Tumors of the Lung, Pleura, and Mediastinum

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35 Tumors of the Lung, Pleura, and Mediastinum

Kenneth E. Rosenzweig, MD, Chein Peter Chen, MD, PhD, Sue S. Yom, MD, PhD, Lee M. Krug, MD

Epidemiology and Etiology

Lung cancer is the leading cause of cancer mortality for men and women, exceeding the mortality of breast, colon, and prostate cancer combined.¹ In the United States, more than 219,000 new cases of lung cancer and 159,000 deaths were anticipated in 2009.¹

The epidemiologic data on smoking and lung cancer fulfill the criteria for causal association, including the consistency of results across studies, the strength of relationship, its specificity, the correct temporal sequence between exposure and disease, and the coherence of the association as evidenced by a dose-response relationship.² It is estimated that cigarette smoking is the cause of 90% of all lung cancers.³ Multiple genetic alterations of tumor suppressor genes and oncogenes can lead to the pathogenesis of lung cancer. Carcinogens in cigarette smoke are involved in these genetic alterations, mainly through the formation of deoxyribonucleic acid (DNA) adducts.⁴ There is a clear dose-response relationship between the risk of lung cancer and the number of cigarettes smoked per day, the degree of inhalation, and the age at initiation of smoking.⁵ The relative risk of developing lung cancer decreases as the time from cessation increases.⁵

Approximately 10% of lung cancers are thought to be caused by carcinogens other than cigarette smoking. Among nonsmokers, 30% of lung cancer deaths are attributed to radon exposure.³ Increases in lung cancer risk also accompany exposure to carcinogens such as asbestos, bis(chloromethyl) ether, polycyclic aromatic hydrocarbons, chromium, nickel and inorganic arsenic compounds.⁶^,⁷ The association with occupational exposure to these agents appears to be independent of cigarette smoking. In addition, a number of occupations with high smoking prevalence have increased cancer risk. Women who work as waitresses, cashiers, nurses’ aides, and orderlies have smoking prevalences in excess of 40%, as do men who work as drivers, construction workers, painters, mechanics, and watchmen.⁸

Chemoprevention strategies have failed to demonstrate the ability to reduce the risk of developing lung cancer. Epidemiologic and case control trials previously reported an inverse relationship between the incidence of lung cancer and the intake of many food groups, including dietary carotenoids such as beta-carotene and lycopene.⁹ The mechanism of this interaction was theorized to be related to scavenging of free radicals or through antioxidative effects. However, the Beta-Carotene and Retinol Efficacy Trial (CARET), which included more than 18,000 participants, found that supplementation with betacarotene actually increased the risk of developing lung cancer by 12% versus patients who received placebo, and even increased all-cause mortality by 8%.¹⁰ Likewise, the retinoid isotretinoin was ineffective in reducing the development of second primary tumors in 1166 patients with prior stage I non–small cell lung cancer (NSCLC), and even increased the risk of death for active smokers.¹¹

Anatomy

The external anatomy of the lung is dominated by the fissures and the concave cardiac notch on each lung. On both the left and the right lung, the oblique fissure extends from the surface of the lung to the hilum and divides the lung into upper and lower lobes, which are connected only by the lobar bronchi and vessels. On the right lung, a horizontal fissure passes from the anterior margin into the oblique fissure to separate the wedge-shaped middle lobe from the upper lobe. This separation is incomplete in most patients. The visceral pleura covering the surface of the lung extends inward to line the depths of the fissures. The trachea divides into a left and right main stem bronchus at the carina. The right main stem bronchus (approximately 4.5 cm long) gives off a right upper lobe bronchus and continues as the bronchus intermedius, which separates into middle- and lower-lobe bronchi. The left main stem bronchus gives off three branches, but the upper and middle ones are fused before they separate into the upper lobe and lingular lobe. The other branch is the lower-lobe bronchus. Each lobar bronchus in turn gives off segmental bronchi totaling 10 segments on each side of the lung.

Pathogenesis and Histologic Findings

Pathogenesis

There is increasing evidence that lung cancer is derived from a pluripotent stem cell that is capable of expressing a variety of phenotypes. This epithelial stem cell, in normal histogenesis, differentiates into those cells found in the tracheobronchial tree, including pseudostratified reserved cells, ciliated goblet columnar cells, and neuroendocrine cells as type I and II pneumocytes seen lining the alveoli. Those cells that are capable of division can express hyperplastic, metaplastic, or neoplastic change. Lung cancer may exhibit two or more histologic patterns; the frequency of this occurrence may depend of the number of sections examined. In one study, when at least 10 blocks from each tumor were examined, 45 of the 100 cases showed elements of both squamous cell carcinoma and adenocarcinoma.¹²

Squamous Cell Carcinoma

Squamous cell carcinoma arises most frequently in proximal bronchi and is associated with squamous metaplasia and carcinoma in situ. Histologically, the squamous cell tumor is composed of sheets of epithelial cells that may be well- or poorly differentiated. Most well-differentiated tumors demonstrate keratin pearl formation. The more poorly differentiated tumors, if determined to be squamous cell carcinomas, have positive keratin staining.

Adenocarcinoma

Adenocarcinoma is now the most frequent tumor, accounting for 40% of all lung cancer. Some of this increase is due to better identification of adenocarcinoma, with fewer tumors being classified as undifferentiated large cell tumors. The majority of these tumors are peripheral in origin, arising from surface epithelium or bronchial mucosal glands and can also be seen arising as peripheral scar tumors. Histologically, these tumors form glands, and produce mucin. Bronchoalveolar carcinomas arise from type II pneumocytes, and grow along alveolar septa showing little desmoplastic or glandular change. These tumors may present in three different fashions: a solitary peripheral nodule, multifocal disease, or a progressive pneumonic form that appears to spread from lobe to lobe, ultimately encompassing both lungs.

Large Cell Carcinoma

Large cell carcinoma is the least common of all NSCLCs, accounting for approximately 15% of all lung cancers. Using histochemical staining, electron microscopy, and monoclonal antibodies, many tumors, previously diagnosed as undifferentiated large cell carcinoma, can now be classified more appropriately as poorly differentiated adenocarcinoma or squamous cell carcinoma. For this reason, the incidence of this type of tumor continues to decrease.

Immunohistochemistry

Thyroid transcription factor 1 (TTF-1) is frequently expressed in lung cancers, especially adenocarcinomas and small cell lung cancers (SCLCs). It is helpful in distinguishing lung cancers from other thoracic malignancies.

Clinical Presentation

The signs and symptoms manifested by patients suffering from lung cancer depend on the location of the tumor, its locoregional spread, and the effects of metastatic growth. Common presenting complaints resulting from the pulmonary mass include shortness of breath, cough, hemoptysis, or chest pain. However, a high proportion of patients have symptoms related to metastatic disease at presentation, including bone pain caused by osseous metastases or neurologic symptoms caused by brain metastases. Lung cancer is also frequently associated with paraneoplastic syndromes. In addition, many patients have constitutional symptoms such as anorexia, weight loss, and a decline in performance status at diagnosis. Some patients present with an asymptomatic lesion discovered incidentally on a chest x-ray examination.

Routine screening for lung cancer is being investigated once again. Prior trials conducted in the 1970s failed to show any benefit for the use of chest x-ray examination to screen smokers for lung cancer. More recent studies, however, are exploring the use of computed tomography (CT) scans for screening because they can detect smaller lung nodules. The Early Lung Cancer Action Project was a pilot study of 1000 patients older than the age of 60 with greater than 10 pack-years of smoking who underwent routine screening with low-dose thoracic CT scans. It found almost four times as many cancers as chest x-ray examination alone and these lesions were six times as likely to be early stage and therefore more curable.¹³ A follow-up study, the International Early Lung Cancer Action Project screened 31,567 asymptomatic persons at risk for lung cancer from 1993 through 2005.¹⁴ Of these, 27,456 had repeat screenings 7 to 18 months later. Of the 31,567 participants, 484 were diagnosed with lung cancer, 85% of whom were clinical stage I. The estimated survival in this subgroup was 88%. Other groups have concluded that screening increases the rate of lung cancer diagnosis and treatment, but doesn’t reduce the risk of advanced lung cancer or death from lung cancer.¹⁵ Currently, a large national trial is underway to rigorously assess the benefit of screening in this population.

Diagnostic and Staging Procedures

History and Physical Examination

A detailed history should elicit tobacco use and past exposure to environmental carcinogens that may suggest a higher probability of lung cancer. Symptoms of metastatic disease in the bone and brain can also be determined. Weight loss of greater than 5% from baseline is one of the most important prognostic indicators in lung cancer treatment. Patients can present with signs and symptoms of paraneoplastic syndromes, more frequently in SCLC than NSCLC.

Physical examination of the chest may detect signs of partial or complete obstruction of airways, atelectasis, pneumonia, or pleural effusion. Examination of the neck can reveal evidence of supraclavicular lymphadenopathy, indicative of N₃ disease. Lymphadenopathy in the high neck or axilla may represent metastatic disease. Abdominal examination may detect hepatomegaly. Neurologic examination can detect cerebral, base-of-skull, or spinal cord metastases.

Laboratory studies should include complete blood count, liver function tests, and serum lactate dehydrogenase (LDH). Elevated alkaline phosphatase may indicate liver or bone disease. Renal function tests should be performed to assess whether the patient can tolerate intravenous contrast for radiologic examinations and certain types of chemotherapy.

Imaging Studies

Chest x-ray examination remains an extremely valuable tool in the diagnosis of lung cancer. However, CT scan has enormous advantages in its ability to detect lesions that cannot be visualized on chest x-ray examination. It also plays an important role in staging lung cancer, especially spread to areas of the mediastinum undetected on plain films. Typically, a lymph node is considered normal if it is less than 1 cm in diameter on its short axis. CT may also suggest possible areas of local invasion of the primary tumor to the chest wall, vertebrae, or mediastinal structures. Small pleural effusions or pleural nodules, often undetected on plain films, may be evident on CT. A CT of the chest for lung cancer evaluation should also include part of the upper abdomen, which allows for evaluation of the liver and adrenals for metastatic disease. Scanning with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning can also detect neoplastic activity. Studies have shown CT and PET to be more specific and sensitive than PET alone.¹⁶ Generally, the sensitivity, specificity, and accuracy of CT scan alone is approximately 70%. CT and PET together have an accuracy of approximately 90% in single-institution studies, although these results may worsen when the technique is studied across multiple institutions. Magnetic resonance imaging (MRI) has not been shown to be more effective than chest CT for lung tumor, but may be helpful to evaluate invasion of vertebral bodies in the mediastinum.

Sputum Cytologic Examination

With three sputum samples, up to 80% of central tumors can be diagnosed. The yield is much smaller for peripheral tumors and drops to less than 20% for peripheral tumors less than 3 cm in diameter.

Bronchoscopy

Using flexible fiberoptic instruments, the proximal tracheobronchial tree can be examined up to the second or third subsegmental subdivision and cytologic or histologic specimens can be obtained. When a visible lesion is identified, the diagnostic yield is much more than 90%. Even with no visible lesion, the area of suspicion can be irrigated and lavaged to obtain cytologic material. Using fiberoptic bronchoscopy and image intensification, peripheral lesions can be reached by cytology brushes, needles, or biopsy forceps and specimens can be obtained. This is especially effective for lesions larger than 2 cm in diameter. The bronchoscope is also a valuable tool for staging. The site of a primary tumor in a major airway may affect its T stage, and transbronchoscopic needle aspiration through its airway wall can confirm the presence of a malignancy in mediastinal lymph nodes.

Endobronchial ultrasonography allows detailed imaging of the bronchial wall and peribronchial mediastinum, and may also add to the evaluation of endobronchial lesions.¹⁷

Endobronchial ultrasound-guided biopsy of mediastinal and hilar lymph nodes is becoming more commonly employed in the staging of lung cancer. Yields of this technique are approximately 95% with minimal to no severe toxicity.¹⁸

Mediastinoscopy and Mediastinotomy

Mediastinoscopy is the most accurate technique to assess superior mediastinal lymph nodes, which are frequently involved in NSCLC. The procedure is simple, safe, and effective in experienced hands. In one large series, the complication rate from cervical mediastinoscopy was 2.3% and the mortality was 0%.¹⁹ In patients suspected of having inoperable disease by virtue of mediastinal involvement as detected by CT scanning, confirmation by mediastinoscopy is indicated. For patients who are potentially operable, it is especially important to sample contralateral mediastinal lymph nodes to determine if N₃ disease is present. Involvement of aorticopulmonary lymph nodes are typically assessed by anterior mediastinotomy (Chamberlain procedure).²⁰ It is important to remember that these are first-echelon mediastinal lymph nodes for left lung tumors, especially from the left upper lobe, and they may not be sampled when a cervical mediastinoscopy is performed.

Thoracoscopy

Video-assisted thoracoscopy has been used in the diagnosis and staging of NSCLC. Peripheral nodules can be identified and biopsied or excised using video-assisted techniques and mediastinal lymph nodes can be sampled for histologic examination. This technique can identify suspected pleural disease and has the ability to accurately assess the status of pleural effusions.

Staging of Lung Cancer

In 1997, the sixth edition of the tumor-node-metastasis (TNM) staging system for NSCLC was published.²¹ Some criticisms of the staging included that the sample size was relatively small, the data was from few institutions, the staging was mostly surgical, modern imaging was not incorporated into the staging, and there was minimal external validation. In an attempt to improve on these shortcomings, the International Association for the Study of Lung Cancer (IASLC) revised the TNM staging system in 2009.

There are a number of changes from the sixth edition. T₁ tumors have been subclassified by size into T_1a (≤2 cm) and T_1b (>2-3 cm). T₂ tumors have been subclassified into T_2a (>3-5 cm) and T_2b (>5-7 cm). T₃ classification now includes tumors greater than 7 cm (previously T₂ tumors). Two nodules in the same lobe are now classified as T₃ (previously T₄). An ipsilateral lung tumor is now T₄ (previously M₁). Malignant pleural effusions, which were generally treated in the same manner as metastatic disease, are now classified as M_1a (previously T₄). Contralateral lung tumors are also M_1a. Distant metastases have been reclassified as M_1b. Table 35-1 presents these changes. Table 35-2 presents the new stage groupings. Fig. 35-1A-C shows the mediastinal lymph node mapping, anatomic locations, and survival by the new staging system.²²

Table 35-1 Update on the 7th Edition of the American Joint Committee on Cancer Guidelines

T (Primary Tumor)
TX	Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)^a
T1a	Tumor ≤2 cm in greatest dimension
T1b	Tumor >2 cm but ≤3 cm in greatest dimension
T2	Tumor >3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with these features are classified T2a if ≤5 cm) Involves main bronchus, ≥2 cm distal to the carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a Tumor >3 cm but ≤5 cm in greatest dimension T2b Tumor >5 cm but ≤7 cm in greatest dimension T3 Tumor >7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parictal pericardium; or tumor in the main bronchus <2 cm distal to the carina^a but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in a different ipsilateral lobe N (Regional Lymph Nodes) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) M (Distant Metastasis) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion^b M1b Distant metastasis

a The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1.

b Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as T1, T2, T3, or T4.

Table 35-2 Descriptors, Proposed T and M Categories, and Proposed Stage Groupings

FIGURE 35-1 • A, Mediastinal lymph nodes mapping; B, anatomy of non–small cell lung cancer; and C, overall survival, expressed as median survival time and 5-year survival, by clinical stage using the sixth edition of tumor-node-metastasis staging (A) and proposed International Association of the Study of Lung Cancer recommendations (B).

Prognostic Factors

Early-Stage (I or II) Non–Small Cell Lung Cancer

The major prognostic determinant for this group is the stage of disease, particularly the size of the tumor and the presence or absence of lymph node spread.²³ Sawyer and colleagues reported that in patients with resected N₁ disease, positive bronchoscopic findings, smaller tumor size, and a greater number of resected N₁ nodes were associated with an improvement in clinical outcome.²⁴

Advanced-Stage (III or IV) Non–Small Cell Lung Cancer

Pretreatment stage, performance status, and weight loss are most important.²⁵ The definitions of weight loss have varied among researchers, but weight loss of greater than 5% during the preceding six months is frequently used. Serum LDH, a predictor of survival in SCLC and other malignancies, also appears to be an independent survival variable. Whether any specific metastatic disease site confers a survival advantage remains controversial. Bone and liver metastases have often been cited as predicting shorter survival. Isolated spleen metastases, although rare, might be associated with a better outcome.²⁶ The histologic subtype of NSCLC has little influence on survival in advanced disease.

Non–Small Cell Lung Cancer

Standard Therapeutic Approaches

Selection of Therapy

Patients with stage I and II disease who are medically fit are treated surgically. If such patients are poor surgical candidates or refuse surgery, then radical chemoradiation therapy offers a potential curative alternative. Postoperative radiation therapy (PORT) is typically only used in stage I disease for patients with positive surgical margins. Chemotherapy is recommended as standard therapy postoperatively for patients with stage II disease and select patients with stage I.

Stage III disease is a very heterogeneous entity. Practically, it is often easier to consider patients as having either operable, marginally operable, or inoperable tumors. Marginally operable disease consists of tumors that might become operable if they are successfully treated with induction chemotherapy. A typical scenario might be a large central lung tumor that requires pneumonectomy initially, but with tumor shrinkage might be treated with a lobectomy.

There are many reasons that a tumor may be considered unresectable, including cytologically positive effusions, vertebral body invasion, invasion or encasement of the great vessels, tumor extensively involving the carina or trachea, recurrent laryngeal nerve paralysis, extensive mediastinal lymph node metastases, and N₃ disease. A patient may be medically inoperable because of severe coronary artery disease, cor pulmonale, patient refusal, or poor pulmonary function.

Patients with stage III disease are best managed with combined-modality therapy. There is ample evidence that the addition of chemotherapy and possibly PORT can improve survival and decrease tumor recurrence in patients with resected stage IIIA disease. Patients with locally advanced, unresectable disease are managed with chemotherapy and radiation.

Stage IV disease is incurable and treatment is palliative. Traditionally, this has consisted of palliative chemotherapy, palliative radiation therapy, medications, supportive care, and hospice care.

Operable Non–Small Cell Lung Cancer

Patient Selection

The preoperative assessment of patients considered for surgical treatment of lung cancer includes clinical staging of the disease to assess its resectability, assessment of the cardiopulmonary reserve of the patient to determine whether the intended pulmonary resection is possible, and assessment of the patient with regard to the perioperative risk of the procedure. Traditionally, patients are suitable candidates for pneumonectomy if the ultimate forced expiratory volume in 1 second (FEV 1) is greater than 1.2 L, the patient does not suffer from hypercarbia, and cor pulmonale is not present.²⁷^–²⁹ Pulmonary function studies best suited to assess these parameters include spirometry, arterial blood gases, diffusion capacity, and, where indicated, ventilation-perfusion scans to estimate the proportions of functioning pulmonary tissue required to be excised. Patients requiring lobectomy or lesser resections require similar pulmonary function parameters.³⁰^,³¹ Pulmonary complications increase remarkably when the FEV 1 forced vital capacity (FVC) ratio is less than 75% of predicted, indicating significant airways obstruction. FEV 1/FVC ratios of less than 50% of predicted lead to unacceptable postoperative morbidity and mortality.

Technique

If complete excision can be obtained by lobectomy, this has results equal to those of pneumonectomy.³² In proximally situated tumors, in which a pneumonectomy may be required for total excision, lung-conserving operations using bronchoplastic procedures to preserve uninvolved lobes (e.g., sleeve lobectomy) have been demonstrated to be feasible, but may have higher local recurrence rates. The role of mediastinal lymphadenectomy as part of the surgical procedure remains hotly debated. Complete mediastinal lymphadenectomy provides the best possible surgical staging by removing all lymph nodes, which can then be analyzed pathologically for metastatic involvement. This can help to identify patients who may require postoperative adjuvant radiation therapy. At minimum, for accurate final surgical-pathologic staging, lymph node sampling of all draining areas should be performed at the time of surgical resection. Pneumonectomy should be performed with a mortality of less than 6%, lobectomy less than 3%, and lesser resections 1% or less. These mortality figures are significantly affected by the age of the patient, the stage of disease, and the extent of resection.³³

Lobectomy has been shown to be superior to more limited surgical resections such as wedge resection or segmentectomy. In a randomized trial conducted by the Lung Cancer Study Group (LCSG), there was improved local control in patients having the more extensive resection.³⁴ A recent trial, Cancer and Leukemia Group B (CALGB) 39802, evaluated the role of video-assisted thoracic surgery in lobectomy. They found that 86.5% of patients with stage I disease were able to undergo a successful procedure with a shorter procedure length and chest tube duration than typically seen.³⁵ With the advent of improved imaging and the possible role of screening CT scans, this issue might need to be re-examined, particularly for tumors that are subcentimeter in size.

Results

According to the recent IASLC lung cancer staging project, following surgical resection for lung cancer, the 5-year survival is 73% for stage IA, 58% for stage IB, 46% for stage IIA and 36% for stage IIB.³⁶

Patterns of Failure Following Surgery

Recognition of prognostic and surgical factors that predict for specific anatomic failure patterns can allow selection of patients for local, systemic, or combined therapy. In general, patients who fail after surgery present with disease outside of the chest 70% of the time, locally 20% of the time, and local and distant simultaneously 10% of the time.³⁷ Therefore, systemic treatment is most likely to yield benefit postoperatively. Because of the relative chemoresistance of NSCLC, any benefit would likely be modest and would take a large trial to detect. Postoperative treatment can also be difficult to tolerate. Unlike breast cancer, in which patients recover quickly after modified radical mastectomy or lumpectomy, thoracic surgery, even if done thoracoscopically, requires significant recovery time. It has been shown in many studies that patients are only able to tolerate 60% of the intended treatment after surgery.

Second primary lung cancers occur frequently in all surviving patients at a rate of approximately 1% per year.³⁸^,³⁹

Preoperative Radiation Therapy

Radiation therapy may be delivered preoperatively or postoperatively. Theoretically, preoperative induction irradiation may improve resectability of larger tumors, sterilize cells beyond the margins of resection, prevent dissemination by surgical manipulation, and use lower doses of radiation than are required postoperatively when surgical changes induce conditions of hypoxia and relative radioresistance. Compared with PORT, the disadvantages of preoperative radiation therapy are that the precise surgical stage may not be known and some patients may be treated unnecessarily, the exact anatomic extent of tumor may not be appreciated, and the risks of postoperative complications are increased.

In 1975, the National Cancer Institute published two separate but integrated multi-institutional randomized trials addressing the use of preoperative radiotherapy followed by surgery in both operable and inoperable NSCLC without evidence of preoperative radiotherapy advantage.⁴⁰ It is clear from both the nonrandomized and randomized data that preoperative irradiation alone does not improve long-term survival and has no role as a single-induction modality in the management of marginally resectable or unresectable stage IIIA or IIIB disease. The use of radiation therapy as a single preoperative modality is no longer studied consistently because of the advent of effective chemotherapy agents. Most current trials investigate the use of preoperative concomitant chemoradiotherapy.

A German trial evaluated the role of preoperative chemoradiation in patients with stage III NSCLC.⁴¹ A total of 524 patients were randomly assigned to two treatment groups. The experimental arm consisted of three cycles of cisplatin and etoposide followed by twice-daily radiation with concurrent carboplatin and vindesine and then surgical resection. Patients with positive margins or unresectable disease received more radiation. The control group received three cycles of cisplatin and etoposide followed by surgery and PORT. There was no difference in progression-free survival (9.5 months versus 10 months), the primary endpoint of the study. The preoperative radiation arm did have an increased rate of mediastinal downstaging and pathologic response. However, there was no difference in the rate of pneumonectomy (35% in both arms), which suggests that the there is minimal to no role of the use of preoperative radiation to achieve the goal of minimizing the surgical intervention. If a patient needs a pneumonectomy prior to radiotherapy, it is likely he or she will still need a pneumonectomy after induction chemoradiation. The role of preoperative radiotherapy for superior sulcus tumors is somewhat unique and is discussed later in this chapter.

Postoperative Radiation Therapy

The LCSG investigated the efficacy of postoperative mediastinal irradiation in completely resected stage II and III squamous cell carcinoma of the lung. This trial randomized 210 patients to receive 50 Gy in 25 fractions after surgery versus observation alone. The locoregional failure rate (as first site of failure) was reduced from 41% to 3% with radiotherapy for all node-positive patients. Despite this improvement, the increase in locoregional control with radiotherapy did not translate into a survival benefit for stage II patients because more than two thirds of first failures were distant.⁴² The LCSG failed to separate patients with N₁ and N₂ disease but rather combined and analyzed them as a single group.⁴² A trend toward improved survival was observed in N₂ patients receiving radiotherapy. Eastern Cooperative Oncology Group (ECOG) trial 3590 randomized 488 patients with stages II through IIIA disease after surgery to either radiation therapy alone or radiation therapy and concurrent cisplatin-etoposide. Five-year survival was 40% and 38%, respectively (P = not significant).⁴³

The Medical Research Council of the United Kingdom also completed a randomized adjuvant trial in which 308 patients with stage II and III disease were treated with either 40 Gy or no further therapy, although a trend toward improved survival was seen in the N₂ subgroup. Again, no overall survival benefit was observed.⁴⁴

The meta-analysis performed by the Medical Research Council confirms these results. They report local recurrences in 276 patients in the surgery-only arms of the trials. There were 195 local recurrences in patients receiving PORT. In addition, there was a trend toward improved survival in stage III and N₂ patients, although it did not reach significance ⁴⁵ (Fig. 35-2). Stage I and II patients had decreased survival from PORT, presumably from increased toxicity of treatment without any benefit from the radiation.

FIGURE 35-2 • Results of the Medical Research Council’s meta-analysis of postoperative radiation therapy (PORT). These results show that PORT is of no value to patients with stage I and II disease but might be of benefit to those with stage III (N₂) disease.

There have been criticisms of the meta-analysis because of its methodologic flaws. The trials studied had variable and unspecified staging, used cobalt-60 or other low-energy photons, and had inadequate treatment planning. Also, the interval between surgery and PORT was inconsistent and sometimes not reported. A Surveillance, Epidemiology and End Results (SEER) analysis showed that the use of PORT decreased after the publication of the metaanalysis.⁴⁶

Machtay and colleagues investigated whether the excess toxicity observed from PORT in the meta-analysis was evident in their patient population.⁴⁷ They reviewed 202 patients retrospectively who received PORT for stage II and III disease with a median dose of 55 Gy. They found the actuarial rate of death from intercurrent disease was 13.5% compared with the expected rate of 10%. A re-examination of the ECOG trial E3590 also attempted to evaluate the risk from PORT.⁴⁸ They found that the risk of death from intercurrent disease was 12.9% in patients receiving PORT or PORT plus chemotherapy versus an expected rate of 10.1%. Therefore, there is some toxicity associated from the PORT treatment, but of a lower magnitude than seen in the meta-analysis.

A SEER analysis of the association between PORT and survival in patients with stage II or stage III disease was performed.⁴⁹ It showed that for patients with N₂ disease, the use of PORT was associated with a significant increase in survival and that for patients with N₀ disease, it was associated with significant decrease in survival. A subgroup analysis of the Adjuvant Navelbine International Trial Association (ANITA) trial of adjuvant chemotherapy evaluated the role of PORT.⁵⁰ Of the 840 patients in the ANITA trial, 232 received PORT. In univariate analysis, PORT had a deleterious effect on the overall population survival. Patients with pN₁ disease had an improved survival from PORT in the observation arm (median survival [MS] 25.9 versus 50.2 months), whereas PORT had a detrimental effect in the chemotherapy group (MS 93.6 months and 46.6 months). In contrast, survival was improved in patients with pN₂ disease who received PORT, both in the chemotherapy (MS 23.8 versus 47.4 months) and observation arm (MS 12.7 versus 22.7 months).

Therefore, the role of PORT remains controversial. It has not been shown to produce a benefit in early-stage disease and should not be recommended in these patients except in the case of suspected residual microscopic or macroscopic residual disease. It has been shown to improve local control in patients with mediastinal nodal disease, but has no proven survival benefit. There is likely a subgroup of patients, such as those with micrometastatic disease, who will have an improved survival from PORT; however, this patient population has yet to be identified.

Technique of Postoperative Radiation Therapy

PORT for patients with microscopic residual disease or with resected hilar or mediastinal involvement is planned as follows. The area to be treated is determined by correlating preoperative imaging studies, intraoperative findings, surgical clips, and the pathologic review of the resected specimen. Generally, the objective is to treat the ipsilateral hilum, the mediastinal nodes bilaterally, and the ipsilateral supraclavicular area. Peripheral primary tumors that do not abut the mediastinum or hilum and are not adjacent to the chest wall are usually removed with generous margins. After surgery, their preoperative location is occupied by relocated and uninvolved lung parenchyma, which does not need therapy unless there is clear evidence or strong suspicion of residual disease. The standard postoperative dose is 50.4 Gy in 1.8-Gy fractions or 50 Gy in 2-Gy fractions. If there are positive margins, an additional boost to 60 to 61.2 Gy can be considered. The most common approach to treatment is three-dimensional conformal radiation therapy (3D-CRT). The clinical target volume (CTV) should consist of the nodal area to be treated. This technique can decrease the radiation dose to the heart and lungs. Anterior-posterior opposed fields with off-cord obliques can also be effectively used.

Preoperative Chemotherapy

Initial studies using a variety of chemotherapy regimens suggested that preoperative chemotherapy could be administered for selected stage IIIA and a few stage IIIB patients and may be beneficial in this setting.⁵¹^,⁵² Combination chemotherapy with high-dose cisplatin (120 mg/m²), vinca alkaloids, and mitomycin (MVP) was used preoperatively in the stage IIIA patients with clinically apparent ipsilateral mediastinal spread.⁵³ In a group of 73 patients, the objective major response rate to MVP chemotherapy was 77% with a 10% complete-response rate. Overall, 60% of patients underwent complete resections and the median survival was 19 months.⁵³

There are multiple trials in which patients undergoing surgical resection were randomized to induction chemotherapy or no treatment.⁵⁴^,⁵⁵ The first trial reported by Pass et al.⁵⁴ was a small trial that suggested a survival benefit in patients treated with preoperative cisplatin and etoposide. In 1994, two trials were published, each of which was closed due to early stopping rules after enrollment of approximately 60 patients. Both trials used induction regimens containing cisplatin and showed a significant increase in survival with chemotherapy and surgery as opposed to surgery alone. The largest trial, from Depierre et al.,⁵⁵ enrolled 355 patients and treated them with three cycles of induction mitomycin, ifosfamide, and cisplatin, and two cycles postoperatively. Median survival improved from 26 months to 37 months, but was not statistically significant (Table 35-3).

Table 35-3 Induction Chemotherapy and Surgery in Stage III NSCLC: Results of Randomized Trials

Adjuvant Chemotherapy Following Complete Resection of Non–Small Cell Lung Cancer

In 1995, the Non–Small Cell Lung Cancer Collaborative Group published a meta-analysis of 17 adjuvant chemotherapy trials spanning the years 1965 through 1991 and involving 4467 patients.⁵⁶ The use of chemotherapy regimens that incorporated alkylating agents worsened survival, and the use of 5-fluorouracil–based regimens had no effect. However, treatment with a cisplatin-based chemotherapy regimen resulted in a nonsignificant (P = 0.08) trend toward improved survival of 5% over 5 years. At that time, most oncologists chose not to administer adjuvant chemotherapy because the toxicity of the treatment outweighed the benefit.

This sentiment has now shifted since the publication of multiple other larger phase III trials showing more consistent benefit. The first of these was the International Adjuvant Lung Cancer Trial, which randomized 1867 patients to chemotherapy or no chemotherapy following surgical resection for patients with stage I through IIIA disease.⁵⁷ All patients received cisplatin (80-120 mg/m²) and a second agent chosen by the investigator, either etoposide or a vinca alkaloid. PORT was given at the discretion of the institution. With a median follow-up of 56 months, 5-year survival significantly improved from 40.4% to 44.5%. In a study conducted by the National Cancer Institute of Canada, 482 patients with resected stage IB or II disease were randomized to treatment with vinorelbine and cisplatin or observation.⁵⁸ The treatment effect was even larger in this trial, with median survivals of 94 and 73 months (P = 0.04) and 5-year survival rates of 69% and 54% (P = 0.03) respectively. The ANITA study also employed vinorelbine-cisplatin for patients with stage IB through IIIA disease.⁵⁹ The median survival improved from 44 to 66 months and the 5-year survival improved by 8.6%. Not all studies showed a benefit to adjuvant chemotherapy, however, with negative results reported in the Adjuvant Lung Cancer Project Italy⁶⁰ and the Big Lung Trial. Only CALGB studied adjuvant carboplatin, in combination with paclitaxel, and this was tested selectively in stage IB disease.⁶¹ This smaller study with 344 patients demonstrated no improvement in survival (HR 0.83, P = 0.12). An exploratory analysis from that trial did show a benefit for patients with tumors greater than 4 cm (HR 0.69, P = 0.043).

Ultimately, another meta-analysis compiled the results of the trials that used cisplatin-based chemotherapy regimens. Coined the Lung Adjuvant Cisplatin Evaluation Meta-analysis, this basically showed the same level of benefit noted in the 1995 analysis: 5% over 5 years. However, with larger patient numbers, the benefit was statistically significant (HR 0.89, P = 0.005).⁶² The degree of benefit was affected by stage: For stage IA, the HR was 1.40; for stage IB, the HR was 0.93; for stage II, the HR was 0.83; and for stage III, the HR was 0.83. Patients with a good performance status also benefitted more, but gender, type of surgery, and the choice of chemotherapy agent given with cisplatin had no effect.

In summary, administration of adjuvant cisplatin-based chemotherapy has become the standard of care for patients with resected stage II and IIIA disease. The benefit for patients with stage IB disease is less clear, although this may be appropriate for fit patients with large tumors. Toxicity remains a roadblock, with only 50% to 60% of patients completing all planned therapy in the studies mentioned. Substitution of carboplatin for patients who cannot tolerate cisplatin has not been studied in appropriately powered phase III trials. Various pathologic markers, such as expression of the DNA repair enzyme, ERCC-1, or metagene profiles may identify patients most likely to benefit from adjuvant chemotherapy, but these have not completed prospective assessment.⁶³^,⁶⁴

Preoperative Chemoradiotherapy

The Southwest Oncology Group (SWOG) reported on 126 patients in a phase II trial who received 45 Gy with concurrent cisplatin and etoposide prior to surgical resection. There was 59% response rate and 89 patients (71%) underwent resection and 58% had a pathologic complete response or minimal microscopic disease. Despite this, patients with advanced disease (T_2-3N₂, T₄N_2-3) had only a 12 month median survival. Patients with more limited disease (T₁N₂, T₄N_0-1) had a 32-month median survival.⁶⁵

Superior Sulcus Tumors

The management of superior sulcus tumors (Pancoast tumors) is difficult. Radiation therapy is an essential component of treatment either as definitive therapy, preoperative therapy, postoperative therapy, or as intraoperative brachytherapy.

The use of preoperative radiation therapy was pioneered by Paulson.⁶⁶ Preoperative doses of 3000 to 3500 R were used to reduce the volume of tumor, thus facilitating complete resection. Operations were performed 1 month after the completion of radiation therapy to allow time for pain relief with an accompanying improvement in performance status, resolution of skin changes facilitating good wound healing, and in some patients to exclude the emergence of distant metastases that would make radical local therapy inappropriate. In the initial report of this procedure, five of nine patients followed for more than 1 year were disease-free.⁶⁷ in a number of series a variety of preoperative doses of radiation have been used and survival figures range from 20% to 34% at 5 years.

Generally accepted contraindications to surgery in patients with superior sulcus tumors include extensive involvement of the brachial plexus, involvement of the subclavian artery, vertebral bodies, esophagus, mediastinal node metastases, or distant metastases. Fig. 35-3 shows a CT scan of a right-lung T₄ Pancoast tumor. The patient was treated with chemoradiation therapy followed by surgical resection. Patients with unresectable T₄ tumors or mediastinal nodal metastases can be treated with radical radiation therapy. In general, fields are designed as described in the section on radiation techniques and total doses of 60 Gy or greater are used.