivered to these areas ranged from 18 Gy to 45 Gy, depending on the location of the primary tumor and involved nodes as well as the technique employed. Further, there was no significant difference in dose delivered to much of the elective nodal basin between extended and limited ENI. In the only prospective study of ENI versus IFRT, Yuan et al.199 demonstrated an increase in local control with IFRT of 8% and 15% at 2 and 5 years, respectively. This increase, however, was only statistically significant at the 5-year time point. Additionally, Yuan et al.199 demonstrated an improved OS rate at 2 years with IFRT (39.4% vs. 25.6%, p = .048) and significantly higher pneumonitis rates in patients treated with ENI (29% vs. 17%, p = .044). Although interesting, this study has been criticized for the imbalances in several factors, including the radiation dose delivered (68 to 74 Gy for IFRT vs. 60 to 64 Gy for ENI) and V20 between the two arms, making attribution of the results observed solely to IFRT or ENI problematic. In a recently published single-institution retrospective cohort comparison of patients receiving definitive 3D-CRT for locally advanced NSCLC, Fernandes et al.200 analyzed 108 consecutive patients treated with either ENI or IFRT. The median follow-up time for survivors was 18.9 months. The median dose for patients treated with IFRT was 69.9 Gy versus 63.6 Gy for ENI. In a multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high-grade esophagitis (odds ratio 0.31, p = .036). There was a suggestion of improved 2-year local control with IFRT (59.6% IFRT vs. 39.2% ENI); however, this was not significant (p = .23). There were no significant differences in elective nodal control (84.3% vs. 84.3%), distant control (52.7 IFRT vs. 47.7% ENI), and OS (43.7% IFRT vs. 40.1% ENI) rates between ENI and IFRT. The authors concluded that IFRT had a favorable therapeutic ratio compared with ENI owing to reduced acute toxicity. Taken together, these data suggest that IFRT can be employed in patients with locally advanced NSCLC without risk of significant compromise in clinical outcome.
Combined Modality Therapy for Inoperable Stage III Non–Small Cell Lung Cancer
Sequential Chemoradiotherapy
Although dose escalation was achievable and appeared to be associated with improvements in local control in locally advanced NSCLC, the dominant pattern of failure in these patients is through distant dissemination in about 75% to 80% of patients.185 To address the issue of systemic disease in locally advanced cases, the CALGB initiated a phase III randomized trial of 155 patients with unresectable stage III NSCLC with excellent performance status and minimal weight loss to either radiotherapy alone to 60 Gy or to induction chemotherapy with cisplatin (100 mg/m2 given intravenously on days 1 and 29) and vinblastine (5 mg/m2 given intravenously on days 1, 8, 15, 22, and 29) followed by radiotherapy to 60 Gy. Median survival was improved with induction chemotherapy to 13.7 months versus 9.6 months with radiotherapy alone (p = .0066). The 5-year survival was improved from 6% to 17% with induction chemotherapy.201 A subsequent intergroup trial was launched randomizing 490 patients with inoperable locally advanced NSCLC to one of the following regimens: (a) standard radiation therapy to 60 Gy, (b) induction chemotherapy followed by standard radiation therapy to 60 Gy, and (c) twice-daily radiation therapy to 69.6 Gy as 1.2 Gy given twice daily. Median survival was improved to 13.8 months with induction chemotherapy compared to 11.4 months with standard radiotherapy and 12.3 months with hyperfractionated radiotherapy (p = .03).202 A third prospective randomized trial reported by Le Chevalier et al.136 examined a total of 325 patients with unresectable locally advanced NSCLC who were randomized to either radiotherapy alone to 65 Gy delivered in a split course in 26 fractions over 45 days or 3 monthly cycles of VCPC therapy: vindesine, 1.5 mg/m2 on days 1 and 2; lomustine, 50 mg/m2 on day 2 and 25 mg/m2 on day 3; cisplatin, 100 mg/m2 on day 2; and cyclophosphamide, 200 mg/m2 on days 2 through 4 followed by radiotherapy to 65 Gy in 26 fractions delivered in a split-course fashion over 45 days starting 2 to 3 weeks after the third cycle of chemotherapy. The 2-year survival rate was 14% in patients receiving radiotherapy alone and 21% in the chemoradiotherapy group (P = .08). The distant metastasis rate was significantly lower in patients receiving induction chemotherapy, with the relative risk of metastasis twofold higher in the radiotherapy-alone arm compared to the chemoradiotherapy group (p <.001). Overall, these trials established the role of chemotherapy, in addition to radiation, in the management of inoperable stage III NSCLC (Table 51.8).
Concurrent Chemoradiotherapy
The EORTC performed a phase III randomized trial comparing concurrent cisplatin-based chemoradiation to radiotherapy alone and demonstrated a clear survival benefit to this approach.138 Of note, there was no difference in rate of distant metastases; thus, the authors concluded that the benefit in OS was attributable to an improvement in local control secondary to enhanced radiosensitization of the tumor by low-dose cisplatin. A meta-analysis performed in 2010 to examine the value of concurrent chemotherapy in definitive management of NSCLC by O’Rourke et al.203 included 19 randomized studies with a total of 2,728 patients with NSCLC (stages I through III), who were randomized to receive either concurrent chemoradiotherapy or radiotherapy alone. Concurrent chemotherapy significantly reduced overall risk of death (HR 0.71) and improved overall PFS at any site (HR 0.69). However, this clinical benefit came at the expense of increased acute toxicity, especially severe esophagitis with concurrent treatment (RR 4.96).
TABLE 51.8 SEQUENTIAL CHEMOTHERAPY VERSUS RADIATION THERAPY ALONE FOR LOCALLY ADVANCED NON–SMALL CELL LUNG CANCER
Concurrent Versus Sequential Chemoradiotherapy
Initial phase II trials suggested that concurrent chemoradiotherapy might be an even more effective treatment than sequential chemoradiotherapy.204 Therefore, Furuse et al.205 performed a phase III randomized trial comparing concurrent chemoradiotherapy with mitomycin, vindesine, and cisplatin (MVP) to sequential chemotherapy and radiation therapy. They demonstrated a statistically significant survival advantage to the concurrent approach (median survival of 16.5 months vs. 13.3 months and 5-year survival of 15.8% vs. 8.9%). RTOG 9410 compared two different concurrent regimens (cisplatin and vinblastine with conventional radiotherapy, arm 1, or cisplatin and oral etoposide with hyperfractionated radiotherapy, arm 2) with a “standard” sequential regimen of cisplatin followed by conventional radiotherapy (arm 3). Comparing arm 1 to arm 3 (as per the study design), median survival times improved significantly (17 vs. 14.6 months), as did 5-year survival (15% vs. 10%) with an increase in acute grade 3 through grade 5 nonhematologic toxicities.206,207 The survival in arm 2 was not significantly better than arm 1, although this intensive regimen was associated with much higher esophageal toxicity. Fournel et al.208 reported the results of a smaller randomized trial that did not show a statistically significant survival advantage for concurrent chemoradiotherapy, with a median survival of 14 months with sequential chemoradiotherapy versus 16 months with concurrent chemoradiotherapy (p = .24). Nevertheless, a consistent trend favoring concurrent chemoradiotherapy in median, 2-, 3-, and 4-year survival rates was observed.208 More recently, a meta-analysis performed by Auperin et al.209 analyzed data from six clinical trials involving 1,205 patients. The median follow-up was 6 years. They observed a significant benefit favoring concurrent over sequential chemotherapy and radiotherapy with respect to OS (HR 0.84, p = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. PFS was also improved with concurrent chemoradiotherapy (HR 0.90, p = .07). Concurrent chemoradiotherapy decreased locoregional progression (HR 0.77, p = .01), although not distant progression. Again, this improvement in locoregional control came at the expense of greater acute toxicity for the patient receiving concurrent chemoradiotherapy, with an increase in acute esophageal toxicity (grades 3 and 4) from 4% to 18% with a relative risk of 4.9 (p<.001).209
Because of the increased toxicity with concurrent chemoradiation, especially acute esophagitis, there are often treatment delays that are potentially detrimental in terms of radiobiologic efficacy. Cox et al.210 examined the impact of prolonged treatment time in stage III NSCLC treated with radiotherapy alone and documented an association with decreased locoregional control and 5-year survival (15% vs. 0%). To determine whether treatment time had a similar impact in the setting of concurrent chemoradiation, Machtay et al.211 performed a retrospective study of three prospective RTOG trials (RTOG 9106, 9204, and 9410), all of which included good performance status stage III NSCLC patients treated with cisplatin-based concurrent chemoradiotherapy. The authors defined “short” treatment time as finishing treatment within 5 days of the projected end date. They found that “long” treatment time was significantly associated with acute esophagitis. They also found a nonsignificant trend toward improvement in median survival in the “short” (19.5 months) versus “long” treatment time (14.8 months). This study, although retrospective, indicated that even with concurrent chemoradiation, there could be a detrimental effect on survival with delayed treatment time.211 Thus, appropriate patient selection and maneuvers to minimize toxicity are increasingly important to minimize the likelihood of treatment delays that can compromise the efficacy of concurrent therapy.
In summary, these data strongly support concurrent chemoradiotherapy as the standard approach for patients with good performance status and minimal weight loss. This therapeutic strategy results in improved OS, likely driven by an improvement in locoregional control in patients with locally advanced NSCLC. Of note, this comes at the expense of greater toxicity to the patient, and therefore patient selection is critical when using this approach.
Cytotoxic Platforms for Concurrent Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer
The management of patients with locally advanced NSCLC remains a therapeutic challenge. The era of combined modality therapy was ushered in by Dillman et al.201 when the CALGB demonstrated superior survival for chemotherapy with vinblastine and cisplatin followed by definitive radiation (XRT) versus radiation alone. The benefits of sequential chemotherapy followed by radiation were reinforced by subsequent trials by the RTOG and in France.212–213,214 In fit patients with minimal weight loss (<5% to 10% from baseline) and intact performance status (ECOG performance status 0 to 1), concurrent chemoradiation with a platinum-based combination has demonstrated clear superiority to radiation alone and to sequential chemotherapy followed by radiation.138,205,207,208,215,216 A meta-analysis by Auperin217 reinforced this observation, demonstrating a 5% absolute increase in long-term survival. Multiple studies in this arena have confirmed 4- to 5-year survival rates of 10% to 20%, which are clearly better than the 5% to 7% observed with XRT alone in this setting205,207,208,217,218–219,220,221 (Table 51.9). In the absence of significant comorbidity, hearing loss, or renal compromise in patients who can readily tolerate an acute fluid load, cisplatin-based therapy is considered the standard of care. Most North American clinicians have opted for the EP combination. Unlike limited SCLC, where cisplatin is dosed at 60 mg/m2 every 3 weeks and etoposide at 80 to 120 mg/m2 daily × 3 both during and after radiation, an alternative dose and schedule is generally used.222 There are abundant data from the SWOG and RTOG for a schedule that was ultimately phase III tested in RTOG 9309 and later by the Hoosier Oncology Group: cisplatin 50 mg/m2 days 1 and 8, 29 and 36; and etoposide 50 mg/m2intravenously days 1 through 5 and days 19 through 33.139,140,223,224 This schedule, while inconvenient, is tried and tested and usually safe. Ideally, radiation to a minimum total dose of 60 Gy is given concurrently day 1 with chemotherapy.
TABLE 51.9 CONCURRENT CHEMORADIOTHERAPY FOR STAGE III NON–SMALL CELL LUNG CANCER
In frailer patients or older patients, and in those with significant comorbidity including renal insufficiency (creatinines of 1.5 to 3.0), hearing loss, congestive heart failure, or severe COPD, a carboplatin combination is clearly better tolerated compared to cisplatin, and paclitaxel is often substituted for etoposide. Pilot trials by Belani225 and Choy226 clearly demonstrated the safety and efficacy of carboplatin (area under the concentration-time curve [AUC] 2 weekly) and paclitaxel (45 to 50 mg/m2 weekly) both initiated day 1 of thoracic radiation, followed by two cycles of full-dose “consolidative” chemotherapy once radiation is completed.227,228 Conventionally, during the consolidation phase, carboplatin AUC 6 and paclitaxel 200 mg/m2 are administered for two cycles at 3-week intervals. This regimen has become the platform for multiple cooperative group phase II and phase III trials, most notably RTOG 0617.
Many have argued that carboplatin-based therapy is inferior to cisplatin in the treatment of locally advanced NSCLC. However, recent data from Japan in a combined modality trial (West Japan Oncology Group Trial WJTOG 0105) evaluating various concurrent chemoradiation regimens failed to show superiority for cisplatin over carboplatin in the context of concurrent chemoradiation.221 Investigators led by Nobuyuki Yamamoto compared their erstwhile standard of MVP to weekly carboplatin in combination with either irinotecan or paclitaxel during XRT; in each arm, those without disease progression or untoward toxicity went on to receive two cycles of full-dose chemotherapy during the “consolidation” period using the same agents administered during XRT. The paclitaxel-carboplatin regimen resulted in less toxicity, fewer dose reductions or omissions, and equivalent if not superior survival at 5 years: 19.5% versus 17.5% for MVP and 17.8% for irinotecan-carboplatin. In fairness, this study also compared second-generation to third-generation chemotherapy; to date, this study is the only phase III trial to attempt to address the platinum question, which arises continually in the clinic. There are additional data to suggest that third-generation regimens are superior to second-generation therapy. Segawa et al.218 form the Okayama Lung Cancer Study Group in Japan that demonstrated therapeutic superiority for docetaxel in combination with cisplatin compared with MVP in combination with XRT. An ongoing, pharmaceutical-based, randomized phase III trial in the context of chemoradiation is comparing pemetrexed-cisplatin (another third-generation regimen) followed by single-agent pemetrexed during the consolidation period to EP during XRT followed by investigator’s choice during the consolidation period.229
In patients with baseline V20s (percentage of normal lung that will receive >20 Gy) >35% or in those with borderline pulmonary function or other comorbidities, many clinicians consider administration of chemotherapy first for two or even three cycles, followed by radiation alone or concurrent chemoradiation if there has been sufficient tumor shrinkage to allow a more reasonable radiotherapy treatment field. In those with minimal or no tumor shrinkage using this approach, some investigators omit concurrent chemotherapy during XRT to avoid untoward toxicity, proceeding with XRT alone. These patients are often much more symptomatic than those with smaller-volume tumors, with postobstructive symptoms including wheezing, pneumonitis, and hypoxia, and often have compromised performance status. However, the one study to isolate the role of induction therapy prior to concurrent chemoradiation with paclitaxel and carboplatin failed to show a survival advantage compared to concurrent chemoradiation alone.220
Toxicity mitigation is another major challenge that has been inadequately addressed. Both acute esophagitis and long-term pneumonitis and pulmonary fibrosis are common complications of combined-modality therapy. A recent meta-analysis by Auperin et al.217 demonstrated a sixfold increase in short-term esophagitis, grade 3 or worse (18% vs. 3%) in those receiving concurrent chemoradiation as opposed to asynchronous or sequential chemotherapy and radiation. A phase III study evaluating amifostine as an esophageal protectant failed to show a significant reduction in esophagitis rates, as determined by objective measures, compared to a control arm that did not feature this agent26; however, a subsequent analysis based on patient-reported outcomes suggested a modest benefit with reduction in pain and weight loss.114,230 There is continued interest in evaluating mucosal protectants, including palifermin and other agents, although to date, no prospective randomized phase III trial has demonstrated a palliative benefit. Consequently, the approach to in-field toxicity has generally been reactive rather than pre-emptive. Newer technologies including proton beam may help to reduce the severity and duration of acute and late esophageal and pulmonary effects. This is currently under investigation.
Consolidative Chemotherapy
Consolidative chemotherapy remains highly controversial. A SWOG trial using the EP/XRT regimen as a platform investigated the role of consolidation docetaxel in stage IIIB patients, yielding a 5-year survival rate of nearly 30%, which is virtually unprecedented in the realm of locally advanced NSCLC.139 However, in a phase III randomized Hoosier Oncology Group trial, docetaxel consolidation failed to yield a survival advantage compared to standard “observation” in patients who had completed concurrent chemoradiation with EP, in part because the reference arm “outperformed” its historic controls.224 These results were disappointing. However, there was a borderline significant imbalance in baseline pulmonary function favoring the control arm: nearly 60% of patients on the arm featuring no consolidation had an FEV1 ≥2 L, compared to slightly >40% in the investigational arm. Similarly, empiric use of gefitinib as maintenance therapy in a SWOG trial led to a paradoxical survival decrement compared to placebo after completion of docetaxel consolidation.231 Hence, based on these trials, there is no proven role for consolidative chemotherapy in patients who have already received systemically dosed chemotherapy during thoracic XRT. In those who receive a radiosensitizing schedule of chemotherapy during XRT, the general consensus favors at least two cycles of full-dose chemotherapy after chemoradiation is completed. Despite the disappointments with docetaxel and empiric gefitinib in this setting, the role of consolidation or maintenance therapy after chemoradiation remains an open question.
Targeted Agents in Locally Advanced Disease
There are no data as yet to support the empiric use of EGFRs, TKIs, EGFR monoclonal antibodies (MAbs), or angiogenesis inhibitors either during or after chemoradiation. The CALGB mounted a randomized phase II trial of concurrent radiation and chemotherapy with carboplatin and pemetrexed followed by “consolidative” pemetrexed with or without cetuximab.232 The latter did not appear to exacerbate typical in-field toxicities, nor did it yield a significant improvement in long-term survival. The RTOG separately spearheaded a phase II study evaluating cetuximab in combination with standard thoracic radiotherapy and weekly paclitaxel-carboplatin, demonstrating feasibility as well a promising median survival approaching 2 years.233 The phase III trial comparing higher dose XRT (74 Gy) to standard dose (60 Gy) was amended early on to address the role of cetuximab in a 2 × 2 design. Although the component of the trial testing higher versus standard dose XRT was closed because of futility, the C225 question remains open and RTOG 0617 continues to accrue; enrollment completed in November of 2011 and results are eagerly awaited. In higher-risk patients with >5% weight loss or compromised performance status, the CALGB is evaluating induction therapy with nab-paclitaxel and carboplatin followed by concurrent XRT and erlotinib. A previous, analogous phase II CALGB study in higher-risk patients evaluating induction carboplatin and paclitaxel followed by concurrent XRT and gefitinib yielded a median OS of 19 months.234 Attempts to integrate bevacizumab into the combined-modality approach have been unsuccessful, with adverse events including tracheoesophageal fistulas and pulmonary hemorrhages.235,236
Dose Escalation with Concurrent Chemoradiotherapy
Although concurrent chemoradiotherapy has emerged as the standard therapeutic approach for fit patients with unresectable locally advanced disease, this has come at the cost of increased toxicity to the patient. It is therefore unclear whether dose escalation in the setting of concurrent chemotherapy will provide meaningful clinical benefit. The Lineberger Comprehensive Cancer Center group reported the results of a single-institution phase I dose escalation study with concurrent chemoradiation. They performed a stepwise escalation of thoracic radiation dose from 60 to 74 Gy in conjunction with paclitaxel-carboplatin without a clinically significant increase in toxicity.237 The median survival of 24 months and 5-year survival of 25% in this study were promising, although patient numbers are small. In 2006, the RTOG opened a 2 × 2 phase III randomized trial to simultaneously examine the question of 60 Gy versus 74 Gy and concurrent chemoradiotherapy with or without cetuximab for patients with inoperable stage III NSCLC. After a planned interim analysis, the high-dose radiation therapy (74 Gy) arms of RTOG 0617 were closed to accrual effective June 17, 2011. In a communication to all RTOG trial investigators, Bradley238 stated that the “high dose arms crossed a futility boundary, meaning that high dose radiation therapy cannot result in a survival benefit with further accrual or follow up of patients on these 2 arms.” At the 2011 American Society of Therapeutic Radiology and Oncology (ASTRO) annual meeting, the initial results of this trial were presented, actually demonstrating a statistically significant detriment to survival with 74 Gy (p = .02). The interim analysis did not identify patient safety concerns and gave no indication of a statistical difference in high-grade toxicity between arms, nor any clear explanation for the observed decrement in survival. Regardless, the 74-Gy arm for this trial has been closed and 60 Gy remains the standard dose in all RTOG lung cancer trials going forward.239
Superior Sulcus Tumors and Pancoast’s Syndrome
SSTs were first described in 1838 and the characteristic accompanying neurologic symptoms in 1932 by Dr. Henry Pancoast.240 The most common tumors of the superior sulcus are bronchogenic, primarily squamous cell, followed by adenocarcinoma, and less likely small cell. SSTs account for <5% of all lung cancer.241
Signs and Symptoms
The most common symptom among patients with SST is pain in the shoulder, which may radiate down the arm. This can be attributable to direct tumor invasion of the parietal pleura, vertebral body, ribs one through three, or the brachial plexus (Fig. 51.5). Pain radiating down the ulnar aspect of the arm past the elbow indicates involvement of the T1 nerve root, whereas extension to the fourth and fifth digits indicates involvement of the C8 nerve root or more distally the ulnar nerve. There may be weakness or atrophy of the intrinsic muscles of the hand. SSTs that invade the neural foramina may cause spinal cord compression, which can ultimately occur in up to 25% of patients. Involvement of the stellate ganglion may manifest as Horner’s syndrome: the triad of ptosis, papillary miosis, and facial anhidrosis. Irritation or compression of the adjacent sympathetic chain may cause ipsilateral flushing and sweating of the face or reflex sympathetic dystrophy, a regional syndrome of burning neuropathic pain. Pancoast’s syndrome is a constellation of signs and symptoms including shoulder/arm pain, Horner’s syndrome, and unilateral upper extremity weakness.
Diagnosis and Staging
SSTs are staged in the same way that SCLC and NSCLC are staged elsewhere in the thorax. For patients without metastatic disease, it is important to assess resectability. Surgery typically involves lobectomy with en bloc resection of the chest wall, which may be accompanied by resection of portions of the parasympathetic chain, stellate ganglion, lower trunks of the brachial plexus, subclavian artery, and portions of vertebral bodies.
Management
Determining the feasibility of resection is a critical decision point in the management of NSCLC SSTs. Because of the apical location of the tumor, invasion of the brachial plexus, vertebral bodies, and subclavian vessels is not uncommon and may eliminate surgical resection as an option, depending on the extent of invasion. In addition to CT, PET, and bone scan, MRI is useful in documenting the extent of involvement of the brachial plexus, spinal nerve roots, vertebral bodies, and subclavian vessels and is more sensitive than CT for this purpose.242 Small cell SSTs in patient with good performance status are treated with concurrent chemoradiotherapy for limited-stage disease or chemotherapy for extensive-stage disease.
FIGURE 51.6. Tumor motion during a patient’s normal respiratory cycle. The yellow wireframe shows the tumor position at full inspiration. The blue wireframe shows the tumor position at full expiration.
Multimodality Therapy for Superior Sulcus Tumors
Several large retrospective series and prospective trials have investigated outcomes of multimodality treatment of SSTs. SWOG 9416/Intergroup 0160 included 110 patients with T3-4, N0-1 SSTs. All patients were treated with two cycles of EP with radiotherapy (45 Gy in 25 fractions), followed by surgery within 3 to 5 weeks, and then two further cycles of chemotherapy.243 The study included patients with apical tumors and Pancoast’s syndrome, or SSTs with chest wall invasion, or involvement of the vertebrae or subclavian vessels. In this study, 88 patients (80%) underwent surgery, and 83 (76%) had complete resection. The 5-year OS was 44%. As well, 61 resected patients (56%) had a pathologic complete response to induction therapy, and their 5-year survival was significantly better at 54%. A Japan Clinical Oncology Group (JCOG) study enrolled 76 patients and used induction mitomycin, vindesine, and cisplatin with 45 Gy in 27 fractions (split course) followed by surgery.244 The study included patients with SSTs, staged T3-4, N0-1, and nonbulky N2 disease; 76% of patients underwent resection, and 68% had complete resection. The 5-year OS was 56%. A single-institution French study enrolled 107 patients with SSTs in a prospective trial of induction chemoradiotherapy.245 The study excluded those with bulky N2 or N3 disease. All patients received EP concurrently with radiotherapy to 45 Gy; 72 patients underwent resection; unresectable patients received an additional 25 Gy. The 3-year OS was 40%.
In patients who are resectable at diagnosis, surgery may be offered as initial therapy. A prospective trial at the University of Texas MD Anderson Cancer Center enrolled 32 patients with resectable or marginally resectable SSTs.246All patients had gross total resection initially; 28% had microscopic residual disease. Postoperatively, patients were treated with radiotherapy to 60 Gy in 1.2-Gy fractions (for negative margins) or 64.8 Gy in 1.2-Gy fractions (for positive margins) with concurrent EP. The 5-year locoregional control was 76%, and 5-year OS was 50%.
Chemoradiotherapy
Retrospective evidence suggests that patients who undergo surgery have better local control and survival than those treated with radiation therapy, although such data is subject to significant selection bias.247 Patients with unresectable localized SSTs and those with stage III disease and bulky N2 (or N3) lymph nodes should be treated with definitive chemotherapy and radiation. Early studies of radiotherapy alone for SSTs show acceptable local control and survival. In a series of 32 patients treated with definitive radiation, 91% of patients with pain reported relief, and 75% of patients with Horner’s syndrome had symptomatic improvement.248 The addition of concurrent chemotherapy improves local control and survival in patients with stage III NSCLC—an observation that has led to the widespread use of concurrent therapy in SSTs. Small series in patients with SSTs appear to support this. A retrospective analysis from the Netherlands examined the outcome of patients treated with chemoradiotherapy.249 In this study, 49 patients with stage II or III SST received 66 Gy with daily cisplatin (6 mg/m2); 19 patients had sufficient response to undergo resection, and in these patients there was a 53% pathologic complete response rate. The 5-year OS was 18% in patients who received chemoradiotherapy and 33% in patients who were able to undergo surgery.
RADIOTHERAPY TECHNIQUES AND FUTURE DIRECTIONS
Gross Tumor Volume
The clinically macroscopic disease, as typically identified on any imaging modality, is defined as the GTV. The GTV in the lung cancer patient is usually derived from a treatment planning CT or PET-CT obtained during quiet respiration. Intravenous contrast is usually not required for identification of the primary tumor unless it is located adjacent to the hilum or mediastinum. Studies have shown that the size of the contoured GTV is highly sensitive to the windowing of the CT data set.250 Harris et al.250 reported that measurements of pulmonary nodules using the standard “lung” windowing width of 850 Hounsfield units, with a windowing length of –750 Hounsfield units resulted in highly accurate sizing of the parenchymal tumor. Therefore, lung windowing should be used for delineation of the primary tumor GTV. An FDG-PET may be of additional value in the setting of atelectasis.65 However, the optimal standardized uptake value threshold for defining tumor edge remains to be defined.
Identification of the mediastinal nodal GTV may prove more challenging. Intravenous contrast may be valuable in identifying nodal disease and may be used if there are no contraindications such as allergy or renal insufficiency. Chapet et al.251 at the University of Michigan developed an axial CT-based definition of the thoracic nodal stations for use in radiation treatment planning and nodal identification. On CT, a short-axis diameter ≥1 cm is often employed for identification of pathologically involved nodes.252 However, this cutoff is unsatisfactory, having a relatively poor accuracy of approximately 60% for correctly identifying the location and size of nodal disease.253 FDG PET-CT can add significant value to CT alone in the identification of mediastinal nodal disease. Dwamena et al.254 performed a meta-analysis of FDG-PET and CT for the identification of mediastinal nodal disease in lung cancer. They reported a mean sensitivity and specificity of 0.79 and 0.91, respectively, for PET and 0.60 and 0.77, respectively, for CT.254 Although this represents a significant improvement, the gold standard for identification of mediastinal nodal disease is through invasive staging. When feasible, the mediastinum should be pathologically staged through either cervical mediastinoscopy or endobronchial ultrasound with transbronchial needle aspiration; this information should be incorporated into delineating the nodal GTV.
Clinical Target Volume
The clinical target volume (CTV) represents a volumetric expansion of the GTV to encompass microscopic disease. For the primary tumor, pathologically derived correlative data have shown that a 9-mm margin would encompass all microscopic disease in approximately 90% of lung adenocarcinomas.255 Others have advocated the use of a differential margin based on histology of 8 mm for adenocarcinoma and 6 mm for squamous cell carcinomas to account for 95% of the microscopic extension of disease.256 For nodal disease, surgical series have shown that a 3-mm margin will encompass 95% of the microscopic extranodal extension of disease in lymph nodes <2 cm. However, larger margins may be required for lymph nodes >2 cm.257
Internal Target Volume
The internal target volume (ITV) is defined by International Commission on Radiation Units and Measurements (ICRU) 62 as an expansion of the CTV to account for tumor motion. However, as the CTV includes subclinical disease whose motion cannot be visualized, most clinicians will create an “IGTV,” which represents the summation of the contoured GTV on all CT data sets obtained in a respiratory-correlated (or four-dimensional [4D]) CT using established methodologies for image acquisition and correlation.258 In the absence of a 4D-CT, a “slow” CT may be used with an extended image acquisition time to encompass a full breathing cycle.259 The IGTV can then be expanded with a uniform volumetric margin to account for microscopic extension of disease and generation of a CTV.
Planning Target Volume
The planning target volume (PTV) is a volumetric expansion of the CTV to account for setup variability. In the past, empiric margins have been used to account for daily variations in patient positioning. However, with the incorporation of image guidance to aid in patient positioning and daily setup, these margins can likely be reduced. Grills et al.261 showed that calculated population setup margins were reduced from 9 to 13 mm for patients immobilized with a stereotactic body frame and positioned without cone-beam CT to 1 to 2 mm with cone-beam CT. Ideally, with greater integration of image guidance into lung cancer treatment delivery, patient specific margins will be employed to account for tumor setup uncertainty.260,261
Dose Constraints
Normal tissue organs at risk (OARs) should be defined using guidelines outlined in prospective protocols, or using a consensus contouring atlas,262 so that consistent data can be collected and analyzed. The bilateral lungs excluding the GTV, esophagus, and spinal cord should be defined for all patients undergoing 3D planning. The heart, pericardium, and brachial plexus should be defined when clinically indicated. For all patients, normal tissue dose limits should be considered in balance with adequate coverage of the target volume. There are multiple, valid models of normal tissue toxicity, including normal tissue complication probability (NTCP) modeling, threshold dose (Vdose), and mean dose. Recently, a multidisciplinary effort was undertaken—the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC)—to summarize the published 3D dose-volume/toxicity data in the literature, review NTCP modeling, and provide practical guidance for the clinician.263,264
From collected data in the QUANTEC effort, the risk of radiation pneumonitis (RP) is <20% when the mean lung dose (MLD) is less than approximately 20 Gy, or for V20 <30 to 35 Gy, or V5 <60% with conventional fractionation.265 Caution is warranted when using IMRT and absolute dose-volume thresholds, because planning algorithms may meet strict dosimetric constraints at the cost of higher dose at other, unconstrained cut points. For esophagus, the collected data suggest that volumes treated at >40 to 50 Gy correlate with acute symptoms and that no dose above prescription be allowed to even small volumes of esophagus. This latter is especially important for heterogeneous IMRT planning.266 For heart and pericardial dose, the conclusions of QUANTEC reflect a conservative interpretation of the existing literature: if the V25 is <10%, then the excess risk of cardiac mortality attributable to ischemic changes is <1% at 15 years. The risk of pericarditis can be minimized by keeping the mean pericardial dose <26 Gy or the pericardial V30 <46%. Heart and pericardial exposure should otherwise be minimized, without compromise of target coverage.267 Brachial plexopathy is rare in patients who have received ≤60 Gy, and proposed brachial plexus dose limits for radiotherapy planning vary considerably; RTOG 0617 suggests a point maximum limit of 66 Gy. RTOG 0972/CALGB 36050 limits the V20 to ≤35%.
THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY AND INTENSITY MODULATED RADIOTHERAPY FOR LUNG CANCER PLANNING AND DELIVERY
Introduction
Accurate treatment planning and delivery of radiation for the treatment of lung cancer is confounded by several technical factors, including proper patient setup and localization, the mobility of lung tumors, and tissue inhomogeneity in the vicinity of the lung, as well as the physical and biologic dose implications of delivering dose in >30 fractions versus ≤5 fractions, as in the case of SBRT. To understand the effects of these factors on the accuracy of treatment, one must look more closely at each of the procedures involved in treatment planning and delivery, including treatment simulation, treatment planning, plan evaluation and quality assurance, and treatment delivery. Among other studies, comprehensive reviews of current techniques for lung cancer treatment planning and delivery have been presented by Martel,268 Senan et al.,269 and Slotman et al.270
Treatment Simulation
The goal of treatment simulation is to acquire an image-based representation of the patient for the purposes of tumor and normal organ delineation for treatment planning. The imaging study is traditionally performed with CT. Serial CT images are acquired of the patient in the same treatment position, using the same immobilization devices as those used during radiation treatment. Slice thickness is typically ≤5 mm; smaller slice thicknesses allow for reconstruction of higher-resolution digitally reconstructed radiographs (DRRs),269 which may improve localization accuracy during treatment. The anatomic region scanned should include both lungs and often extends from the level of the cricoid cartilage to the second lumbar vertebra.269 Immobilization refers to the process of “patient fixation” to ensure reproducible patient setup during treatment and between treatment fractions. Custom devices, composed of Styrofoam or other materials that mold to the patient surface, are often fabricated for immobilization. Examples include the Alpha Cradle (KGF Enterprises, Chesterfield, MI) and BodyFIX (Elekta Oncology Systems, Norcross, GA) immobilization systems. In the context of SBRT, the American Association of Physicists in Medicine (AAPM) Task Group Report No. 101271 recommends the use of 1- to 3-mm axial slice thickness during CT acquisition and the use of standard-of-care immobilization/fixation systems (including stereotactic body frames272) for reproducible treatment setup.
Management of Tumor Motion
Motion can result in significant distortion of axial or helical CT scans, manifested as artifacts in the vicinity of the tumor in the 3D image data set.273 Motion-related artifacts not only render it difficult to assess the full extent of motion but also confound the ability to contour the target accurately on the planning CT data set. As a result of this, the AAPM Task Group Report No. 76273 recommends that motion management strategies be considered when the range of tumor motion is >5 mm in any direction. The recommended 5-mm criterion may be reduced for techniques, such as SBRT, where tumor motion may become an accuracy-limiting factor.273 Several different techniques have been proposed to manage and mitigate the effects of tumor motion.269,270,273 To assess the range of mobility of tumors in the coronal plane, investigators have employed fluoroscopy.269 Information from fluoroscopy cannot be directly linked to the volumetric simulation CT scan and is also limited by visualization of the target, although the use of implanted markers may overcome this problem.274 Motion-encompassing methods are utilized to manage the effects of motion during the planning process. These include the generation of 4D-CT scans, which contain spatial and temporal information during the CT acquisition process. 4D-CT scans are typically reconstructed to generate multiple data sets at different phases of the respiratory cycle, ultimately generating an “envelope” of the moving tumor for treatment planning.275–277 The use of “slow” CT scans (4 seconds per slice) acquired during quiet respiration has also been shown to capture reproducible target volumes for peripheral lung cancers.259 Methods to limit motion, such as shallow breathing that is forced using abdominal compression devices, have shown to be effective in patients who can tolerate these devices.278 Techniques such as deep inspiration breath-hold,279 automatic breathing control,280 respiratory gating,281–283 and tumor tracking,284 although technically challenging to implement, can afford improvement in normal lung sparing, particularly in circumstances where the magnitude of motion is large.269,273
With regard to motion-encompassing approaches, automatic tools have been developed to improve efficiency in the contouring of GTVs on multiple data sets to form an ITV. The maximum intensity projection (MIP) represents the highest intensity value encountered along the viewing ray for each pixel in the volumetric data set for the respective breathing phase. The summation of MIP images for each breathing phase therefore results in a composite view of the tumor incorporating all phases of motion. Other techniques, such as a color intensity projection (CIP) technique, in which the motion information from the cumulative 4D data sets are composited into a single color image, have also been proposed.285 Figure 51.6 provides views of variance in GTV position in different phases of the breathing cycle.
Treatment Planning
The goal of treatment planning is to optimize the therapeutic ratio—that is, to maximize the dose to the target while minimizing dose to surrounding normal organs286,287 (Fig. 51.7). As described earlier, target and OAR volumes are defined based on imaging studies, primarily CT and PET. PET can be used to differentiate atelectasis from tumor and to determine nodal involvement for central disease.268 Respiratory-induced mobility of the tumor is accounted for using the internal margin, which represents the “envelope” encompassing tumor movement determined during the simulation 4D-CT acquisition. The internal margin is expanded to form the PTV, which accounts for geometric variation in the CTV owing to day-to-day (interfraction) uncertainties in the patient setup. According to ICRU Report No. 62,288 a margin (planning risk volume [PRV]) should also be added to an OAR to account for interfraction variation in the OAR position. Margins for the PTV must be designed with an understanding of the random and systematic errors associated with patient setup.289 For advanced-stage NSCLC, typical margins for the PTV are on the order of 5 to 10 mm if an ITV is used for motion compensation and daily image-guided radiotherapy (IGRT) is employed during treatment. In the absence of motion compensation or IGRT, margins should typically be larger (10 to 20 mm) to minimize the chance of missing the target as a result of motion. Daily IGRT-based setup has been shown to significantly reduce residual errors and, consequently, planning margins.288–290 For SBRT-based treatments, where motion management and IGRT are the recommended standard of care,271 PTV margins can range from 3 to 6 mm.270,272,290,291
FIGURE 51.7. A: CT and PET fused image showing FDG-avid primary tumor. B: Axial, coronal, and sagittal views of gross tumor volume contour C: Transverse CT image of field arrangement and dose color wash of treatment plan. D: Dose volume histogram showing coverage of the planning target volume (orange) and dose to the esophagus (light blue), spinal cord (dark blue), total lung (purple), and heart (red).
Beam arrangements for treatment planning can range from simple two-field, parallel opposed fields (e.g., anterior-posterior, opposed, anterior-posterior/posterior-anterior [AP/PA]) for late-stage NSCLC to complex multiple gantry angle, modulated beams for more focal treatments. Beams are shaped with a multileaf collimator (MLC), which enables conformation of radiation to the target. Treatment plans should be designed to minimize dose to surrounding normal organs and thereby limit the risk of treatment toxicity, implying sharp gradients in the dose falloff outside the target.271 AP/PA fields may be considered when disease is more extensive and located centrally. The goal in such cases is to produce a homogeneous dose distribution across the treated volume to encompass the extent of the disease. However, AP/PA beams can only be used for cumulative PTV doses in the range of 40 to 45 Gy (in 1.8 to 2 Gy per fraction) because of spinal cord tolerance. “Off-cord” fields are typically required beyond this dose. When treating large volumes of lung, it is especially important to design treatment plans that adhere to normal lung tolerance doses; dose indices, such as V20, V5, and MLD, must be closely observed to avoid possible treatment complications.292 For treatment planning of localized disease, more conformal dose distributions employing multiple beam angles are warranted. Treatment plans can be developed using 3D-CRT or IMRT techniques and should include beams from multiple gantry angles, particularly in the context of SBRT.
For IMRT-based planning, one must bear in mind the interplay effect, which describes the interplay between a given MLC position and instance of radiation delivery with the position of the tumor in the respiratory-induced motion cycle at the same instance.293 The interplay effect has been shown to average out over the course of ≥30 treatment fractions.293,294 However, in the SBRT setting, where 3 to 5 dose fractions are delivered, the interplay effect may compromise the planned dose distribution, suggesting that IMRT must be used cautiously for SBRT. Planning for SBRT must be done with an understanding of the dose gradients so as to develop dose distributions with sharp gradients. This is typically achieved using multiple nonoverlapping and noncoplanar beams as necessary and a MLC with ≤5 mm leaf width.271 The dose prescription line can be low (e.g., 80%) with much smaller margins for beam penumbra (“block edge”) than conventional radiotherapy; the motivation is to produce a faster dose falloff and thereby improve sparing of surrounding healthy tissues.271 The AAPM Task Group No. 101 discourages the use of calculation grid sizes >3 mm for SBRT planning.271
Low-density lung tissue in the vicinity of or surrounding thoracic tumors significantly confounds the radiation dose computation problem in lung cancer treatment planning. Conditions of loss of charged-particle equilibrium are produced when the field size is reduced such that the lateral ranges of the secondary electrons become comparable to (or greater than) the field size; such conditions occur for larger field sizes in lung than in water-equivalent tissues because of the increased electron range in lung. Under such circumstances, the dose to the target is determined primarily by the secondary electron interactions and dose deposition. Because conventional dose algorithms do not account explicitly for transport of secondary electrons, they can be severely limited in accuracy under nonequilibrium conditions. Moreover, in low density, lung-equivalent tissues, the range of the secondary electrons contributes to the dose “build-down” effect at the edges of the tumor (at the lung-tumor interface), an effect that increases with beam energy. The article by Reynaert et al.295 and AAPM Task Group No. 105295 provide examples of numerous studies reporting on the inaccuracies associated with conventional algorithms for dose calculations in the lung. Therefore, for lung cancer treatment planning in general, and especially when dealing with smaller tumors, where the field sizes are less than 5 × 5 cm2, more advanced dose algorithms such as convolution/superposition or the Monte Carlo method are necessary—the latter accounts explicitly for electron transport.271,297 The AAPM TG Report No. 101271 and other articles298 recommend that pencil-beam algorithms not be utilized for SBRT-based lung dose calculations.
Plan Evaluation and Quality Assurance
Plan evaluation of IMRT and SBRT treatment plans requires careful evaluation of DVHs and the entire 3D dose distributions.271,299 The following items, among others, must be considered to properly evaluate a treatment plan prior to radiation delivery:271 organ contours and dose-volume–based organ constraints; planning margins for targets and OARs; intrafraction motion and impact on margins; inhomogeneity corrections; dose uniformity and “hot” or “cold” spots in the target region; normal tissue tolerance doses; plan deliverability—that is, the presence of many low-intensity segments that could possibly be removed without compromising plan quality; and unusual beam orientations that might involve collision during gantry rotation. In accordance with national practice guidelines for IMRT300 and SBRT,271 redundant verification of the patient-specific treatment plan monitor units and verification measurements of the planned isocenter and 2D dose distributions are necessary. When performing patient-specific verification measurements of highly modulated IMRT fields or SBRT plans, special consideration must be given to the detector size and performance under nonequilibrium conditions.297 A properly commissioned Monte Carlo dose algorithm may prove valuable for patient-specific verification of IMRT and SBRT treatment plans, given the complexities with accurate measurements under nonequilibrium conditions.271,297
Treatment Delivery Technologies
Radiation delivery for lung cancer treatment is generally performed using IGRT-based systems, which can be acquired using megavoltage (MV)- or kilovoltage (kV)-based planar imaging, as well as volumetric, cone-beam CT imaging to localize the patient prior to treatment. Gating or tracking systems, which aim to deliver radiation during a given phase of the breathing cycle or “track” the tumor in real time, respectively, may also be employed. Image-guidance protocols, including type and frequency of imaging, as well as the need for gating or tracking should be decided by the treatment planning team after consideration of factors such as stage of the disease, location of the tumor, degree of tumor mobility, and quality of the IMRT or SBRT treatment plan. Reviews of technologies utilized in the treatment of lung cancer using IMRT and SBRT are provided elsewhere.268,273,285,301 More recently, volumetric modulated arc therapies (VMATs) have become available for treatment of lung cancers. In one study, an SBRT lung treatment plan performed with VMAT was compared with that of a conventional IMRT plan using the same optimization objective function and constraints.302 The VMAT plan consisted of a single arc, with partial angles to spare the contralateral lung. The VMAT plan yielded improved target coverage and comparable normal tissue doses compared with the conventional IMRT plan while reducing treatment time by approximately 60%.302 The faster delivery of radiation with VMAT is likely to substantially mitigate patient movement on the treatment table as a result of discomfort during a long treatment procedure, thereby improving delivery quality. However, as with conventional IMRT, VMAT-based plans are also subject to the interplay effect, which must be considered depending on the mobility of the tumor and the degree of modulation of the MLC fields. Further investigation of the interplay between MLC leaves and tumor motion in the context of VMAT is warranted.
Particle Beam Radiotherapy for Non–Small Cell Lung Cancer
Because of their physical properties and method of interaction with matter, particle beams, such as protons, neutrons, and heavy ions, have the potential to offer improved dose deposition profiles in tissue when compared with photon beam radiation. Although protons have a similar biologic potency to photons, neutrons and heavy ions such as carbon ions deliver a more biologically effective dose than either photons or protons. Limited data on particle beam radiotherapy for lung cancer are available; however, clinical data are emerging on the application of proton beam radiotherapy in these patients. The favorable dose deposition profile of particle beam radiotherapy has generated interest in the potential for this modality to deliver tumoricidal doses in the lung cancer patient while maintaining or improving the therapeutic ratio. Proton beam radiotherapy for the treatment of cancer was originally described by Wilson303 in 1946, and there has been growing interest over the past decade in clinical application of this modality in a variety of solid tumors, including lung cancer. In a dosimetric comparative study between protons and photons in patients with inoperable NSCLC, Chang et al.304 reported that proton beam radiotherapy significantly reduced dose to critical normal structures including the esophagus, spinal cord, and heart, even with dose escalation, when compared with photon therapy delivered with advanced treatment delivery techniques such as 3D-CRT or IMRT. Further studies are emerging to assess the potential role of particle therapy in the management of lung cancer.
Early-Stage Disease
Considering the relative unavailability of particle beam radiotherapy and the complexities of delivery of this treatment to a mobile lung tumor, prospective data on the clinical efficacy of this approach in early-stage NSCLC are limited. Bush et al.305 reported on a series of 68 patients with unresectable stage I NSCLC: the first 22 patients were treated to 51 cobalt gray equivalent (CGE) protons in 10 fractions, and an additional 46 patients were treated to 60 CGE. With a median follow-up of 30 months, the 3-year local control rate was 74% in all patients with 87% local control in T1 (87%) and 49% in T2 tumors. The treatment was well tolerated, with no cases of RP or esophageal or cardiac toxicity. In a smaller series, Hata et al.306 reported on 21 patients with stage IA/IB treated with a total dose of 50 to 60 CGE at a dose per fraction of 5 to 6 CGE over a median time of 15 days. The 2-year local control and cause-specific survival were 95% and 86%, respectively. There were no grade 3 through grade 5 toxicities in this patient population.306 Chang et al.307 reported on a series of 18 patients with centrally located medically inoperable stage I NSCLC treated to 87.5 CGE in 2.5 CGE per fraction with proton beam radiotherapy. With a median follow-up time of 16.3 months, no grade 4 or 5 toxicities were observed. The most common toxicities observed were dermatitis (grade 2, 67%; grade 3, 17%), followed by grade 2 fatigue (44%), grade 2 pneumonitis (11%), grade 2 esophagitis (6%), and grade 2 chest wall pain (6%). The crude local control in these 18 patients was 88.9%, with 11.1% experiencing regional lymph node failure and 27.8% experiencing distant metastasis. At the time of last follow-up, 12 patients (67%) were still alive with 5 patients dying of distant metastatic disease and 1 patient dying of a cardiopulmonary event unrelated to treatment.307 Miyamoto et al.308 reported the results of a four-fraction phase II trial of carbon ion radiotherapy in early-stage NSCLC; 79 patients were enrolled and received either 52.8 cGE (stage IA) or 60 CGE (stage IB). The local control rate for all patients was 90% (T1: 98%, T2: 80%). The patients’ 5-year lung cancer–specific survival rate was 68% (IA: 87%, IB: 42%). The OS was 45% (IA: 62%, IB: 25%). Half of the deaths were attributable to intercurrent disease. No toxic reactions in the lung greater than grade 3 were detected. Although these results are promising, whether particle beam therapy provides an advantage over photon-based SBRT is not known at this time.
Locally Advanced Disease
Because of the requirement of delivery of tumoricidal doses of radiation to the mediastinal nodes in locally advanced NSCLC, particle beam radiotherapy may be of particular value in this patient population. There are no prospective data to date examining carbon ion radiotherapy in locally advanced disease; however, there are emerging data with proton beam radiotherapy in this setting. Chang et al.309 recently reported the results of the first 44 patients enrolled on a phase II trial of weekly concurrent carboplatin and paclitaxel with proton beam radiotherapy to 74 CGE in patients with inoperable stage IIIA/IIIB NSCLC. With a median follow-up of 19 months, they observed a promising median OS of 29.4 months in these patients. No patient experienced grade 4 or 5 proton-related adverse events. The most common nonhematologic grade 3 toxicities were dermatitis (n = 5), esophagitis (n = 5), and pneumonitis (n = 1). Nine patients (20.5%) experienced local disease recurrence; 4 patients (9.1%) had isolated local failure. Four patients (9.1%) had regional lymph node recurrence; 1 patient (2.3%) had isolated regional recurrence. Nineteen patients (43.2%) developed distant metastasis. The OS and PFS rates were 86% and 63% at 1 year. Although preliminary, these results suggest that proton beam radiotherapy with concurrent chemotherapy may potentially be of benefit in patients with inoperable locally advanced NSCLC.309 More clinical trials are needed.
METASTATIC NON–SMALL CELL LUNG CANCER
Basic Therapeutic Precepts
The treatment of advanced NSCLC has evolved over the past 25 years. In the late 1980s, debate centered on the basic efficacy of systemic therapy in patients with metastatic or recurrent disease. The toxicity of cisplatin-based treatment was considerable, and the survival benefits were marginal at best. Many clinicians felt that the side effects exceeded any putative benefit.
By the early 1990s, however, it was clear that platinum-based chemotherapy could prolong survival, improve symptom control, and yield superior QOL compared with best supportive care.310,311–313 In the 1990s, new agents emerged with enhanced therapeutic index. Carboplatin, although no more effective than cisplatin, was considerably safer with less nephrotoxicity, neurotoxicity, and gastrointestinal toxicity.314–316 In addition, several new agents, including paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan, were tested and proved compatible with either carboplatin or cisplatin. Phase III studies of these agents partnered with platinum demonstrated survival advantages compared to platinum alone or older, more toxic platinum-based combinations, and the benefits of these platinum-based combinations extended to those >70 years of age, as long as they were fit.317–323,324,325–328,329,330–331 By the late 1990s, in addition to frontline therapy, phase III trials had clearly demonstrated the efficacy of “salvage” treatment. Docetaxel was approved as second-line treatment based on two randomized trials: one showing a survival advantage compared to best supportive care and the other showing an advantage compared to either vinorelbine or ifosfamide.332–333 BR10 demonstrated a statistically significant and clinically meaningful response, PFS, and OS benefit for erlotinib compared to placebo in the second- and third-line setting in unselected patients, including those with compromised performance status.334 Finally, a phase III trial led by Hanna et al.335 showed therapeutic equivalence between pemetrexed and docetaxel in the second-line setting, with less toxicity for pemetrexed.
As mentioned previously, histology, for the first time, has become an important determinant in the selection of systemic therapy for advanced NSCLC. An association between nonsquamous histology and both improved response and survival has also been observed with pemetrexed in combination with platinum-based chemotherapy, compared with gemcitabine and a platinum agent.97,98 In contrast, gemcitabine has proven more effective than pemetrexed in the first-line treatment of patients with squamous NSCLC.97 In patients with adenocarcinoma, pemetrexed has demonstrated activity and garnered U.S. Food and Drug Administration (FDA) approval in the first-line, second-line, and maintenance therapy settings and has been tested in phase II trials in combination with carboplatin and bevacizumab in nonsquamous histology, generating a median PFS of 7.8 months and median survival of 14.1 months.97,98,335–337
Additionally, maintenance chemotherapy has now entered into the therapeutic lexicon. Based on recent large phase III randomized trials, both pemetrexed (for nonsquamous histology) and erlotinib (for any histologic subtype) are approved for use as maintenance therapy for those patients who have not progressed on standard platinum-based treatment.338,339
Molecular Determinants of Therapy
The presence of EGFR activating mutations in approximately 10% to 15% of lung cancer patients and their association with heightened sensitivity to EGFR TKIs were first recognized by Lynch et al.108 and Paez et al.340 in 2004. Multiple retrospective analyses and single-arm phase II trials have confirmed this correlation.102,341 However, it is only since 2009 that the association between EGFR mutations and improved response rate and PFS have been confirmed in prospective phase III trials in advanced NSCLC.342,343–345,346,347–349 The Iressa Pan-Asia Study (IPASS), a phase III, multicenter, randomized, open-label, parallel-group study in patients with advanced adenocarcinoma of the lung, was the first trial to demonstrate the potential for EGFR TKIs as first-line therapy in patients with specified clinical and demographic characteristics.342 Treatment-naive East Asian patients (n = 1,217), either nonsmokers or former light smokers, with adenocarcinoma of the lung were randomized to gefitinib monotherapy 250 mg per day orally or to combination paclitaxel 200 mg/m2 and carboplatin (AUC, 5 to 6 mg/mL per minute) every 3 weeks for up to six cycles. Among the overall study population, tumors from 437 patients (35.9%) were evaluable for mutation analysis; approximately 60% carried EGFR mutations. Of those with mutations randomized to gefitinib, the response rate exceeded 70%, whereas wild-type patients randomized to gefitinib had a response rate of roughly 1%. At 12 months, PFS was significantly longer in mutation-positive patients in the gefitinib group compared to patients in the paclitaxel/carboplatin (P/C) group (HR 0.48, 95% CI 0.36 to 0.64, p <.001). Conversely, PFS was significantly shorter for gefitinib compared to chemotherapy in patients whose tumors did not harbor mutations (HR 2.85, 95% CI 2.05 to 3.98, p <.001). However, final OS results for the gefitinib and P/C treatment groups were not significantly different for the overall population: 18.6 months for the gefitinib cohort; 17.3 months for the control group (HR 0.901, 95% CI 0.793 to 1.023, p = .109). Similarly, final OS results between the two treatment groups were not significantly different in the EGFR mutation-positive cohort (HR 1.002, 95% CI 0.756 to 1.328, p = .990) or in the EGFR mutation-negative subgroup of patients (HR 1.181, 95% CI 0.857 to 1.628, p = .309), presumably because of crossover to an EGFR TKI in mutation-positive patients randomized to chemotherapy. Despite the absence of a survival benefit, this trial has irrevocably altered the therapeutic paradigm in advanced NSCLC and has laid the groundwork for subsequent phase III trials comparing EGFR TKIs to standard chemotherapy conducted exclusively in patients with the EGFR mutation (Table 51.10).
Taken together, the results of these trials, particularly with respect to response rate and PFS, support the use of EGFR TKIs in the first-line setting in patients harboring EGFR-activating mutations. To date, however, largely because of crossover at the time of disease progression, this response rate and PFS benefit has not yet translated into an OS advantage. However, it is clear that patients who harbor this mutation live longer than wild-type patients as long as they receive an oral EGFR TKI at some point in their disease course.
TABLE 51.10 PHASE III TRIALS COMPARING EGFR TKI TO STANDARD CHEMOTHERAPY IN EGFR MUTANT POSITIVE COHORTS
Burgeoning Understanding of EML4/ALK in Advanced Non–Small Cell Lung Cancer
ALK positivity defines a distinct molecular subset of NSCLC. Phenotypically, patients whose tumors are likely to prove positive for this molecular marker look similar to those who harbor EGFR mutations. Nearly all have adenocarcinoma, and they are more likely to be nonsmokers. However, ALK translocation (3% to 7%) and EGFR mutation (10% to 15%) are virtually mutually exclusive, and those patients whose tumors harbor ALK translocations do not typically respond to treatment with EGFR TKI.103,350 Crizotinib, a selective inhibitor of the ALK and MET tyrosine kinases, resulted in preliminary activity in a phase I dose escalation study in previously treated patients with NSCLC whose tumors expressed EML4-ALK. Among 113 evaluable ALK-positive patients receiving this agent, the overall response rate was 56% and median PFS 9.2 months.103,350 The most common adverse events were mild to moderate and gastrointestinal in nature and included nausea (54%), diarrhea (48%), and vomiting (44%). Other adverse events included liver function test elevations and transient difficulty with light-dark accommodation. Camidge et al.351 more recently have updated the results of this study; this report included a total of 119 patients treated with crizotinib. The response rate rose to 61% with a median PFS of 10 months. The 1- and 2-year survival rates were 74% and 54%, respectively, and the median survival had not been reached.
During the American Society of Clinical Oncology meeting in 2011, Crino et al.352 reported a preliminary analysis of enrollees in the phase II trial in NSCLC patients positive for EML4-ALK who had been exposed to multiple lines of therapy. Of 133 patients enrolled, the median age was 52 years, 94% had adenocarcinoma, 68% were never smokers, and 53% were female. The overall response rate was 51.1%; the disease control rate was 74%. Toxicities matched those observed in the original phase I trial. PFS and OS data were not yet available. In addition, there were clinically meaningful improvements in symptoms such as cough, pain, dyspnea, and fatigue. This study is ongoing with a planned sample size of 400 patients. An ongoing phase III trial (NCT00932893) compares crizotinib to standard second-line chemotherapy with either docetaxel or pemetrexed in patients with NSCLC harboring a translocation at the ALK locus whose disease has progressed after one prior chemotherapy regimen. In addition, a first-line trial compared crizotinib to combination pemetrexed and cisplatin in chemotherapy-naive patients with ALK-positive advanced NSCLC. As time goes on, it seems apparent that crizotinib may prolong OS and fundamentally alter the natural history of ALK-positive NSCLC. The FDA granted accelerated approval of this agent on August 26, 2011.
Conclusion
The era of customized care in advanced NSCLC has clearly arrived. The previous “one size fits all” approach has been discarded. Therapeutic decisions are now based on both histology and molecular markers. It is anticipated that other markers will emerge over the next 5 to 10 years. KRAS mutations are present in 20% to 25% of all patients with advanced NSCLC; however, to date, no agent has been identified that can adequately target this marker. Other markers, including BRAF and HER-2/neu are present in 1% to 3% of patients with advanced adenocarcinoma and may prove “actionable” in the small percentage who harbor them. Finally, fibroblast growth factor receptor is present in 20% to 25% of those with squamous histology; molecularly driven studies are now addressing the squamous cell carcinoma cohort for which no specific targeted agent has yet been identified.
PALLIATIVE RADIOTHERAPY
Given the propensity of lung cancer for locoregional recurrence and/or distant metastatic disease, radiotherapy plays an important role in the palliation of symptomatic disease in many lung cancer patients.353,354 The most common sites of disease that require palliative radiotherapy include the thorax, bone, and brain. Intrathoracic disease and bone metastasis will be covered here. The reader is referred to the CNS section (see Chapter 93).
Palliation of Intrathoracic Disease
Symptoms from progression of intrathoracic lung cancer that may benefit from a course of palliative radiotherapy include cough, hemoptysis, chest wall pain, SVC syndrome, dyspnea from airway obstruction, and hoarseness from involvement of the recurrent laryngeal nerve. In one prospective study following 134 inoperable patients with lung cancer, immediate chest radiotherapy was necessary in 86 patients (64%) because of significant presenting symptoms from intrathoracic disease, and of the remaining 48 patients not receiving initial radiotherapy, 26 patients (54%) required chest radiotherapy later because of symptoms from intrathoracic disease.355 The rate of palliation of local symptoms is high for chest pain and hemoptysis at 60% to 80%, whereas cough and dyspnea are improved in only 50% to 70%.356 For intrathoracic disease with an obstructive component, 30 to 45 Gy in 2.5- to 3-Gy fractions over 2 to 3 weeks is generally recommended.357 For patients with poor performance status or for whom daily radiotherapy over 2 to 3 weeks is logistically difficult, hypofractionated regimens (of 1 to 2 fractions) have been utilized with good palliative results.358,359 An ASTRO evidence-based guideline for palliative thoracic radiation in lung cancer has recently been published that emphasized either short- or long-course EBRT as the first-line radiation option in the palliative setting and that use of concurrent chemotherapy in the palliative setting is not supported by the current medical literature.360
Endobronchial brachytherapy provides relief for patients with endobronchial lesions causing obstruction or hemoptysis.361,362 The lesion to be treated should be visible by bronchoscopy and generally located in the trachea, main stem, or lower lobe bronchi. This procedure requires the combined efforts of an interventional pulmonologist and brachytherapist. The pulmonologist performs fiberoptic bronchoscopy, placing an afterloading catheter within the airway adjacent to the tumor under direct visualization. In a retrospective study from MD Anderson Cancer Center involving 175 patients with lung cancer who received high dose rate brachytherapy for metastatic or locally recurrent lung cancer, 115 patients (66%) demonstrated symptomatic improvement.363 A more recent study corroborates the low morbidity and high symptomatic improvement.364 Endobronchial brachytherapy is primarily indicated in patients with obstructive endobronchial lesions who have already received EBRT.360 It can also be combined with other interventions that can acutely relieve symptoms related to airway obstruction such as stenting or debulking procedures.
Superior Vena Cava Syndrome
Lung cancer is the most common cause of SVC syndrome and accounts for approximately 80% of cases at diagnosis.365 If the SVC becomes obstructed because of an extrinsic mass, blood returns to the heart through collateral vessels to the azygous vein or inferior vena cava. Venous collaterals dilate over weeks so that the upper body venous pressure and resulting edema of the arm and face decrease over time. The severity of the symptoms is therefore attributable not only to the degree of SVC narrowing but also to the rapidity with which it develops. The characteristic signs include cyanosis; plethora; distention of subcutaneous veins; and edema of the head, neck, and arm. Patients may report dyspnea or cough. Rarely, severe and acute obstruction can result in cerebral edema or laryngeal stridor. The clinical course may be exacerbated by the development of a thrombus or the simultaneous tumor mass effect on the bronchi or heart.
Traditionally, SVC syndrome was viewed as a medical emergency. Accumulating experience, however, demonstrates that the course of SVC is rarely life threatening. In a review of 107 patients in whom intervention was withheld during evaluation, there were no serious clinical consequences to deferring treatment until diagnosis and staging was completed.366 Symptoms often improve without active intervention, as collateral vessels dilate.367 In malignant SVC syndrome, immediate intervention is warranted when the symptoms are life threatening (e.g., cerebral edema leading to altered mental status, stridor, or clinically significant hemodynamic compromise). When urgent intervention is indicated, intravascular stenting provides the most immediate relief and can be accomplished even when there is complete obstruction. In the absence of life-threatening symptoms, the patient should be appropriately staged and biopsied and the underlying malignancy treated in a manner appropriate for its stage and presentation. The majority of patients with SVC syndrome attributed to SCLC will respond to systemic therapy, and patients with extensive-stage SCLC and SVC syndrome should start chemotherapy after a staging evaluation. Similarly, patients with limited-stage SCLC and SVC syndrome with bulky disease should respond rapidly to a cycle of chemotherapy, after which radiation can be added, treating the smaller, postchemotherapy volume to spare normal lung tissue. Patients with NSCLC and SVC syndrome are less likely to respond to chemotherapy, thus the threshold for starting radiation or placing an endovascular stent should be lower.368 In patients with metastatic NSCLC, palliative radiotherapy is commonly recommended as part of initial therapy.
SMALL CELL LUNG CARCINOMA
In the United States in 2011, approximately 28,000 patients were diagnosed with SCLC, constituting approximately 13% of all lung cancer diagnoses.2 Over the past several decades, the proportion of SCLC among all lung cancer histologies has been decreasing, perhaps because of smoking cessation and the proliferation of low-tar cigarettes.369 Although there has been a modest but statistically significant improvement in 2- and 5-year survival in both limited- and extensive-stage disease in recent decades, the outcomes are still extremely poor, particularly since the majority (approximately 60%) of patients present with extensive-stage disease with an expected 2-year survival of only 4%.
Pathology
The establishment of a firm pathologic diagnosis distinguishing SCLC from NSCLC variants such as carcinoma with neuroendocrine features and carcinoid is extremely important in this disease, as it can have a significant impact on management and clinical outcome. Histologically, SCLC is one of the small, round, blue cell tumors (along with neuroblastoma, rhabdomyosarcoma, Merkel cell carcinoma, etc.) with scant cytoplasm and indistinct nucleoli. Cells are often molded together, and crush artifact is commonly noted after needle biopsy but is not pathognomonic. Almost all SCLC samples are immunoreactive to keratin and epithelial membrane antigen, and approximately 80% express thyroid transcription factor-1 (TTF-1).370 The majority of tumors will stain for neuroendocrine markers including synaptophysin, chromogranin A, neuron-specific enolase, and CD56. Immunohistochemistry alone, however, cannot distinguish SCLC from small cell cancer of nonthoracic origin or from NSCLC with neuroendocrine differentiation. The WHO recognizes that SCLC can occur in a pure type or mixed with NSCLC in up to 30% of cases.
Prognostic Factors in Small Cell Lung Cancer
The most clinically important prognostic factor in SCLC is stage (limited vs. extensive), with a median survival of approximately 23 months for patients with limited disease versus 8 to 9 months for those with extensive disease.222,371 Other clinical factors consistently reported to correlate with improved survival include good performance status, female gender, and normal lactate dehydrogenase levels at baseline.372
Staging Workup
As in patients with NSCLC, patients with SCLC should undergo a timely and efficient history, physical exam, and laboratory and radiographic evaluation. The history and physical should be performed with particular attention to signs and symptoms of paraneoplastic syndromes, including SIADH and elevated ACTH. Laboratory evaluation should include a complete blood count and comprehensive chemistry panel. Radiographic studies should include a CT scan of the chest and abdomen with intravenous contrast and a bone scan.373 All patients with SCLC, regardless of stage, should undergo a brain MRI with gadolinium or a head CT with contrast to evaluate for brain metastases. A diagnostic thoracentesis should be performed for any identified pleural effusion to determine the presence of malignant cells. If limited-stage disease is suspected, an FDG-PET scan is recommended because it has significant value in identifying distant metastatic dissemination as well as additional regional nodal dissemination beyond that typically seen on CT alone.374 The TNM staging system adopted by the American Joint Commission for Cancer (AJCC) in the seventh edition of the Cancer Staging Manual is applicable to both NSCLC and SCLC. Most historical studies and ongoing prospective trials, however, classify patients as having limited or extensive disease based on the 1973 Veteran’s Administration Lung Group staging scheme.375 In this system, limited stage is defined as disease confined to the ipsilateral hemithorax, which can be safely encompassed within a tolerable radiation portal. Virtually all studies in limited disease exclude malignant pleural effusions. From a practical standpoint, hemithoracic radiotherapy to encompass the entire ipsilateral pleura has little justification because it would confer a significant risk of pulmonary toxicity in a high-risk patient population with little chance of cure. As such, patients with malignant pleural effusions are almost always classified as having extensive-stage disease.
Paraneoplastic Syndromes
Paraneoplastic syndromes are commonly encountered in lung cancer; however, the spectrum of paraneoplastic syndromes in SCLC is distinct from that observed in NSCLC. Neurologic paraneoplastic syndromes are more commonly encountered in SCLC and are thought to be primarily autoimmune in nature. LEMS is seen in 3% of all SCLC patients at presentation and is characterized by proximal muscle weakness that improves with continued activity. This syndrome occurs when autoantibodies are generated against voltage-gated calcium channel receptors on the presynaptic membrane, impeding release of acetylcholine into the neuromuscular junction and resulting in muscular weakness. A wide variety of other rare autoimmune neurologic paraneoplastic syndromes have been described in SCLC, including encephalomyelitis, cerebellar degeneration, and retinopathy.376 SCLC can also elaborate hormonally active peptides including ACTH and vasopressin leading to Cushing’s syndrome and SIADH, respectively. Although SCLC is the most common tumor associated with SIADH, only 10% of patients meet the clinical criteria for SIADH. Similarly, only 5% of SCLC patients present with Cushing’s syndrome. Despite the fact that paraneoplastic syndromes may lead to early identification and diagnosis of SCLC, some of these syndromes, such as Cushing’s, have been associated with poorer survival.44 Treatment of the cancer will often, although not always, ameliorate the paraneoplastic syndromes.
General Therapeutic Precepts
Early-stage (i.e., T1-2, N0) SCLC is diagnosed in <5% of incident cases. For these patients, definitive surgical resection is a potential therapeutic option. In a population-based study, lobectomy without adjuvant radiation was associated with an approximately 50% OS.377 Given the propensity for early nodal dissemination with SCLC, invasive staging of the mediastinum should be performed prior to surgical resection. After surgical resection, the primary mode of failure for these patients is distant dissemination. Tsuchiya et al.378 reported the results of JCOG9101, a JCOG Lung Cancer Study Group multi-institutional phase II prospective trial evaluating adjuvant EP after complete surgical resection of stage I through stage IIIA SCLC. The majority of patients enrolled had clinical stage I disease (44/62). Three-year survival was 61% overall, 68% in patients with clinical stage I disease, 56% in patients with stage II disease, and 13% in patients with stage IIIa disease.378 These data suggest a possible role for surgical resection in select patients with pathologically proven stage I or II SCLC.
The majority of patients present with evidence of nodal or distant dissemination at the time of diagnosis. Multiagent chemotherapy, usually etoposide in combination with carboplatin or cisplatin, is an essential part of therapy for these patients. For patients with limited-stage disease, the addition of thoracic radiation significantly improves survival and therefore is an integral part of their treatment regimen. Two meta-analyses have demonstrated not only an improvement in thoracic control but also a significant improvement in absolute survival of about 5% (and relative improvement of about 50%) in patients with limited-stage disease treated with combined modality therapy compared to those treated with chemotherapy alone.379,380 Patients with extensive-stage disease are usually treated with systemic chemotherapy alone. For select good performance status patients with extensive-stage disease who have complete resolution of their extrathoracic tumor burden, consolidative thoracic radiotherapy may be of benefit to reduce the risk of intrathoracic failure.381 Patients with limited-stage disease (and selected patients with extensive-stage disease) who respond to initial therapy should be offered prophylactic cranial irradiation (PCI), as this has been shown to provide a significant improvement in absolute survival for these patients.371,382
Combining Radiation and Chemotherapy for Limited-Stage Disease
A randomized trial by the JCOG evaluated concurrent versus sequential chemotherapy and thoracic radiation in patients with limited-stage SCLC.383 All patients received 45 Gy in 1.5-Gy fractions twice daily and were randomized to receive four cycles of cisplatin (80 mg/m2 on day 1) and etoposide (100 mg/m2 days 1, 2, and 3) every 4 weeks concurrent with radiotherapy (beginning day 2) or every 3 weeks sequentially before radiotherapy. Patients treated concurrently had longer median survival compared to patients treated sequentially: 27 months versus 20 months. A second randomized trial by the National Cancer Institute of Canada compared early with late concurrent chemoradiotherapy.384 In this trial, 308 patients received cyclophosphamide, doxorubicin, and vincristine alternating with EP and were randomized to 40 Gy in 15 daily fractions given with either the first cycle of EP (week 3) or the last (week 15). The median survival improved to 21 months with early radiotherapy versus 16 months with late treatment (p = .008).384 These two trials were included in a meta-analysis by Fried et al.385 that included >1,500 patients from seven randomized trials evaluating the timing of radiotherapy when given concurrently with multiagent chemotherapy. The use of early thoracic radiotherapy, with cycle 1 or 2 of chemotherapy, was associated with improved 2-year OS compared to delayed or sequential chemotherapy and radiation. The benefit was more pronounced when the radiotherapy was given with platinum-based chemotherapy.
The EP combination is the most commonly used first-line chemotherapy regimen in patients with SCLC, either alone (in patients with extensive disease) or in combination with thoracic radiation (in patients with limited-stage disease). In patients with extensive disease, alternative combinations including cisplatin and irinotecan (IP), the addition of an anthracycline or taxane to EP, and higher-dose therapy have been investigated; however, to date, they have not proven superior to EP. The only exception is Japan, where IP has displaced EP. Carboplatin as a substitute for cisplatin is an equivalent regimen to EP in extensive-stage disease with a lower risk of nephropathy. In limited-stage disease, in those fit enough to tolerate it, combination EP administered concurrently with thoracic radiation remains the standard regimen.
Dose and Fractionation
The optimal dose and fractionation scheme for concurrent chemoradiation for limited-stage small cell is an area of active investigation. SCLC is highly radiosensitive, suggesting that hyperfractionation could be employed to reduce late normal tissue toxicity. It also has a high proliferative rate, arguing for accelerated treatment to counteract repopulation. Between 1989 and 1992, 417 patients were enrolled in a randomized, intergroup trial of concurrent accelerated hyperfractionated radiotherapy versus standard daily radiotherapy in patients with limited-stage SCLC.386 All patients received four cycles of cisplatin (60 mg/m2 on day 1) and etoposide (120 mg/m2 on days 1, 2, and 3), and radiotherapy began with cycle 1. In the once-daily arm, patients received 45 Gy in 1.8-Gy fractions over 5 weeks. In the twice-daily arm, patients received 45 Gy in 1.5-Gy fractions over 3 weeks. Patients who achieved a complete response were offered PCI. OS was significantly higher in the twice-daily arm, 26% versus 16% at 5 years, and local recurrence was significantly lower, 36% versus 52%. There was a significant increase in grade 3 acute esophagitis, 26% versus 11%, in the twice-daily arm, with no difference in late toxicity. The 5-year survival rate observed in this study is among the best reported for limited-stage disease; consequently, this treatment approach is considered by many the current standard of care for the management of limited-stage disease.
The perceived radiosensitivity of SCLC led to the initial utilization of modest dose approaches to treat this disease (45 to 50 Gy). However, the intrathoracic relapse rate observed in the once-daily arm of the Turrisi study was 75%, highlighting the inadequacy of these modest doses to achieve meaningful local control.222 The observed improved survival in the twice-daily arm in this study highlighted the importance of local control in this disease. Therefore, dose escalation, either through an altered fractionation or conventionally fractionated approach, has been explored with a goal of improving intrathoracic control of disease. In 2005, the RTOG reported the results of a phase I dose escalation trial in which 64 patients were enrolled and dose escalated in a stepwise fashion from 50.4 Gy to 64.8 Gy in 1.8 Gy per fraction.387 The lowest dose cohort received 1.8 Gy once daily for 20 fractions, followed by 1.8 Gy twice daily on the final 3 days. Dose escalation was achieved by the addition of a second daily fraction on the last 5, 7, 9, or 11 days, retaining the 5-week treatment duration. The maximum tolerated dose was determined to be 61.2 Gy in 5 weeks using this scheme. In a follow-up phase 2 study, RTOG 0239,388 72 patients were treated to 61.2 Gy in 5 weeks, with twice-daily radiotherapy for the last 9 treatment days. With 19 months median follow-up, 2-year OS was 37% and 2-year locoregional control was 80%.
Dose escalation has also been examined utilizing a daily fractionation scheme. Choi et al.389 conducted a phase I dose escalation study with both twice-daily and once-daily arms. In the twice-daily arm, 45 Gy in 30 fractions over 3 weeks was the maximum tolerated dose. In the once-daily arm, the dose was escalated to the maximum of 70 Gy in 35 fractions over 7 weeks without dose-limiting toxicity. CALGB 39808 tested the feasibility of this approach with concurrent platinum and etoposide.390 In this study, 63 patients were treated with two cycles of induction paclitaxel (175 mg/m2 day 1) and topotecan (1 mg/m2 days 1 through 5), followed by concurrent thoracic radiation with carboplatin (AUC 5) and etoposide (100 mg/m2 days 1 through 3). Thoracic radiation consisted of 44 Gy to the mediastinum and primary tumor delivered in 2 Gy per fraction, followed by a cone-down to encompass the involved nodes and primary tumor alone for an additional 26 Gy, totaling 70 Gy in 35 fractions over 7 weeks. Grade 3 or 4 esophagitis was noted in 21% of patients. The OS at 2 years was 48%. Intriguingly, 10 of 63 patients had local relapse within the high-dose field with no relapses within the lower-dose 44-Gy volume, suggesting that a relatively radioresistant subpopulation of tumor cells may exist in some small cell tumors.390
In summary, the optimal dose and fractionation approach for SCLC remains to be defined. An ongoing intergroup effort (CALGB 30610, RTOG 0538, NCT00632853) seeks to determine the optimal radiation schedule. Patients are randomized to one of three arms: (a) 45 Gy in 30 fractions over 3 weeks, (b) 61.2 Gy in 5 weeks per RTOG 0239, or (c) 70 Gy in 35 fractions over 7 weeks per CALGB 39808. All patients receive concurrent EP, and radiotherapy begins with cycle 1 or cycle 2. A similar effort is under way in Europe. The Concurrent Once-daily Versus Twice-daily Radiotherapy (CONVERT) trial is a 2-arm randomized phase III study: patients receive either 45 Gy in 30 fractions twice daily or 66 Gy in 33 fractions once daily. All patients receive EP; radiotherapy begins with cycle 2.
Radiotherapy Volume
Limited-stage SCLC is frequently bulky at presentation, requiring large treatment fields to encompass all sites of intrathoracic disease. Therefore, induction chemotherapy has been employed to achieve cytoreduction of disease prior to initiation of thoracic radiotherapy. This approach raises the concern of potentially increasing the risk of marginal treatment failure if the postchemotherapy volume alone is included in the radiation portal. To address this question, the SWOG conducted a randomized study, enrolling 191 patients who had a partial response or stable disease after 6 weeks of induction chemotherapy. They were randomized to receive radiotherapy (48 Gy split course) to either the preinduction or postinduction volume.391 There was no difference in local recurrence rates: 32% in the preinduction versus 28% in the postinduction arm. Careful retrospective studies of patients treated with preinduction or postinduction thoracic radiotherapy show that local failure is not significantly higher if smaller fields are used. Furthermore, most intrathoracic failures occur in the smaller postchemotherapy radiation field, arguing, as in locally advanced NSCLC, against the use of ENI.392,393
Thoracic Radiotherapy for Extensive-Stage Disease
Systemic therapy is the essential element in the treatment of patients with extensive-stage SCLC with good performance status; however, thoracic radiotherapy may play a role in selected patients. Based on the observation that patients have high rates of thoracic relapse after systemic therapy alone, a single-institution prospective randomized trial was undertaken in Yugoslavia.381 In this trial, 209 patients with extensive disease were enrolled and treated with three cycles of EP. Of those, 110 patients who had a partial response in the chest and a complete response outside the chest were randomized to receive thoracic radiation with concurrent carboplatin and etoposide, followed by two cycles of EP, versus four further cycles of EP alone. All eligible patients received PCI. The thoracic radiation was delivered in 54 Gy in 36 fractions over 12 days. At 5 years, the OS was higher in the arm that featured thoracic radiation: 9% versus 4%. Thoracic radiotherapy in extensive-stage disease is currently the subject of at least two prospective trials. RTOG 0937 is a randomized phase II study in patients with extensive disease who have no more than three extrathoracic sites of disease; patients are randomized to receive 45 Gy of thoracic radiation in 30 twice-daily fractions followed by PCI, versus PCI alone, after chemotherapy. In the Chest Irradiation in Extensive Stage Small Cell Lung Cancer (CREST) trial conducted by the Dutch Lung Cancer Study Group, patients with extensive-stage disease who respond to chemotherapy are randomized to thoracic radiotherapy (30 Gy in 10 fractions) and PCI versus PCI alone. The results of these trials will help to clarify the role of thoracic radiotherapy in extensive-stage disease.
Prophylactic Cranial Irradiation
Brain metastases are present at diagnosis in approximately 20% of patients with SCLC. The brain is also a frequent site of failure after chemotherapy for extensive disease or chemoradiotherapy for limited-stage disease. Several randomized trials have addressed the value of PCI following a response to initial therapy and have consistently demonstrated a decrease in the incidence of brain metastases. A meta-analysis reported the results of 987 patients treated in seven randomized trials enrolling between 1977 and 1995.394 Here, 85% of these patients had limited stage and 15% extensive. All were randomized to either PCI or to observation following a complete response to initial therapy, although response was most commonly assessed by chest x-ray rather than CT scan. PCI regimens varied from 8 Gy in a single fraction to 40 Gy in 20 fractions. At 3 years, PCI was found to significantly decrease the incidence of brain metastases (59% vs. 33%) and significantly improve OS (21% vs. 15%). There was trend toward improved brain control when PCI was administered earlier and at higher dose. The publication of this study demonstrated the value of PCI in limited-stage SCLC. PCI in extensive-stage SCLC was specifically addressed in a more recent randomized trial conducted by the EORTC. In this trial, 286 patients with extensive-stage SCLC were randomized to either PCI or observation after any response to four to six cycles of chemotherapy. Those assigned to the PCI arm were treated within 4 to 6 weeks of completing systemic therapy. Of note, this study did not require baseline brain imaging, nor did it require repeat brain imaging prior to initiation of PCI. The 1-year cumulative incidence of brain metastases was significantly decreased in the PCI arm at 15% versus 40%, and 1-year OS was significantly increased in the PCI arm at 27% versus 13%. Six different PCI regimens were permitted, with biologically effective dose ranging from 25 to 39 Gy.
Despite the survival benefit reported in the Auperin meta-analysis and the EORTC trial in extensive-stage disease, a variety of dose and fractionation schemes were employed to treat the patients enrolled in the trials. To help define the optimal dose and fractionation for PCI, a multi-institutional intergroup trial was launched to examine standard-dose PCI versus high-dose PCI. Patients with limited-stage SCLC who had achieved a complete response to chemoradiotherapy were randomized to receive PCI in standard dose, 25 Gy in 10 daily fractions, or high-dose, 36 Gy in either 18 daily fractions or 24 twice-daily fractions.395 In this study, 720 patients were randomized; at 2 years, the cumulative incidence of brain metastases was not significantly different between the two arms: 29% in the standard dose arm versus 23% for high dose. Surprisingly, there was poorer OS in the high-dose arm: 2-year survival was 42% in the standard dose arm versus 36% for high dose. This was attributed to a higher cancer-related mortality in the high-dose arm. Patients enrolled in this trial participated in baseline and follow-up neuropsychological test batteries along with QOL assessments. Wolfson et al.396 recently reported the results of these assessments and observed an increased incidence of chronic neurotoxicity at 12 months after PCI in the 36-Gy cohort (p = .02). Taken together, these results establish 2.5 Gy in 10 fractions as the current preferred regimen to deliver PCI.
NORMAL TISSUE TOXICITY
The risk and severity of radiation toxicity in normal tissue are related to the dose and volume irradiated, as well as the functional organization of the OAR. In serial tissue such as spinal cord, esophagus, and trachea and bronchi, injury of any one organ subunit may result in total organ dysfunction. Therefore, high dose to even small volumes can lead to significant toxicity. In parallel tissues, such as lung, dysfunction of any one organ subunit leads to partial organ dysfunction. In this case, the volume irradiated, even to lower doses, plays a larger role.
Emami et al.397 published partial-volume organ tolerances for normal tissue that served for more than a decade as the standard source for radiation dose limits. Dose limits were defined for specific toxicity end points, using a 5% complication rate at 5 years (TD5/5) or 50% complication rate at 5 years (TD50/5). These parameters were based predominantly on clinical data from 2D radiotherapy planning. Recently, a multidisciplinary effort was undertaken, the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC), to summarize the published 3D dose-volume/toxicity data in the literature, review NTCP modeling, and provide practical guidance for the clinician263,264(Table 51.11).
Lung
Clinically significant pneumonitis occurs in 5% to 20% of patients receiving radiation for lung cancer and is one of the key dose-limiting factors in radiation planning for patients with locally advanced disease. RP may occur during fractionated treatment or up to 18 months afterward, with a peak incidence at 2 to 6 months posttreatment. The most common clinical presentation includes a persistent nonproductive cough, dyspnea, low-grade fever, and fatigue. Chest x-ray or CT scan may be normal, or, depending on the time course, there may be ground glass opacification (within 2 to 6 months), patchy consolidation (4 to 12 months), or fibrosis (10 months or more) that loosely corresponds to the radiation field. Pulmonary function testing shows reduced lung volumes, tidal volumes, and diffusion capacity.
TABLE 51.11 DOSE-VOLUME CONSTRAINTS FOR NORMAL TISSUES USING STANDARD FRACTIONATION TO TARGET VOLUME AND TRADITIONAL ESTIMATES OF NORMAL TISSUE TOLERANCE OF THERAPEUTIC IRRADIATION
A variety of dose-volume models have been evaluated as predictive metrics of RP, including threshold volumes (i.e., Vdose), MLD, and Lyman-Kutcher-Burman NTCP models. MLD and dose-volume threshold models are more widely used because of their simplicity, and MLD-based risk assessment for RP correlates closely to that calculated using NTCP modeling. A logistic regression of RP versus MLD and the cross-correlation of various Vdoseparameters suggest a gradual increase in dose response, with no safe threshold dose below which the risk of RP is zero.265
From collected data in the QUANTEC effort, the risk of RP is <20% when the MLD is less than approximately 20 Gy with conventional fractionation. With regard to Vdose threshold models, where the volume of lung outside of the GTV or PTV receiving a threshold dose is quantified, individual data sets have found different thresholds to be optimal, reflecting the interdependence of the dosimetric parameters as well as differences in technique and the specific clinical end point used. The risk of RP is <20% for V20 <30 to 35 Gy or V5 <60% with conventional fractionation.
All models of conventional fractionation are extrapolated from data sets using standard, simple planning techniques and may have lower predictive power for IMRT, proton therapy, or hypofractionated radiotherapy. Several reports indicate a lower risk of pneumonitis than dose-volume metrics would predict when IMRT is used.398,399 Caution is warranted when using IMRT and absolute dose-volume thresholds, because planning algorithms may meet strict dosimetric constraints at the cost of higher dose at other, unconstrained cut points. IMRT for the treatment of mesothelioma after pneumonectomy has been associated with an unexpectedly high risk of severe RP and therefore warrants particular care.400
RP occurs less commonly after SBRT in comparison to conventionally fractionated radiation.401 The risk of symptomatic RP does seem to follow a similar relationship to dose and volume irradiated as seen in conventionally fractionated treatment,402 although specific dose thresholds corresponding to risk thresholds have not yet been fully elucidated. In one large series, the risk of grade 2 or greater RP was 17% when the MLD was >4 Gy versus 4% for lower values and 16% when the V20 was >4% versus 4% for lower values.403 The AAPM Task Group 101 report included a first approximation of tissue dose tolerances for SBRT.271 For bilateral lung, they recommended maximum dose to 10 and 15 cc of lung of 7.4 and 7 Gy for single-fraction SBRT, 12.4 and 11.6 Gy for three-fraction SBRT, and 13.5 and 12.5 Gy for five-fraction SBRT.
Radiotherapy-induced dyspnea may have several contributing causes, including not only RP but also radiotherapy to other thoracic OARs. Emerging evidence suggests an interaction between cardiac dose and RP,404 or there may be additive dyspnea owing to pleural and pericardial effusions, restrictive pericarditis, cardiomyopathy, and bronchial stenosis or bronchiectasis. Bronchial toxicity has been reported with conventional radiotherapy after dose escalation,405 and QUANTEC recommendations include the caution that doses >80 Gy to the major airways should be avoided.265 For SBRT, the risk of bronchial stenosis is felt to be higher because of the higher biologically effective dose delivered, and this may be one cause of the reported higher risk of pulmonary toxicity when lesions near the proximal bronchi are being treated.174 The AAPM Task Group 101 recommends maximum doses to 4 cc and maximum point doses to the proximal tracheobronchial tree of 10.5 and 20.2 Gy for single-fraction SBRT, 15 and 30 Gy for three-fraction SBRT, and 16.5 and 40 Gy for five-fraction SBRT.
Several patient- and treatment-related factors impact the risk of RP, independent of dose and volume. In a large data set derived from patients treated on RTOG trials, the risk of RP was significantly higher for tumors in the lower lung fields.406 Older age may increase the risk of RP, and patients who continue to smoke through their radiotherapy may be at decreased risk, although the benefits of smoking cessation far outweigh any potential benefit in terms of reduction of risk of RP.265 Several chemotherapy agents that are commonly administered to lung cancer patients are associated with an increased risk of RP, including docetaxel and gemcitabine.
Glucocorticoids are commonly used to treat developing RP, although this has not been evaluated in a prospective fashion, and the starting dose and tapering schedule are undefined. A starting dose of approximately 60 mg or 1 mg/kg of prednisone may be given for 1 to 2 weeks, followed by a slow taper over 4 to 8 weeks. Symptoms may recur when steroids are discontinued, and although it is hoped that treatment may mitigate the development of lung fibrosis, this has not been established. Prophylactic antibiotics or anticoagulants do not appear to effect the development of RP. Pentoxifylline is a xanthine derivative that improves microvascular blood flow; it was used in a single randomized trial of 40 patients undergoing breast or lung irradiation.407 The number of patients with grade 2 or 3 pulmonary toxicity was significantly lower in the patients who received pentoxifylline (20% vs. 50%), as was the measured diffusion capacity. Amifostine has been tested in several randomized trials, with mixed results.230,408 Captopril is an angiotensin-converting enzyme inhibitor that has been shown to reduce the development of radiation-induced fibrosis in rats, although no such protective effect has been demonstrated in humans.409
Esophagus
Acute esophagitis is often the most prominent symptom during fractionated radiotherapy for thoracic malignancy, leading to inpatient admissions, dehydration, weight loss, and treatment interruption. Late esophageal toxicity may include stricture, perforation, or fistula formation. Grade 3 or greater acute esophagitis (symptoms requiring hospitalization, endoscopic intervention, surgery, or treatment breaks) occurs in 15% to 25% of patients during or shortly after chemoradiation. Acute esophagitis may coexist with, and be exacerbated by, comorbid conditions such as candidiasis or reflux disease. Severe late toxicity is less common, occurring in <5% of patients,410,411 and manifests as stenosis or, more rarely, fistula formation.
Several dose-volume metrics have been evaluated as predictors of severe esophagitis. The maximum esophageal dose correlates with symptoms, as do multiple absolute dose and volume thresholds. These are highly cross-correlated, and no consensus has been reached regarding the optimum parameter for radiotherapy planning. Circumferential measures (i.e., limits to the length of entire esophageal circumference treated to threshold dose) have also been significantly correlated with symptoms, as has the mean esophageal dose.412,413 Two studies independently established consistent parameters for NTCP modeling of grade 2 or greater esophagitis,412,414 suggesting that this method may be clinically useful. The QUANTEC analysis concludes that volumes treated above 40 to 50 Gy correlate with acute symptoms and suggests that no dose above prescription be allowed to even small volumes of esophagus. This latter information is especially important for heterogeneous IMRT planning.266
Esophageal toxicity is related to both dose and volume of irradiation, and the risk and severity are therefore also a function of the size, anatomic arrangement, and proximity of target structures. Other factors identified as increasing the risk or severity of acute esophagitis include the use of accelerated fractionation,222 older patient age, and the use of concurrent chemotherapy.201,205,415 Recently, an unexpectedly high risk of tracheoesophageal fistula formation was reported after radiotherapy with concurrent chemotherapy and bevacizumab.235
Treatment of acute esophagitis is primarily supportive care, frequently requiring topical agents, dietary changes, and narcotic pain medication. It is often prudent to evaluate patients for viral or candidal esophagitis. Patients may be treated empirically with antifungal agents or with proton pump inhibitors for comorbid reflux disease. The radioprotectant amifostine has been evaluated in several prospective trials in an effort to reduce the risk and severity of acute esophagitis. Although several small trials showed promising results,408,416,417 no “objective” benefit (in physician-reported esophageal toxicity) was noted in a large cooperative group trial.230 However, patient-reported outcomes suggested a significant benefit when “subjective” measures centering on swallowing function and pain control were analyzed, suggesting a key “disconnect” between physician and patient perspectives.418 When esophageal stricture develops, it is usually reversible with repeated dilations. An esophageal fistula can be life threatening, although stenting or surgical management may restore function.
Heart
The cardiotoxicity of radiotherapy has been primarily studied after treatment for breast cancer or mediastinal lymphoma. The overall excess risk of cardiac mortality after thoracic radiotherapy is low but depends on the dose, volume, and the patient’s existing cardiac risk factors.267 Reported toxicities include acute pericarditis, which can progress to chronic pericardial fibrosis, effusion, or rarely constrictive pericarditis. Ischemic changes in the cardiac muscle can manifest after a long latency and may lead to congestive heart failure or ultimately a higher cardiac mortality. Valvular abnormalities have been reported, presumably owing to late fibrotic changes.
Most of the data regarding dose and volume tolerances for the heart are derived from patients treated for breast cancer or lymphoma, typically with distinct beam arrangements that have limited application to 3D conformal or IMRT treatment of lung malignancies. The risk of pericardial toxicity has been correlated with treatment of >50% of the heart contour in 2D planning419 and to the volume receiving ≥30 Gy in 3D planning.420 Perfusion studies demonstrate that late ischemic changes to cardiac tissue are also volume dependent,421 although this has not been directly correlated to clinical outcomes. NTCP modeling has been done using both breast and lymphoma patient data; the derived parameters differ, reflecting the significant differences in technique-related cardiac exposure and underlying patient risk factors. Recommendations made as part of the QUANTEC effort reflect a conservative interpretation of the existing literature: if the V25 is <10%, then the excess risk of cardiac mortality attributable to ischemic changes is <1% at 15 years. The risk of pericarditis can be minimized by keeping the mean pericardial dose <26 Gy or the pericardial V30 <46%. Heart and pericardial exposure should otherwise be minimized without compromise of target coverage.267
Other clinical risk factors for cardiac mortality increasing the risk of radiotherapy-induced cardiac toxicity422 include hypertension, diabetes, obesity, and genetic predisposition. The risk of cardiac mortality from radiotherapy has been specifically demonstrated to be increased in patients >60 years old and by tobacco use.423,424 The sequential use of anthracyclines increases cardiac risk in breast cancer patients, and there are some reports that concurrent paclitaxel may increase the risk.425,426
Brachial Plexus
Radiation brachial plexopathy is relatively poorly described with a low incidence. There are case reports of an early, transient plexopathy that occurs during or within weeks to months of radiation at relatively low dose and may resolve spontaneously.427 Late radiation plexopathy is more clinically significant; it manifests years after radiation to the supraclavicular area with hypesthesia, paresthesia, and weakness of the affected arm and shoulder. It may progress to total paralysis of the affected arm and severe pain.
The dose tolerance of the brachial plexus is less defined than other thoracic organs, partly because of the difficulty in contouring and defining the OAR. A contouring atlas has been proposed so that more robust clinical data can be collected.262 Peripheral nerves respond as a serial organ, thus it is thought that the maximum point dose should be predictive of plexopathy. Late plexopathy is rare in patients who have received ≤60 Gy. Proposed brachial plexus dose limits for standard, fractionated radiotherapy planning vary considerably; RTOG 0617 suggests a point maximum limit of 66 Gy. RTOG 0972/CALGB 36050 limits the V20 to ≤35%.
For SBRT, brachial plexopathy has been reported after treatment of apical tumors. In a series of 37 apical tumors in 36 patients treated with SBRT at Indiana University, 7 patients developed plexopathy at a median of 7 months posttreatment.428 The cumulative risk of grade 2 to 4 plexopathy was 46% when the plexus received >26 Gy versus 8% when the plexus received ≤26 Gy. AAPM Task Group 101 recommends maximum dose to 3 cc and maximum point dose of 14 and 17.5 Gy for single-fraction SBRT, 20.4 and 24 Gy for three-fraction SBRT, and 27 and 30.5 Gy for five-fraction SBRT.271
Quality of Life in Lung Cancer
There has been an increased interest in health-related QOL as a clinically meaningful end point for patients with lung cancer.429 QOL is a type of patient-reported outcome, defined as any report of the status of a patient’s health condition provided directly by the patient, without interpretation of the patient’s response by others. Two validated QOL instruments that include both generic and site-specific lung modules are the Functional Assessment of Cancer Therapy-Lung (FACT-L) and the EORTC QOL Questionnaire Core-30 (QLQ-C30) and QLQ-LC13.430,431 The Lung Cancer Symptom Scale (LCSS) is a shorter (9-item) QOL instrument that is specific for lung cancer.432
There are many compelling reasons to study QOL in lung cancer patients. QOL end points, when used to assess the impact of palliative regimens, can identify important differences that may not have been anticipated. Recently, Temel et al.116 assessed the impact of early palliative care on QOL (using FACT-L) among patients with newly diagnosed metastatic NSCLC116 randomized to early palliative care or to standard care. They found that patients in the early palliative care arm not only had significant improvement in QOL, with less depression or anxiety, but also had longer median survival (p = .02), despite receiving less therapy.116
Another clinically relevant aspect of QOL is its ability to serve as an independent prognostic factor for survival. Movsas et al.114 reported that the baseline QOL score independently predicted for 5-year survival in patients with stage III NSCLC treated with chemoradiation on RTOG 9801. Studies are beginning to elucidate the biologic underpinnings supporting the relationship between QOL and survival.433 Importantly, studies have highlighted a critical “disconnect” between patient-reported outcomes and the physician-reported observations.418 For example, RTOG 9801 was a phase III study testing whether the radioprotector amifostine would reduce the rate of chemoradiation esophagitis in patients with locally advanced NSCLC.230 Although there was no significant difference in grade ≥3 esophagitis rates, amifostine significantly lowered patient reported swallowing dysfunction (p = .03) and pain (p = .003). To help address this “disconnect,” the National Cancer Institute initiated the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) project to create patient-reported versions of symptom criteria.
Perhaps the most important reason to study QOL is simply because patients want to be asked about their QOL. Detmar et al.434 reported on 273 patients receiving palliative chemotherapy, as well as 10 physicians. Almost all patients wanted to discuss QOL issues; however, 25% would discuss emotional or social functioning only if the physician initiated the discussion. Patients have a clear desire to discuss QOL issues.434,435 Ultimately, QOL should become a routine tool in the clinical care for our patients with lung cancer.
ACKNOWLEDGMENTS
The authors thank Mindy Langer for her exhaustive and critical review of the chapter. They also thank Eric Xanthopoulos for his input and assistance in the preparation of the figures and tables.
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