Epigenetic mechanisms of gene regulation also appear to participate in the tumorigenesis of lung cancer. In particular gene promoter inactivation by hypermethylation may be an important mechanism in the inactivation of tumor suppressor genes such as p16^INK4a (p16), an inhibitory regulator in the cyclin D-retinoblastoma cell cycle pathway. In patients with premalignant lesions such as squamous dysplasia and carcinoma in situ, both allelic loss and hypermethylation of p16 have been identified, with associated decreases in p16 protein expression,²⁸ suggesting that loss of p16 may be an important early event in NSCLC tumorigenesis.²⁹

Over the past decade genome-wide studies have revolutionized the study of complex disease processes including NSCLC. Efforts by groups comprising The Cancer Genome Atlas have yielded detailed and comprehensive characterization of mutational events across the entire cancer genome.^30,31 Distinguishing those genes that appear to be involved causally in lung cancer tumorigenesis from those genes that are regulated secondarily is critical for our understanding of this disease and for the identification of potential targets for therapeutic intervention.

2 Targeted molecular therapy has been shown to have clinical benefit notably for patients with advanced NSCLC. For example, among patients whose tumors are shown to carry specific mutations in the epidermal growth factor receptor (EGFR) gene, treatment with small molecule tyrosine–kinase inhibitors targeting EGFR has been associated with improved progression-free survival as demonstrated by several randomized trials.³² Whether such treatment regimens might be effective in the adjuvant setting for patients with earlier stage NSCLC who have undergone curative-intent lung resection has yet to be established, but is the focus of a recently initiated cooperative group trial. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) will evaluate patients with resected lung adenocarcinomas (stage IB to stage IIIA). Those subjects found to have tumors carrying activating EGFR mutations or the ALK-echinoderm microtubule-associated protein-like 4 (EML4) fusion gene will be randomized for “maintenance” treatment with either erlotinib (EGFR) or crizotonib (ALK fusion), respectively, following completion of standard-of-care adjuvant chemotherapy with or without radiation therapy. Enrolled patients found to have neither of the targeted mutations will be followed in an observational study until tumor recurrence. These studies represent an exciting potential application of gene expression studies for use in determining patient prognosis, as well as guiding the clinical management of lung cancer and preventing over- or undertreatment of patients.

NON–SMALL CELL LUNG CANCER

Diagnosis

The diagnosis of lung cancer should be directed by the presumed stage of disease at patient presentation. Accurate and reproducible TNM staging of lung cancer allows clinicians to provide consistent treatment of lung cancer and provides the basis for uniform reporting of clinical research across institutions and study groups. In 1997, revisions in the International System for Staging Lung Cancer (Table 79-2) were adopted by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC), based on 5,319 cases of lung cancer.³ Revisions implemented for the most recent iteration of the TNM classification schema arose from evaluation of 67,725 cases of NSCLC with broad geographic diversity including subjects from Asia, Australia, Europe, and North America^33,34 and addressed both T³⁵ and M³⁶ designations (Table 79-3), with no changes implemented for the current nodal designations (Table 79-4).³⁷ Stratification of patient survival, particularly among subjects with pathologic stage IB and IIA cancers, was more distinct with application of the 7th edition criteria (Table 79-5).

Guidelines for surveillance of the incidentally detected subcentimeter nodule (<8 to 10 mm) or larger solitary pulmonary nodule (8 to 10 mm or larger) have been published by the Fleischner Society for Thoracic Imaging and Diagnosis,³⁸ the American College of Chest Physicians³⁹ and others⁴⁰ and are incorporated in a suggested algorithm (Algorithm 79-1) for evaluation of these common incidental chest findings. As with any algorithm, assessment of patient risk factors (pretest probability) for cancer³⁹ as well as comorbidities³⁸ should be taken into consideration before following these guidelines in one’s practice.

3 One recent goal in the diagnosis of lung cancer has been the early detection of tumors arising in asymptomatic high prevalence populations, for example, older patients with a history of tobacco use. Low-dose chest CT screening appears to reduce lung cancer–related mortality as demonstrated by two modern clinical trials,^7,8 while remaining cost-effective.⁴¹

4 The aims of the initial evaluation of a patient with NSCLC are to determine whether distant metastatic disease is present and to assess the extent of intrathoracic disease. A multidisciplinary approach, involving input from pulmonary medicine, chest radiology, medical and radiation oncology, and thoracic surgery, should be undertaken in the selection of the most suitable testing for any individual patient. One general algorithm is provided (Algorithm 79-2). A thorough history and physical examination, combined with a plain chest radiograph and baseline laboratory data (complete blood cell count and measurement of serum sodium, calcium, alkaline phosphatase, and lactate dehydrogenase levels), can suggest the presence of metastatic disease. Common metastatic sites include the brain, supraclavicular lymph nodes, contralateral lung, bones, liver, and adrenal glands. Chest CT and FDG–PET body scans are obtained for noninvasive evaluation and metabolic characterization of suspected lung tumors and evidence of mediastinal or extrathoracic involvement. If necessary, biopsy by needle aspiration or operation can be performed to obtain confirmation of malignancy and to determine the extent of disease.

If the initial clinical evaluation does not suggest the presence of distant disease, the extent of further evaluation by various scans is controversial. Some physicians always perform a complete metastatic workup with CT of the chest and abdomen, CT or MRI of the brain, and FDG–PET scan. CT scan of the chest and upper abdomen as well as FDG–PET scan have become standard, as much to evaluate the extent of the primary tumor and the status of the mediastinal lymph nodes as to detect metastases in the ipsilateral or contralateral lung, liver, or adrenals. Additional scans in asymptomatic patients may detect the 5% to 10% of metastases that are occult, but these scans are not clearly cost-effective in patients with clinical stage IA tumors. In patients who are suitable candidates for operation, who have a suspicious solitary pulmonary nodule that is of indeterminate origin despite appropriate evaluation, excisional biopsy and subsequent lobectomy for resectable lung cancer should be pursued.⁴²

Multi-institutional studies have indicated a benefit for a combined modality approach in the treatment of stage IIIA NSCLC, consisting of neoadjuvant chemotherapy and radiation followed by resection.⁴³ Therefore tissue confirmation of mediastinal nodal involvement (Table 79-4) has implications not only for the staging but the management of patients who are otherwise candidates for resection of locoregionally advanced NSCLC.⁴⁴

Chest CT provides only anatomic clues for tumor involvement of mediastinal lymph nodes (enlargement greater than 10 mm), as demonstrated in a recent meta-analysis of over 3,400 evaluable patients, with a pooled sensitivity of 57% and specificity of only 82%. This meta-analysis also demonstrated that FDG (¹⁸F-2-fluoro-2-deoxy-D-glucose)–positron emission tomography (FDG–PET) scanning appears to provide increased sensitivity of 84% and specificity of 89% in over 1,100 patients studied for the detection of mediastinal malignancy.⁴⁵ Several single-institution and multi-institutional prospective studies have also indicated the superior diagnostic accuracy of FDG–PET imaging.^46–48 Although the overall sensitivity and specificity of FDG–PET staging was 61% and 84%, respectively, there was a significant improvement with FDG–PET over chest CT in the detection of both hilar (N1) lymph node (42% vs. 13%, p = 0.0177) and mediastinal (N2 and N3) tumor involvement (58% vs. 32%, p = 0.004). Whereas FDG–PET scanning can increase the suspicion of malignancy, its negative predictive value for mediastinal lymph node involvement does not appear to be sufficient, with a false-negative rate reported as high as 13%.⁴⁹ PET evaluation of the solitary pulmonary nodule also appears to be somewhat insensitive, with a negative predictive value for benign lesions of only 57%, indicating a false-negative rate of 47%. Reliance on this modality could lead to delayed treatment for resectable early-stage (IA) NSCLC.⁵⁰ Integrated CT–PET imaging, in which concurrently performed chest CT provides anatomic correlation for positive PET findings, appears to provide more precise staging, particularly regarding tumor and nodal status,⁵¹ and also can be used to guide further invasive testing in the accurate staging of lung cancer.

Ultimately tissue confirmation of noninvasive findings should be obtained, particularly in the setting of large, prospective trials being undertaken to determine the efficacy of neoadjuvant and adjuvant therapy.⁵² Noninvasive techniques for clinical staging, particularly chest CT, have a reported false-negative rate of approximately 10% to 15%. FDG–PET scan also has a reported false-positive rate of as high as 50%.⁴⁶ Clinical staging of NSCLC, particularly mediastinal lymph node involvement, can be accomplished by needle aspiration techniques from several approaches: transbronchial (TBNA) with or without endobronchial ultrasound (EBUS) guidance, transthoracic, or transesophageal. EBUS–TBNA is an accurate method for evaluation of the mediastinum, comparable to, if not better than, the accuracy of mediastinoscopy.⁵³ Transesophageal endoscopic ultrasound with fine needle aspiration (EUS–FNA) appears to be particularly useful for sampling of posterior mediastinal nodes such as the subcarinal, periesophageal, or aortopulmonary window stations, particularly in patients with mediastinal lymphadenopathy in these regions. Diagnostic yield is improved with practitioner experience, sampling needle size and onsite cytology examination to determine adequacy of the obtained samples.

Cervical mediastinoscopy remains an important diagnostic modality, particularly for sampling of smaller lymph nodes, or if larger sample sizes are needed either for assessment of tissue architecture, or for supplemental molecular studies. This modality has a procedural sensitivity greater than 90%, and specificity of 100%⁵⁴ as demonstrated in a large retrospective review of a single-institutional experience, including 1,745 patients, which demonstrated a reduction in “unnecessary” exploration, low morbidity (0.6%) and minimal perioperative mortality (0.05%).⁵⁵ For patients with clinically suspicious aortopulmonary lymph node involvement (stations 5 and 6), an area which is generally not accessible by standard mediastinoscopy, anterior mediastinotomy, extended cervical mediastinoscopy, or thoracoscopy can be performed.

Patients presenting with suspected NSCLC and a pleural effusion should undergo thoracentesis, followed by thoracoscopy, should initial cytology specimens be nondiagnostic. Those patients presenting with metastatic (stage IV) disease involving a solitary distant site should obtain tissue confirmation at the site of metastasis, if technically feasible. If noninvasive testing demonstrates multiple metastases (e.g., multiple liver, brain, or bone lesions), then diagnosis of the primary lesion might provide the most efficient means of diagnosis, followed by the initiation of palliative chemotherapy.⁵⁶

Although newer modalities of noninvasive imaging, such as FDG–PET imaging, have improved the accuracy of staging for lung cancer,^8,49 these techniques still rely on factors such as tumor volume, tumor density, and metabolic activity. Unfortunately, current staging procedures do not yet have the sensitivity to detect all lymph node or distant hematogenous metastases.

Risk Assessment

Having established that resection is feasible, a significant number of patients with lung cancer cannot undergo operation due to associated comorbidities that increase operative mortality and postoperative morbidity. Age alone should not preclude patients with resectable disease from operation.⁵⁷ In a population with a high prevalence of prior or continuing tobacco use that has a greater predisposition to atherosclerotic cardiovascular disease, preoperative cardiovascular risk assessment with further noninvasive cardiac testing or coronary angiography, if indicated, should be considered.⁵⁸

Preoperative spirometry, particularly the forced expiratory volume in 1 second (FEV₁), as an assessment of patients’ suitability for pulmonary resection is essential. Measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) provides complementary data to standard spirometry, particularly for patients with evidence of interstitial lung disease or exertional dyspnea. Generally, if a patient demonstrates FEV₁ >2 L (>60% predicted) or DLCO >50% predicted, further evaluation of pulmonary capacity prior to resection is not necessary.^59,60 Patients with limited pulmonary reserve, including those with FEV₁ <1.2 L (40% predicted) or DLCO 35% to 40% predicted, are at higher risk for significant morbidity or mortality following anatomic resection, and should undergo further evaluation.⁶¹

The predicted postoperative (ppo) lung function in patients with marginal pulmonary function can be calculated as follows: ppoFEV₁ (% predicted) = preoperative FEV₁ (% predicted) × (1 – fraction of total number of anatomic segments to be resected). Patients with ppoFEV₁ <0.8 L, or 35% to 40% predicted, are likely at substantially increased risk for perioperative death or complication.^62,63 For patients with heterogeneous lung disease including upper lobe predominant emphysema, quantitative perfusion scanning provides a more accurate assessment. To obtain the ppoFEV₁ (% predicted), the preoperative FEV₁ (% predicted) is multiplied by (100% – %perfusion of the area to be resected).

Preoperative room-air arterial blood gas testing can identify patients at greater risk for perioperative complications or death. In particular, patients with arterial oxygen concentration less than 60 mm Hg, PaCO₂ greater than 45 mm Hg, or oxygen saturation less than 90% may be at greater risk for pulmonary resection.

If available, further testing with formal cardiopulmonary exercise testing (CPET) to calculate maximal oxygen consumption (Vo₂ max) may allow further risk stratification in such marginal patients. In several series, patients with a Vo₂ max <10 to 15 mL/min/kg were at high risk for postoperative complication, whereas those with Vo₂ max >20 mL/min/kg underwent operation without complication or death.⁶³ These findings were corroborated by a recent cooperative group study (CALGB 9238) conducted to determine whether pulmonary resection could be accomplished safely in patients with peak exercise oxygen capacity >15 mL/min/kg, regardless of FEV₁. In this prospective study of 346 patients who underwent thoracotomy for NSCLC, there were 86 subjects whose peak exercise oxygen capacity was less than the threshold of <15 mL/min/kg, or 60% of predicted. This group experienced significantly more cardiorespiratory complications, respiratory failure, or death than the remaining subjects whose peak exercise oxygen capacity was >15 mL/min/kg. From these data, the authors concluded that patients with peak exercise oxygen capacity >15 mL/min/kg, even if FEV₁ and/or DLCO were less than 70% predicted, could undergo pulmonary resection with curative intent.⁶⁴

Informal exercise testing, particularly stair-climbing, may also aid the clinician in determining a patient’s suitability for resection. Patients who are able to climb at least two flights of stairs likely will tolerate pneumonectomy, whereas those who cannot climb a single flight likely will not tolerate lobectomy. Furthermore, oxygen desaturation, greater than 4%, during exercise testing may also be an indicator for increased risk of perioperative complication. Careful preoperative physiologic assessment will allow the clinician to identify patients at increased risk for perioperative complication or death, and allow such patients to make an informed decision regarding operation.⁶⁵ Measures to minimize postoperative complications, including aggressive efforts to encourage smoking cessation, pre-and postoperative chest physiotherapy, incentive spirometry, early extubation and mobilization, and the use of postoperative thoracic epidural analgesia, are important for all patients undergoing pulmonary resection, especially those with marginal pulmonary function (Algorithm 79-3).

Treatment

5 Pulmonary resection, with definitive tumor staging, remains the mainstay of treatment for stage I, II, and selected stage III NSCLC. The extent of resection, segmentectomy, lobectomy, bilobectomy, or pneumonectomy, is determined by the location and size of the primary tumor and also whether adjacent bronchopulmonary nodes are involved. At operation, tumor extent is evaluated by examination of the parietal pleura, pericardium, and mediastinal structures. Complete resection must achieve microscopically negative bronchial and vascular margins. Potential postoperative complications after pulmonary resection are listed in Table 79-6.

If a tumor extends directly into the chest wall, diaphragm, or pericardium, an en bloc resection of the adjacent involved structure should be performed with the pulmonary resection. Reconstruction is performed as necessary (Fig. 79-1). If extensive endobronchial involvement is present without involvement of the surrounding vascular or lymphatic structures, the tumor can sometimes be removed completely by lobectomy with segmental resection of the bronchus and/or pulmonary artery (bronchovascular sleeve resection), thus preserving lung function.

Patients with centrally located tumors should undergo sleeve lobectomy rather than pneumonectomy if complete resection can be achieved and such an approach is technically feasible. Several retrospective studies^66–70 have demonstrated that operative mortality is reduced among patients undergoing sleeve lobectomy (0% to 5.2%) when compared with patients undergoing pneumonectomy (1.7% to 8.9%). Moreover, overall 5-year survival is improved among patients undergoing sleeve resection, particularly among those with N0 or N1 nodal status. For peripherally located clinical stage I tumors, particularly among patients with limited pulmonary reserve or those at high risk from other comorbidities, segmental or nonanatomic “wedge” resection can be performed. Sublobar resection also may be appropriate for patients with good pulmonary function and who otherwise would be candidates for lobectomy (Table 79-7). Whether such patients are at greater risk for locoregional recurrence, as suggested in earlier series^71–73 but not borne out in modern series,⁷⁴ is under investigation in an ongoing multi-institutional prospective and randomized cooperative group clinical trial (CALGB 140503).

Although noninvasive techniques for preoperative assessment of mediastinal nodes have improved, nodal status should be confirmed by intraoperative mediastinal lymph node sampling or mediastinal lymph node dissection. Accurate pathologic staging provides not only prognostic information but is also important in the decision on whether to proceed with adjuvant chemotherapy. Systematic sampling should include tissue from at least three N2 lymph node stations, using standard nomenclature and numbering as depicted in (Table 79-4). Complete mediastinal lymph node dissection does not appear to confer increased perioperative morbidity⁷⁵ but also does not confer a survival advantage for patients with early stage (T1, T2, N0, and N1) NSCLC as staged at the time of lung resection. The long-term survival impact of mediastinal lymph node dissection has not been evaluated well for patients with clinical staging obtained solely by radiography or for patients with higher-stage NSCLC.^76–78

Survival

Long-term survival after resection for NSCLC is linked to the pathologic stage of disease. The overall 5-year survival rates are shown in Table 79-5. They range from 60% to 70% for stage I tumors, from 40% to 50% for stage II tumors, and from 15% to 30% for stage IIIA tumors. Nodal involvement has the strongest adverse influence on survival. Large peripheral tumors that extend directly into the chest wall without nodal involvement (T3N0) are associated with a 5-year survival rate of 40% after complete resection, whereas involvement of mediastinal nodes is associated with only a 20% survival rate.

Some series suggest that histology also affects survival. In node-negative NSCLC, large cell neuroendocrine differentiation conferred worse survival than other types of NSCLC.⁷⁹ Different adenocarcinoma subtypes, particularly in more advanced tumors, also appear to confer worse prognosis, but the influence of histology has not been described uniformly in series to-date.⁸⁰ Delineation of tumor biology by more refined histologic and molecular analyses will be needed to define which patients might be at increased risk for recurrence or treatment resistance.

Patterns of Recurrence

The predominant sites of relapse for all stages of NSCLC after resection are distant metastases. Approximately 30% of recurrences are locoregional with tumors of both squamous and nonsquamous histology.⁸¹ For all stages of disease, the brain is the single most common site of relapse, and brain metastases occur more frequently with nonsquamous tumors. Other common metastatic sites include bone, ipsilateral or contralateral lung, liver, and the adrenal glands.^81,82

At least 60% of recurrences develop in the first 2 years after operation, and virtually all recurrences related to the original primary tumor occur within 5 years after surgery. Even the small proportion of patients with stage II or III disease who survive 5 years are likely to survive 10 years or more postoperatively. Recurrences of the original primary tumor are uncommon after 5 years, and after that time the occurrence of new pulmonary cancers becomes the dominant problem. The risk for development of a second lung cancer in patients with a prior history of cancer resection for NSCLC is estimated to be 2% to 3% per patient per year,⁸³ with a second lung cancer developing rarely in never-smokers at the time of initial resection, and at rates of 1.8% per patient-year in former smokers and 2.7% per patient-year in current smokers.⁸⁴ Patients also face a consistent risk for the development of new, nonpulmonary primary cancers during the first 5 years after operation and thereafter. New, nonpulmonary malignancies develop in a wide variety of sites, most commonly breast, colon, and prostate cancers.⁸¹

These data underscore the importance of long-term follow-up after resection of early-stage NSCLC. Guidelines provided by the American College of Chest Physicians⁸⁵ and the National Comprehensive Cancer Network support regular oncologic surveillance after curative-intent lung resection. In coordination with the primary or referring physician, recommended surveillance includes directed clinical assessment, every 6 to 12 months the first 2 years and then annually thereafter. Although there is no single modality to detect recurrence, follow-up should include a combination of history, physical examination, serial chest radiographs, and low-dose spiral chest CT. Neither PET scan nor MRI studies are recommended as part of routine surveillance.^85,86

Adjuvant Therapy for NSCLC

The risk for recurrent disease, even after resection of early-stage NSCLC, has led to efforts to improve overall survival rates through the use of adjuvant therapy, even though no specific method is available to identify which patients will relapse. Various types of adjuvant therapy have been tested, including immunotherapy,^87–89 radiation, chemotherapy, and combined chemotherapy and radiation.

Radiation has been evaluated extensively as adjuvant therapy. Although early retrospective series suggested that postoperative radiation therapy (PORT) potentially improved overall survival,^90–92 subsequent relatively small randomized trials comparing adjuvant radiation with no further treatment failed to demonstrate any significant difference in overall survival.^93–97 Distant metastases remained the most common form of recurrent disease and were not affected by postoperative radiation to the mediastinum. Several of these trials^93,94,96,97 showed that radiation significantly decreased the risk for locoregional recurrence in tumors of all histologic types (Table 79-8). A meta-analysis of several randomized controlled studies of postoperative radiation therapy suggested an adverse effect on survival, particularly among patients treated with PORT with early-stage (I or II) lung cancer.⁹⁸ Postoperative thoracic radiation appears to be appropriate for patients who are at high risk for locoregional recurrence such as those found to have unexpected mediastinal (N2 or N3) nodal disease or those with evidence of residual tumor (R1 resection) at surgical margins.⁹⁹

Because distant metastases are the predominant mode of relapse after resection of early-stage NSCLC, multiple randomized trials (Table 79-9) have been performed to determine if postoperative adjuvant chemotherapy improves survival. Early trials evaluated agents, including nitrogen mustards, cytoxan, methotrexate, and nitrosourea, now known to have no activity in NSCLC.^100–103 More recently, several studies have demonstrated that cisplatin-based chemotherapy regimens appear to provide a modest survival benefit. A meta-analysis of 9,387 patients entered into 52 randomized clinical trials showed a 5% survival benefit at 5 years for adjuvant cisplatin-based chemotherapy in comparison with surgery alone. Trials comparing adjuvant radiation with radiation plus chemotherapy showed an absolute survival benefit of 4% at 2 years in favor of combined-modality treatment.¹⁰⁴

Recent trials of adjuvant chemotherapy in patients with completely resected NSCLC appear to indicate a therapeutic benefit. The multicenter International Adjuvant Lung Cancer Trial evaluated the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of NSCLC. A total of 1,867 patients with resected stage I, II, or III NSCLC were randomized to receive cisplatin-based chemotherapy, cisplatin-based chemotherapy and radiation, radiation alone, or no adjuvant treatment. Individual institutions administered additional chemotherapeutic agents at their discretion (“open-choice design”), with nearly half of the treated patients receiving cisplatin (100 mg/m²) and etoposide for 3 or 4 cycles. The total dose delivered of cisplatin was greater than 240 mg/m² for 73.8% of treated patients. Additional agents used were vinorelbine, vinblastine, or vindesine. Cisplatin dosing varied from 80 to 120 mg/m²/cycle, for a total expected dose of 300 to 400 mg/m². Statistically significant benefits were observed for both overall (absolute difference, 4.1%) and disease-free (absolute difference, 5.1%) survival at 5 years, for patients treated with cisplatin-based chemotherapy, with or without adjuvant radiation.⁴ Planned radiotherapy did not appear to provide any added benefit. In subgroup analysis, the benefits of cisplatin-based adjuvant chemotherapy appeared to confer the greatest benefit upon patients with stage III NSCLC. In longer-term follow-up, disease-free survival HR remained improved at 0.88 (95% CI 0.78 to 0.98, p = 0.02) for patients receiving adjuvant therapy over 7 years following operation, but the previously observed improvement in overall survival was no longer statistically significant with HR 0.91 (95% CI 0.81 to 1.02, p = 0.10).¹¹⁵

Several subsequent studies support the use of adjuvant chemotherapy, particularly in stage II and III lung cancer. These studies are summarized in recent meta-analyses of combined modality therapy in the treatment of resectable lung cancer,^116,117 which confirm the benefit of adjuvant chemotherapy following lung cancer resection for curative intent, with an absolute improvement in survival of 4% to 5.4% at 5 years of follow-up or beyond.

Notably, clinical trials evaluating adjuvant treatment for resected NSCLC have shown that approximately half of all patients actually received the planned dose of chemotherapy.^105,109 It remains to be determined whether patients undergoing minimally invasive approaches to pulmonary resection can tolerate adjuvant chemotherapy better than similar patients recovering from open operations. Thoracoscopic lobectomy, for example, may facilitate subsequent adjuvant chemotherapy.¹¹⁸ In a series of 100 patients, 43 underwent thoracotomy and 57 had pulmonary resection performed by thoracoscopy. Those undergoing thoracoscopic resection were found to have a higher compliance rate with adjuvant treatment. Chemotherapy doses were delayed in significantly fewer patients in the thoracoscopic group (18% vs. 58%). Chemotherapy doses were reduced in only 26% of subjects undergoing thoracoscopy compared with 49% in the thoracotomy group. In addition, a significantly higher percentage of thoracoscopy patients received 75% or more of the planned regimen. There was no significant difference in the time to initiation of chemotherapy or toxicity.

Treatment of Stage III Disease

Stage III NSCLC indicates locoregionally advanced disease that encompasses several anatomic subsets which vary considerably in the likelihood that resection will provide durable oncologic benefit. Stage IIIB is generally considered unresectable. There is no role for resection for patients with T4 (stage IIIB) disease due to malignant pleural or pericardial effusion, infiltration of the heart, or those with contralateral or supraclavicular nodal metastases (N3). Several small series from specialized centers have demonstrated that curative intent operation can be considered for selected patients with invasion of mediastinal structures such as the superior vena cava, left atrium, carina, vertebrae or aorta, with consideration for induction chemoradiation, to “downstage” such tumors.^119–121 These series indicate that complete resection is essential to obtain survival benefit from this approach.

Stage IIIA includes patients with extrapulmonary disease involving the ipsilateral hemithorax, that is, T3N1 and T1–3N2. The management of patients with stage IIIA disease due to mediastinal nodal involvement (N2) has evolved considerably over the last several decades. Local therapy alone for curative intent, that is, pulmonary resection or definitive-dose radiation therapy is not recommended.

Role of Resection

The most controversial and complex part of the treatment of stage IIIA NSCLC is the management of patients with N2 disease. Reported 5-year survival rates after resection for N2 disease are usually 20% to 30% but range from zero to 40%. This variation reflects the extent of mediastinal nodal involvement, the T status of the primary tumor, and the ability to perform a complete resection. With respect to mediastinal nodal involvement, adverse prognostic factors include the presence of extracapsular nodal disease, multiple levels of involved lymph nodes and superior mediastinal nodal metastases.^122,123

Rationale for Neoadjuvant Therapy

Although some patients with “minimal” N2 disease survive for long periods of time after resection, most have more extensive nodal involvement and do not benefit from either surgery or radiation therapy alone as their primary treatment. Efforts to improve outcomes following local control strategies have been limited by relapse at distant sites. Two early, randomized clinical trials challenged the concept of resection as the primary treatment for any patient with N2 disease. Rosell and colleagues^124,125 randomized 60 patients with stage IIIA NSCLC (16 of whom did not have N2 disease) to undergo resection or to receive three cycles of cisplatin-based chemotherapy followed by resection. The median survival of the patients who received preoperative chemotherapy was significantly longer (26 vs. 8 months) than the survival of patients who underwent only resection. A study of similar design from the M. D. Anderson Cancer Center corroborated these results.^126,127 Both trials were stopped early because of highly significant differences between the two study arms. These two studies suggested that it is appropriate to consider all patients with N2 disease diagnosed at mediastinoscopy for induction chemotherapy. Since pretreatment mediastinoscopy was not mandated in either trial, some patients who did not have N2 disease were included. The results of these trials are not universally accepted because of the small numbers of patients enrolled, the lack of systematic pretreatment staging, and the unusually poor survival of the patients in the control (surgery-only) arms.

Early Trials of Neoadjuvant Therapy

The concept of preoperative therapy followed by resection (neoadjuvant therapy) dates back to 1955, when Bromley and Szur¹²⁸ used radiation (at an average dose of 47 Gy) to treat 66 patients before resection. At operation, no viable tumor was found in 29 of 62 (47%) patients, but 10 patients died of complications in the first month, and only two patients survived to 5 years after operation. At the time, the natural history of NSCLC was not well understood, the methods of staging before resection not very accurate, and the risk for distant metastases not fully recognized. Effective chemotherapy did not exist and it was hoped that an approach that increased resectability might lead to better long-term survival. Thus, early neoadjuvant trials focused on the use of preoperative radiation.

Several subsequent studies further explored this approach.¹²⁹ All these trials were flawed by a lack of pretreatment staging, by the use of widely varying amounts of radiation, and by excessively long intervals between irradiation and resection. Nonetheless, it became apparent that aggressive local treatment did not improve long-term survival, even though radiation provided local control in a significant number of patients. The development of distant metastases in 50% to 80% of patients during or shortly after treatment underscored the need for systemic therapy in stage III NSCLC.

Recent Trials of Neoadjuvant Therapy

Because of a better understanding of the natural history of early-stage lung cancer and more universal adoption of the UICC/AJCC TNM staging system, recent trials have defined more uniform patient populations, so that it has been easier to interpret trial results. Although many different treatment regimens have been used in neoadjuvant trials, they can be grouped into three major categories: (a) chemoradiation without resection, (b) chemotherapy followed by resection, and (c) chemoradiation followed by resection.

Trials of Chemoradiation without Resection

These trials cannot be equated with trials of neoadjuvant therapy that include resection because patients entered into nonsurgical trials are staged clinically without tissue confirmation of mediastinal lymph node involvement. Therefore, nonsurgical trials include a mix of patients with stage IIIA and IIIB cancers, and might even include some patients with earlier-stage disease who were thought erroneously to have stage III disease because of benign mediastinal adenopathy diagnosed only by axial chest imaging.

With the acceptance of chemotherapy and radiation as standard treatment, attention has focused recently on the optimal means to deliver both modalities.¹³⁰ Several studies have demonstrated that concurrent treatment is superior to sequential chemoradiotherapy. A cochrane database systematic review identified fourteen randomized studies comparing concurrent chemoradiation and radiation therapy alone. In this meta-analysis of 2,393 subjects, concurrent therapy was associated with a reduction in risk of death at 2 years (RR 0.93; 95% CI 0.88 to 0.98; p = 0.01) and improved 2-year progression-free survival, locoregionally (RR 0.84; 95% CI 0.72 to 0.98; p = 0.03) or distant (RR 0.90; 95% CI 0.84 to 0.97; p = 0.005). Concurrent chemoradiotherapy also had improved survival compared with sequential chemotherapy and radiation (RR 0.86; 95% CI 0.78 to 0.95; p = 0.003). In a separate meta-analysis of studies evaluating the addition of sequential or concurrent chemotherapy to radiation therapy in over 1,200 patients, a substantial overall survival benefit was observed for patients receiving concurrent treatment, with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years (from 10.6% to 15.1%).¹³¹ Although concurrent chemoradiation was associated with less locoregional disease progression, no significant differences were observed between these two treatments, concurrent or sequential therapy, in terms of distant disease progression.¹³¹ Toxicities, particularly esophagitis, also were greater for patients receiving concurrent chemoradiation.^131,132

Trials of Neoadjuvant Therapy with Resection

These trials have used two different treatment strategies, induction chemotherapy alone or concurrent chemoradiation before resection. The rationale for chemotherapy alone as induction treatment is that it potentially allows the use of a more intense dose and the use of some drugs, such as mitomycin, that cannot be administered in conjunction with radiation. Proponents of this approach also believe that chemotherapy is as effective as induction treatment as is combined chemoradiation, and that separating the two modalities allows irradiation to be used postoperatively, when a higher total dose can be given. Proponents of concurrent preoperative chemoradiation believe that this approach provides adequate systemic treatment of micrometastatic disease and more effective control of bulky primary and mediastinal tumors.

Neoadjuvant Trials of Chemotherapy Alone before Resection

One of the best-known early trials to demonstrate the feasibility of combining induction chemotherapy with subsequent pulmonary resection in patients with stage III NSCLC was developed by Martini et al.¹³³ at Memorial Sloan-Kettering Cancer Center. In 1984, this group initiated a trial of high-dose, cisplatin-based (120 mg/m²) chemotherapy followed by resection for patients with clinical N2 disease. Vindesine or vinblastine and subsequently mitomycin were added to form the so-called “MVP” regimen. Postoperative radiation was given to patients who had persistent mediastinal nodal tumor at thoracotomy, and all patients received two additional cycles of chemotherapy postoperatively. In 136 patients treated from 1984 to 1991, the major response rate to induction chemotherapy was 77% (105/136), and the complete resection rate was 65% (89/136). A complete pathologic response was noted in 19 patients (21%) at the time of resection. The overall survival at 5 years was 17% and the median survival was 19 months; a distinct improvement over the historical survival for this group of patients. Seven treatment-related deaths (5%) occurred in this study, five of which were postoperative.

A phase II trial, reported by the CALGB in 1995, of induction chemotherapy enrolled 74 patients, treated with two cycles of cisplatin (100 mg/m² on days 1 and 29) and vinblastine (5 mg/m² per week) without mitomycin followed by resection for patients with mediastinoscopy-proven stage IIIA N2 disease.¹³⁴ In addition, two cycles of chemotherapy and 59.4 Gy of radiation were given postoperatively. Sixty-three patients (85%) had either an objective response or stable disease after induction therapy and underwent thoracotomy, with operative mortality rate of 3.2%. Twenty-three patients (37% of thoracotomies, 31% of all patients) had a complete resection, with 3-year survival of 46%. The overall 3-year survival was 23%. The lower resectability rate in this trial than in the study performed at Memorial Sloan-Kettering potentially reflected both the multi-institutional nature of this trial and the use of a less intensive chemotherapy regimen (primarily because of the omission of mitomycin). The overall long-term survival appeared similar for the two trials.

Trials of Induction Chemoradiation Followed by Resection

The second approach to combined-modality therapy and resection for stage III NSCLC has been to combine chemotherapy and radiation preoperatively (Table 79-10). This strategy aims to control micrometastatic disease while utilizing the synergism of concurrent radiation and chemotherapy to reduce tumor bulk in the primary site and mediastinum.

The largest reported phase II neoadjuvant trial of concurrent chemotherapy and radiation was a multi-institutional study performed by the Southwest Oncology Group.¹³⁸ Both stage IIIA and stage IIIB patients were entered, although notably, pathologic documentation of the initial tumor stage, usually by mediastinoscopy, was required. The induction regimen included two cycles of cisplatin (50 mg/m² on days 1 and 8) and etoposide with 4,500 cGy of concurrent radiation in 25 fractions. All patients underwent thoracotomy unless their disease progressed. The objective response rate to induction therapy in the 126 eligible patients was 59%. The resectability rates were 85% for the IIIA N2 group and 80% for the IIIB group. Nearly two-thirds of the patients had no viable tumor or only minimal residual foci of tumor in their surgical specimens. The 3-year survival rate was 27% for the IIIA group and 24% for the IIIB group, with median survival of 13 and 17 months, respectively. The best predictor of survival after surgery was the absence of tumor in the mediastinal nodes at surgery (3-year survival of 44%). The majority of recurrences were distant, and the brain was the single most common site. The operative mortality rate was 6%, and the overall treatment-related mortality was 10%. An important finding of SWOG 8805 was that survival was the same for patients with stage IIIB NSCLC by virtue of T4 tumor status and patients with stage IIIA N2 disease. Patients with N3 disease had a poor overall survival. Importantly, the long-term follow-up of this study showed that the survival rates at 3 years were sustained at 6 years.¹⁴² Important differences between the Southwest Oncology Group trial and earlier neoadjuvant trials were the careful documentation of pretreatment stage, the use of a higher dose of continuous radiation (4,500 cGy rather than 3,000 cGy of continuous or 4,000 cGy of split-course radiation), and the fully concurrent manner in which the chemotherapy and radiation were administered.

A North America Intergroup clinical trial sought to determine whether neoadjuvant therapy including resection is superior to nonsurgical treatment with chemotherapy and higher-dose radiation in patients with stage IIIA NSCLC. In the Intergroup 0139/RTOG 9309 trial,^43,140 patients with proven pN2, stage IIIA NSCLC were randomized to receive neoadjuvant chemotherapy with concurrent thoracic RT (TRT) followed by operation or continuation with definitive TRT.

Of 429 patients accrued over 92 months, 396 patients were considered eligible, and were treated with cisplatin (50 mg/m²), on days 1 and 8, and etoposide (50 mg/m²), on days 1 to 5, every 3 weeks for 2 cycles, as well as 45 Gy TRT. Patients randomized to resection (n = 202) underwent operation 4 to 6 weeks later. Patients randomized to definitive radiation (n = 194) continued without break to a total of 61 Gy. Following operation or completion of TRT, consolidation with 2 cycles of cisplatin and etoposide was given. Of note, less than two-thirds of patients undergoing operation received consolidation treatment, compared with over 75% of patients receiving chemoradiation only. There was no mortality in either group during induction chemoradiation. Mortality in the surgical treatment arm was 8%, with 14 of 16 deaths occurring in patients undergoing pneumonectomy.

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