According to the current International Union

Treatment of Stage II Non-small Cell Lung Cancer* Walter J. Scott, MD, FCCP; John Howington, MD, FCCP; and Benjamin Movsas, MD Based on clinical assessment alone, patients with stage II non-small cell lung cancer (NSCLC) comprise only 5% of all patients with NSCLC. In addition, patients with stage II NSCLC represent a heterogeneous group, since stage II consists of patients with T1-2N1 or T3N0 tumors. By definition, patients with tumor invading the chest wall apex, mediastinum, diaphragm, or even the mainstem bronchus may all have T3 tumors. The extent of the data available regarding treatment of each of these different groups is therefore limited. The quality of the data is limited as well, because information often comes from small series of patients. Studies of adjuvant therapy after complete resection of stage II NSCLC are an important exception to this generalization, since data from large, randomized studies of adjuvant radiation therapy, chemotherapy, or a combination of the two are available for analysis. Superior sulcus tumors are discussed elsewhere in these guidelines. (CHEST 2003; 123:188S 201S) Key words: carcinoma; bronchogenic; chemotherapy; guidelines; lung; neoplasms; neoplasm; staging; practice guidelines; radiotherapy; surgery Abbreviations: CI confidence interval; LCSG Lung Cancer Study Group; NSCLC non-small cell lung cancer According to the current International Union Against Cancer and American Joint Committee for Cancer Staging system, stage II non-small cell lung cancer (NSCLC) is defined as a T1 or T2 cancer with N1 nodal metastasis and no distant metastasis (T1-2N1M0) or a T3 cancer with no nodal or distant metastasis (T3N0M0). 1 Definitions Stage IIA consists of T1N1 cancers. For review, T1 tumors by definition are 3 cm in size and do not involve the visceral pleura or a main bronchus. N1 denotes metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of the primary tumor. 2 Stage IIB includes T2N1 and T3N0 cancers. T2 denotes a tumor with any of the following features: 3 cm in greatest dimension, involves a main bronchus 2 cm distal to the carina, invades the visceral pleura, or is associated with atelectasis or *From the Department of Surgical Oncology (Dr. Scott), Section of Thoracic Surgical Oncology; the Department of Radiation Oncology (Dr. Movsas), Fox Chase Cancer Center, Philadelphia, PA; and Department of Surgery (Dr. Howington), Division of Thoracic Surgery, University of Cincinnati Medical Center, Cincinnati, OH. Correspondence to: Walter J. Scott, MD, FCCP, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; e-mail: W Scott@fccc.edu 188S obstructive pneumonitis that extends to the hilar region but does not involve the entire lung. T3 denotes a tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pleura, parietal pericardium, or tumor in the main bronchus 2 cm distal to the carina, but without involvement of the carina, or associated atelectasis or obstructive pneumonitis of the entire lung. 2 The Current Staging System Stage IIA is an uncommon presentation for NSCLC, representing 1 to 5% of patients treated in most recent surgical series. 3 6 In the article by Mountain 2 on revision of the lung cancer staging system, only 5% of patients had clinical N1 disease and only 7% were found to have pathologic N1 disease. Mountain 2 noted the infrequent nature of clinical stage IIA cancer and the tendency for stage migration to pathologic stage IIA cancer. Stage IIB cancers, in contrast, represent approximately 15 to 25% of resected cancers in several large surgical series. 3 5 Several authors have published data supporting the current staging system for NSCLC (Table 1). 3 6 Inoue and colleagues 3 evaluated the prognoses of 1,310 surgically resected patients with NSCLC. All patients underwent complete surgical resection and Lung Cancer Guidelines

systematic nodal dissection in a period from 1980 through 1993. Routine chest and brain CT as well as bone scan was performed prior to surgical resection. They confirmed a significant difference in survival between patients with T1N1M0 (stage IIA) cancers (57%) and patients with T2N1M0 (stage IIB) cancers (42%). They found no significant difference between patients with T2N1M0 and T3N0M0 cancers. Patients with pathologic T1N1M0 tumors made up only 4.4% of the 1,310 resected patients, while 14.3% of patients were pathologically staged IIB patients. 3 A retrospective review of 2,361 patients treated with surgical resection of NSCLC in stages I, II, and IIIA was reported by van Rens and colleagues. 4 None of the patients received prior treatment for NSCLC. Resection was considered complete in 89.9% of the patients. Again, only 3.6% of patients had stage IIA cancers. They found a significant difference in 5-year survival between patients with T1N1M0 (IIA) cancer (52%) and patients with T2N1M0 (IIB) cancer (33%). They found no difference in survival between patients with T2N1M0 cancers and patients with T3N0M0 cancers. 4 Like Mountain 2 and Inoue et al 3, van Rens and colleagues 4 found no significant difference in 5-year survival between patients with stage IB cancers and patients with IIA cancers. In addition, both van Rens et al 4 and Inoue et al 3 failed to find a significant survival difference between patients with T3N0M0 cancers and patients with T3N1M0 cancers. Adebonojo and colleagues 5 reported on the results of surgical management of lung cancer at a military medical center. The authors performed a retrospective review of 552 patients who underwent surgical resection with curative intent at Walter Reed Army Medical Center between January 1984 and December 1996. Thoracic lymphadenectomy was not routinely performed, but mediastinal sampling was obtained from at least four mediastinal stations for pathologic staging. They also found a significant difference in the survival rate between patients with T1N1M0 (IIA) and patients with T2N1M0 (IIB) Table 1 Five-Year Survival Based on Pathologic Stage II Grouping* Source Stage IIA Survival, pt1n1m0 Stage IIB Survival pt2n1m0 pt3n0m0 Mountain 2 76 (55) 288 (39) 87 (38) Inoue et al 3 57 (57) 141 (42) 46 (34) van Rens et al 4 84 (52) 541 (33) 137 (33) Adebonojo et al 5 17 (57) 50 (48) 42 (47) Jassem et al 6 6 (17) 64 (24) 55 (30) *Data are presented as No. (%). cancers (57% and 48%, respectively). There was no significant difference between patients with T2N1M0 and T3N0M0 cancer. They also noted the uncommon nature of stage IIA cancer, with only 17 of the 552 patients (3%) having T1N1M0 cancers. 5 Jassem and colleagues 6 analyzed the survival data of 586 patients who underwent complete pulmonary resection and pathologic staging at one institution. Only six patients (1%) were identified as having stage IIA cancer. This prevented evaluation of any significant difference in survival among patient with stage IIA and stage IIB cancers; however, there was no significant difference between survival of patients with T2N1M0 and T3N0M0 cancers (27% and 30%, respectively). 6 The studies by Inoue et al, 3 van Rens et al, 4 and Adebonojo et al 5 confirmed the finding of Mountain 2 of a statistically significant difference in 5-year survival between patients with stage IIA (T1N1M0) cancers and patients with stage IIB (T2N1M0 and T3N0M0) cancers. The study by Jassem et al 6 had too few patients with stage IIA cancers, along with a strikingly low 17% 5-year survival (one of six patients) to evaluate for any significant difference between stage IIA patients and other stage groupings. All four studies have found a significant difference in survival between patients with T3N0M0 cancer and patients with T1-3N2M0 cancer, supporting the movement of T3N0M0 from stage IIIA to stage IIB. 3 6 Several authors found no significant difference in survival between patients with T3N1M0 (IIIA) cancers and patients with stage IIB (T3N0 and T2N1) cancers (Table 2). 3,4,6 However, others, including Downey and colleagues, 7 have identified N1 disease as a significant factor in decreased survival in patients with T3 NSCLC. 8,9 In one series, the survival at 5 years was 49% for 100 T3N0 patients, compared to a 27% 5-year survival among 24 patients with T3N1 NSCLCs. 7 N1 nodal disease represents patients with cancer metastasis or direct extension to subsegmental, segmental, and lobar lymph nodes (levels 14, 13, and 12), as well as metastasis or direct extension into interlobar (level 11) and hilar (level 10) lymph nodes. The presence of N1 nodal disease denotes a group of patients with intermediate survival. Several studies have compared the survival results of patients with lobar (levels 12 to 14) nodal disease with patients with extralobar/hilar (levels 10 and 11) nodal disease. Yano and colleagues 10 retrospectively reviewed the outcomes of 78 patients with pathologic N1 disease who underwent complete resection with mediastinal lymph node dissection. The overall 5-year survival was 49.2%. The pathologic T stage, the type of resection, or the addition of adjuvant www.chestjournal.org CHEST / 123 / 1/ JANUARY, 2003 SUPPLEMENT 189S

Table 2 5-Year Survival Based on Pathologic Staging* Stage IIB Survival Stage IIIA Survival Source Pathologic T2N1M0 Pathologic T3N0M0 Pathologic T3N1M0 Pathologic T1-3N2M0 Mountain 2 288 (39) 87 (38) 55 (25) 344 (23) Inoue et al 3 141 (42) 46 (34) 39 (38) 252 (n/a) van Rens et al 4 541 (33) 137 (33) 89 (25) 261 (16) Jassem et al 6 64 (24) 55 (30) 26 (35) 128 (7) *Data are presented as No. (%). n/a authors did not provide data for all N2 patients. therapy did not significantly impact survival in this group of pathologic N1 patients. Lobar nodes (levels 12 and 13) were involved in 38.5% of patients, and extralobar/hilar nodes (levels 10 and 11) were involved in 61.5% of patients. The survival of lobar N1 disease was significantly better than that of extralobar/ hilar disease (64.5% vs 39.7% at 5 years, p 0.014). A multivariate analysis revealed that the level of N1 disease (lobar or extralobar) was the only prognostic factor for patients with pathologic N1 disease. van Velzen and colleagues 11 analyzed the outcomes of 391 patients with pathologic T2N1M0 NSCLC. Lymph node involvement in the 391 patients was by metastasis in 218 patients (55.8%) and direct extension in 173 patients (44.2%). The cumulative 5-year survival rate for hospital survivors (n 369) was 37.8%. The 5-year survival for patients with lobar (levels 12 and 13) metastases was significantly better than that of patients with extralobar/ hilar metastases (57.3% vs 30.3%, p 0.0028). In addition, they found patients without visceral pleura invasion had a significantly better prognosis than patients with pleural invasion (survival at 5 years, 43.9% vs 31.1%; p 0.0093). In a review of 256 patients with pathologic N1 disease treated with complete surgical resection and mediastinal lymph node dissection, Riquet and colleagues 12 reported an overall 5-year survival rate of 47.5%. Survival was not related to the pathologic T factor, type of resection, number of N1 stations involved, nor to type of lymph node involvement (direct extension or metastases). Five-year survival was significantly better for patients with lobar (levels 12 and 13) metastases (53.6%) compared to patients with extralobar/hilar (levels 10 and 11) metastases (38.5%, p 0.02). Several retrospective series have noted a decreased survival in patients with central T3 lung cancers involving the diaphragm or mediastinum compared to patients with cancers involving the lateral chest wall or the superior sulcus of the chest. A retrospective review from Memorial Sloan Kettering reported by Burt et al 13 found a 10% 5-year survival among patients with pathologic T3N0M0 cancers where the mediastinum was involved by direct tumor extension. In another retrospective review, Pitz and colleagues 14 reported a greater mean 5-year survival in patients with T3 cancers involving the main bronchus (40%) compared to mean 5-year survival among patients with T3 cancers with invasion of mediastinal structures (25%). This difference failed to reach statistical significance (p 0.05). Both Inoue et al 3 and Adebonojo et al 5 noted a worse prognosis for patients with T3N0M0 cancers involving the pericardium or diaphragm compared to the chest wall. The numbers in both studies are too small for statistical significance, and both authors recommend further evaluation with a larger cohort of patients. 3,5 In a brief communication, Weksler et al 15 reported on the rare occurrence of T3 tumors involving the diaphragm, and the poor survival in these patients when N2 nodal disease was identified. The eight patients in this series represented just 0.17% of the patients operated on for lung cancer during the 21-year period in which these eight patients presented for treatment. T3 cancers with invasion of the mediastinum most often do poorly if treated by surgical resection alone. This is explained in part by the high number of incomplete resections as noted in the retrospective review by Martini and colleagues, 16 in which 20 of 58 patients (34%) with T3 cancer involvement of the mediastinum underwent an incomplete resection. It has been well established that incomplete resection is a predictor of decreased survival. Treatment Guidelines Stage II NSCLC (T1-2N1M0) Intraoperative Management: Sleeve Resection vs Pneumonectomy No randomized trials comparing sleeve lobectomy with pneumonectomy have been reported in the literature. The data available consist of retrospective reviews of the outcomes in patients treated with sleeve lobectomy and compared with matched or unmatched control subjects treated with pneumonectomy. 190S Lung Cancer Guidelines

Gaissert and colleagues 17 at the Massachusetts General Hospital reviewed their experience with 72 consecutive patients treated with sleeve lobectomy for NSCLC. They compared the results in this cohort to an unmatched group of patients undergoing pneumonectomy for lung cancer between 1986 and 1990. The actuarial survival at 5 years was 42% for the patients undergoing sleeve lobectomy and 44% for patients undergoing pneumonectomy. Local recurrence occurred in 14% of the patients undergoing sleeve lobectomy, while the local recurrence was not reported for the unmatched pneumonectomy cohort. The majority of the local recurrences occurred in the mediastinum. There was a higher mortality (9% vs 4%) and major complication rate (16% vs 11%) among patients undergoing pneumonectomy. In a retrospective review of 29 patients undergoing sleeve lobectomy for lung cancer and compared with a matched cohort of patients undergoing pneumonectomy, Yoshino et al 18 found no difference in the 3-year disease-free survival between the two groups. In addition, local recurrence occurred in 1 of 15 patients undergoing sleeve lobectomy with N1 disease and in 2 of 11 patients undergoing pneumonectomy with N1 disease. Operative mortality (6.9% vs 0%) and complication rates (24.1% vs 13.7%) were significantly higher, respectively (p 0.05), in the group undergoing pneumonectomy compared to patients undergoing sleeve lobectomy. Okada et al 19 compared the outcomes after sleeve lobectomy and pneumonectomy for patients with NSCLC distributed according to their nodal involvement status. Between June 1984 and December 1998, 151 patients underwent sleeve lobectomy while 60 patients underwent pneumonectomy. A matched group of 60 patients undergoing sleeve lobectomy was compared with the patients undergoing pneumonectomy. The operative mortality rate was 0% in the sleeve lobectomy group and 2% in the pneumonectomy group. Local recurrence developed in five patients (8%) after sleeve lobectomy and six patients (10%) after pneumonectomy. Patients undergoing sleeve lobectomy had a significantly longer 5-year survival (48%) than patients undergoing pneumonectomy (29%). While these studies are limited by their retrospective method and small numbers of patients, the authors agree with the conclusions of these articles that sleeve lobectomy is preferred over pneumonectomy whenever a complete pathologic resection can be obtained using bronchoplastic techniques. Recommendation 1. For patients with N1 lymph node metastases in whom a complete resection can be achieved with either technique, sleeve lobectomy is recommended over pneumonectomy. Level of evidence, poor; benefit, moderate; grade of recommendation, C Adjuvant Radiotherapy for T1-2N1 NSCLC As noted above, completely resected patients with stage II NSCLC have a lower 5-year survival rate than patients with earlier stage disease. In most of these patients, especially those who have N1 lymph node metastases, the final pathologic stage is only determined after histologic analysis of the resected specimen (ie, intraoperatively or postoperatively). Therefore, adjuvant therapy to prevent recurrence and improve survival rates has been studied extensively in this setting. Several trials randomized patients with completely resected NSCLC to postoperative radiotherapy or surgery alone. Data for patients with N1 or stage II NSCLC are shown in Table 3. Lung Cancer Study Group (LCSG) trial 773 randomized 230 patients after complete resection of stage II or III squamous cell carcinoma to receive 50 Gy postoperatively or to surgery alone. 20 Two thirds had stage II disease, and approximately 75% had N1 tumors. For the entire study population, no difference in survival was noted for those receiving adjuvant therapy compared with Table 3 Randomized Clinical Trials of Surgery Alone vs Surgery Plus Adjuvant Radiotherapy in Patients With Completely Resected Stage II NSCLC* 5-yr Survival, % Local Recurrence, % Source Patients, No. Stage Radiotherapy Dose, Gy Surgery Surgery Plus Radiotherapy p Value Surgery Surgery Plus Radiotherapy p Value Weisenberger 20 210 II, III 50 37 38 NS 19 1 0.001 Stephens 21 183 N1 40 25 18 NS 49 40 NS Dautzenberg et al 22 180 II 60 50 24 0.003 Feng et al 23 191 N1 60 47 56 0.288 31 5 0.05 Mayer et al 24 67 N1 50 56 22 42 NS 26 8 NS *NS not significant. www.chestjournal.org CHEST / 123 / 1/ JANUARY, 2003 SUPPLEMENT 191S

those receiving surgery only. However, there was a decrease in local recurrence (defined as a first recurrence in the ipsilateral lung or mediastinum) in the group receiving postoperative radiotherapy. Only 1% of first recurrences were local in the radiotherapy group, compared with 19% in the control group (p 0.001). The Medical Research Council trial compared surgery alone to surgery followed by postoperative radiotherapy (40 Gy in 15 fractions) in patients with pathologically staged T1-2N1-2M0 NSCLC. 21 Patients were stratified according to TNM classification, and 183 patients had N1 disease. In a subgroup analysis, no differences were seen in patients staged N1 with respect to survival (p 0.26). When suspected and definite local recurrences were analyzed together, there was no clear evidence that radiotherapy was beneficial. An analysis of the time to definite local recurrence, however, did show a significant advantage in the radiotherapy study arm (p 0.04). This discrepancy may reflect the difficulty in accurately defining the presence of local failure, particularly in the setting of evolving fibrotic changes after radiotherapy. In a large (n 366) randomized trial from China, radiotherapy was administered postoperatively to 60 Gy in 30 fractions vs observation. 12 Among the 191 patients with pathologic N1 disease, there was a significant decrease in local recurrence from 31 to 5% (p 0.05). The 5-year survival rates marginally (but not statistically) favored radiotherapy: 56% vs 47%. This study, however, has been criticized in that results were analyzed only by the treatment delivered, rather than by the intent to treat. Dautzenberg et al 22 reported the results of a multicenter (Groupe d Etude et de Traitement des Cancers Bronchiques), randomized trial of postoperative radiotherapy (60 Gy) compared to surgery alone in 728 patients with resected NSCLC. The study included 180 patients with stage II NSCLC. This study reported an overall decrease in survival in the postoperative radiotherapy group (43% vs 30%, p 0.002) with no difference in local recurrence rates. In a subgroup analysis, mortality was also found to be higher in patients with stage II NSCLC who underwent radiotherapy (50% vs 24%, p 0.003), although there was no difference noted in local control rates. Unlike the other studies listed in Table 3, this is the only one that showed a decrease in 5-year survival for the radiotherapy study arm compared to the control study arm. This has been directly related to the higher daily radiotherapy doses used by some of centers that participated in the study. A meta-analysis from the Medical Research Council combined data from nine randomized trials (2,128 patients) that compared surgery alone with surgery followed by postoperative radiotherapy. 25 For all patients, postoperative radiotherapy was associated with an absolute decrease in survival of 7% at 2 years. The adverse effect of postoperative radiotherapy on survival was greatest for patients with stage I/II, N0-N1 disease. The problems noted above for the study of Dautzenberg et al 22 are even more applicable to this meta-analysis. Indeed, the trial of Dautzenberg et al 22 made up approximately one third of the patients in the meta-analysis. There was a wide heterogeneity in the doses and fractionation schedules used in the trials included in the postoperative radiotherapy meta-analysis. The dose fractionation schema ranged from a total of 30 Gy in 10 fractions to 60 Gy in 30 fractions. Recent trials suggest that the potential lethal effects of radiotherapy cited in the postoperative radiotherapy meta-analysis are rarely seen today with modern radiotherapy equipment and techniques. 26,27 Because the risk-benefit ratio of adjuvant therapy in the setting of pathologic N1 disease is controversial, other factors may help in making treatment decisions in this situation. For example, Yano et al 10 reported a 5-year survival of 40% for patients with hilar N1 disease compared to 65% for those with lobar N1 disease (p 0.014). Since the survival of patients with lobar N1 disease is similar to that of patients who are pathologic N0, even the local control benefit of adjuvant radiotherapy is likely to be very small in this group of patients. Recommendations 2. For patients who have undergone complete resection of stage II NSCLC with N1 lymph node metastases (stage II [N1] NSCLC), routine administration of postoperative radiation therapy with a goal of improving survival is not recommended. Level of evidence, fair; benefit, none/negative; grade of recommendation, D 3. For patients who have undergone complete resection of stage II NSCLC with N1 lymph node metastases (stage II [N1] NSCLC), routine administration of postoperative radiation therapy (ie, adjuvant radiation therapy) decreases local recurrence rates. For patients who have undergone complete resection of stage II NSCLC with N1 lymph node metastases (stage II [N1] NSCLC), routine administration of postoperative radiation therapy could be used if the goal is to decrease local recurrence with the understanding that survival will not be improved. Level of evidence, fair; benefit, small; grade of recommendation, C 192S Lung Cancer Guidelines

4. For patients who have undergone complete resection of stage II NSCLC with N1 lymph node metastases (stage II [N1] NSCLC), the evidence indicates that adjuvant radiotherapy improves local control but does not increase survival. An overall recommendation cannot be made regarding routine use of adjuvant radiotherapy in this setting. Level of evidence, fair; benefit, none/negative; grade of recommendation, D Adjuvant Chemotherapy Since most patients with completely resected early stage NSCLC develop distant (as opposed to local) recurrences, the administration of postoperative systemic therapy has been tested in a number of different trials, including randomized trials. 28,29 In addition, two meta-analyses have been published. A LCSG study (LCSG 772) randomized 141 patients with resected stage II and II adenocarcinoma and large cell undifferentiated carcinoma to receive postoperative combined chemotherapy with cyclophosphamide, doxorubicin, and cisplatin, or postoperative immunotherapy (intrapleural bacille Calmette-Guérin and levamisole). Holmes 28 reported 130 evaluable patients and noted a significant difference in recurrence-free survival in the chemotherapy study arm, although overall survival between the two groups was not significantly different (p 0.113). The Non-small Cell Lung Cancer Collaborative Group reported a meta-analysis using updated patient data on individual patients from 52 randomized clinical trials. 29 Data on adjuvant chemotherapy compared to surgery alone were available from 14 trials (4,357 patients and 2,574 deaths). Based on data from five trials, the meta-analysis clearly showed that the hazard ratio for death was greater in patients who received alkylating agents postoperatively compared to surgery alone. Analysis of eight more recent trials of cisplatin-based combination chemotherapy (either with cyclophosphamide, doxorubicin, and cisplatin, or cisplatin and vindesine) yielded a hazard ratio for treated patients of 0.87 equivalent to a 13% reduction in the risk of death (p 0.08). This suggested that adjuvant cisplatin-based chemotherapy conferred an absolute survival benefit of 3% at 2 years and 5% at 5 years, with the 95% confidence intervals (CIs) being consistent with a 1% detriment to a 10% benefit in 5-year survival. Three other trials included other drug regimens, either tegafur, or tegafur plus uracil. Based on limited numbers, the data yielded a hazard ratio of 0.89 in favor of chemotherapy (p 0.30). Few patients with stage II NSCLC were enrolled (8.6% and 11.1%, respectively) in the trials of tegafur plus uracil-based therapy. The data from randomized, prospective trials do not clearly demonstrate a benefit from the use of postoperative chemotherapy in patients with stage II NSCLC. While meta-analysis suggested that platinum-based postoperative regimens might provide a clinically significant survival benefit, the same analysis suggested that postoperative chemotherapy with alkylating agents might actually decrease survival of patients following complete resection. Problems with the older data include concerns about staging methods, the lack of modern agents (such as antiemetics and drugs to minimize hematologic toxicity) that minimize the side effects of chemotherapy, and the fact that in many studies only one half of the patients assigned to adjuvant chemotherapy completed the prescribed course of therapy. In addition, the individual randomized clinical trials lacked the statistical power to detect a survival advantage of 5 to 10%, an advantage that many authors have stated is clinically important. All of these problems combined may account for the fact that a survival benefit of postoperative chemotherapy in patients with completely resected NSCLC has never consistently been demonstrated. A better answer regarding the clinical utility of adjuvant chemotherapy must await the results of ongoing and recently completed randomized clinical trials. Recommendation 5. For patients who have undergone complete resection of stage II NSCLC, administration of postoperative chemotherapy should not be considered standard therapy at this time, and its use should be limited to patients enrolled in clinical trials. Level of evidence, good; benefit, none/negative; grade of recommendation, D Adjuvant Chemotherapy and Radiotherapy In order to decrease both the local recurrence rate and the rate of development of distant metastases, postoperative treatment with both chemotherapy and radiation therapy has been compared to postoperative radiotherapy alone in patients with completely resected stage II NSCLC. Two recent trials are important. The Groupe d Etude et de Traitement des Cancers Bronchiques reported by Dautzenberg et al 30 randomized 267 patients (8 patients with stage I, 70 patients with stage II, 189 patients with stage III) to receive postoperative radiation alone or to postoperative radiation and three courses of cyclophosphamide, doxorubicin, cisplatin, vincristine, and lomustine. Radiation therapy consisted of www.chestjournal.org CHEST / 123 / 1/ JANUARY, 2003 SUPPLEMENT 193S

60 Gy in 6 weeks for both groups. Once again, no significant difference was seen in overall survival for the study patients. When a subset analysis of N0/N1 patients was performed, no differences in the rates of local or distant recurrences were noted, but overall survival was better in the group receiving radiation therapy alone (34% vs 17%, p 0.03). The 5-year survival rate of 17% is lower than one would expect in a group of patients with mostly N1 disease, however. The authors did not think this was due to any toxic effects of the chemotherapy. Keller et al 31 reported the results of Eastern Cooperative Oncology Group trial 3590, a randomized trial of postoperative radiotherapy alone compared to concurrent chemotherapy and radiotherapy in 488 patients following complete resection of stage II and III NSCLC. The radiotherapy dose was 50.4 Gy administered in 28 daily fractions. Chemotherapy consisted of cisplatin and etoposide administered concurrently. Survival was not prolonged by concurrent therapy compared to radiotherapy alone (median survival, 38 months and 39 months, respectively; p 0.56). The risk of intrathoracic recurrence was also not decreased by concurrent therapy when compared to radiotherapy alone. A meta-analysis noted previously 29 also included a review of the available data on postoperative radiotherapy compared to postoperative radiotherapy and chemotherapy. Seven trials (807 patients and 619 deaths) were included in the analysis. Six of these trials used a platinum-based chemotherapy regimen. Total planned doses of radiation ranged from 40 Gy in 10 fractions to 65 Gy in 33 fractions. The delay between surgery and first postoperative treatment was scheduled to be no more than 7 weeks. Two of the trials included some patients with complete resections, and two trials limited enrollment only to patients with incomplete resections. The hazard ratio for platinum-based trials was 0.94 (p 0.46). The 95% CI ranged from a 3% detriment to an 8% benefit at 5 years. A benefit from combining postoperative radiotherapy and chemotherapy could not be clearly identified. Recommendation 6. In patients who have undergone complete or incomplete resection of stage II NSCLC, postoperative combined chemotherapy and radiotherapy should not be considered standard therapy at this time, and their use should be limited to patients enrolled in clinical trials. Level of evidence, good; benefit, none/negative; grade of recommendation, D Neoadjuvant (Induction) Therapy for Stage II (N1) NSCLC Administering systemic therapy preoperatively for patients with resectable NSCLC and who are at high risk for recurrence has the following potential advantages over postoperative administration of systemic therapy: (1) patients are more likely to complete the prescribed course of therapy; (2) chemotherapy will have a greater effect on the primary tumor while its blood supply is still intact; (3) occult distant disease will be treated sooner; and (4) surgical resection may be easier once the tumor has decreased in size ( downstaging of the primary and any N1 nodal metastases). Therefore, a phase II trial (the Bimodality Lung Oncology Team Trial) was initiated in the United States to determine if preoperative chemotherapy followed by surgery was effective and safe. The Bimodality Lung Oncology Team Trial was conducted jointly at Memorial Sloan Kettering Cancer Center and M.D. Anderson Cancer Center. 32 Patients with clinical stage T2N0, T1-2N1, and T3N0-1 NSCLC (all with negative mediastinoscopy findings) received two cycles of paclitaxel and carboplatin therapy (paclitaxel, 225 mg/m 2 over 3 h, and carboplatin [area under the curve, 6] every 21 days) preoperatively. Patients who progressed following preoperative chemotherapy did not undergo resection and were treated off-study. Three postoperative cycles of the same chemotherapy were planned for patients undergoing complete resection. Patients with superior sulcus tumors were excluded. There were 94 patients enrolled in the study. At the time of enrollment, the pretreatment clinical stage of the patients enrolled in this study was T2N0 in 42 of 94 patients (45%), T1N1 in 1 of 94 patients (1%), T2N1 in 27 of 94 patients (29%), T3N0 in 17 of 94 patients (18%), and T3N1 in 7 of 94 patients (7%). Of the patients (all stages combined) receiving induction chemotherapy, 56% had a major objective response and 86% underwent complete resection. Patients not undergoing operation had disease progression (n 3), were clinically unresectable (n 1), died (n 1), and were unavailable for follow-up (n 1). Six pathologic complete responses (6%) were observed. Ninety patients (96%) received the planned preoperative chemotherapy vs 45% receiving postoperative chemotherapy. The authors reported no unexpected chemotherapyrelated or surgical mortality and morbidity. They noted 10 episodes of grade III respiratory infection and another 10 episodes of grade III toxicity listed as lung (other), raising the question of whether some possible increase in toxicity resulted from combining preoperative chemotherapy and surgery. A retrospective study 194S Lung Cancer Guidelines

by Siegenthaler et al 33 concluded that preoperative chemotherapy and surgery did not affect overall morbidity and mortality. Roberts and coauthors 34 came to the opposite conclusion. But generally, the results of this phase II trial have been interpreted as proving feasibility and efficacy of the preoperative regimen of paclitaxel and carboplatin. The phase III North American Intergroup trial (S9900) that randomizes patients to surgery alone vs three cycles of preoperative chemotherapy followed by surgery has been enrolling patients since late 1999. The only randomized trial of preoperative chemotherapy to include significant numbers of stage II patients was reported by DePierre et al. 35 Approximately one half of the patients had clinical stage IB or II NSCLC, with the remainder stage IIIA (clinical stage T1N0 patients were excluded). Patients were randomized to undergo surgery or to receive two cycles of chemotherapy (mitomycin, 6 mg/m 2 on day 1; ifosfamide, 1.5 gm/m 2 on days 1 to 3; and cisplatin, 30 mg/m 2 ondays1to3)3 weeks apart before surgery. In both study arms, patients with T3 or N2 disease received postoperative radiotherapy (up to 60 Gy). A total of 355 patients were evaluable. A beneficial effect of preoperative chemotherapy in terms of survival was confined to the group of patients with N0 and N1 disease, with a relative risk of 0.68 (95% CI, 0.49 to 0.96; p 0.027). A phase II study and a phase III trial that included stage IB and II patients suggest that preoperative chemotherapy and surgery may enhance survival in patients with stage IB and II NSCLC with acceptable toxicity; however, questions about the toxicity of induction chemotherapy and surgery remain. 34 Despite promising results, induction chemotherapy and surgery cannot be considered standard therapy for patients with stage IB, II, and T3N1 NSCLC until more experience has been gained. The phase III North American Intergroup trial (S9900) comparing surgery alone to induction paclitaxel and carboplatin followed by surgery began enrolling patients in 1999. Recommendation 7. For patients with stage T2N0, T1-2N1, and T3N0 NSCLC, routine use of preoperative chemotherapy followed by surgery should not be considered standard therapy at this time, and its use should be limited to patients enrolled in clinical trials. Level of evidence, poor; benefit, none/negative; grade of recommendation, I Treatment Guidelines Stage II NSCLC (T3N0M0) CT Assessment of Stage II (T3 [Chest Wall]) NSCLC The ability of chest CT to predict the presence of chest wall invasion by a lung tumor adjacent to the chest wall has been investigated by Ratto et al 36 in a study involving 112 patients. They determined that the presence of a chest wall mass protruding through the ribs on CT was the most sensitive predictor of chest wall invasion, while a ratio of length of chest wall contact/tumor diameter of 0.5 was the best predictor of the absence of chest wall invasion. Other studies have reported similar findings. 37,38 Radiographic signs on chest CT other than a mass protruding thorough the ribs of the chest wall or gross rib destruction are not sufficiently accurate to make a diagnosis of chest wall invasion by a tumor adjacent to or abutting the chest wall. MRI has not generally been shown to provide any advantage over CT in detecting involvement of the lateral chest wall by an adjacent lung tumor. 39 Recommendation 8. For patients with lung tumors that abut or are adjacent to the chest wall based on chest CT (clinical T3 [chest wall] NSCLC), the presence or absence of chest wall invasion should not be assumed based on CT findings alone but should be confirmed by surgical exploration. Level of evidence, poor; benefit, moderate; grade of recommendation, C. Resection of Stage II (T3 [Chest Wall]) NSCLC: Choice of Operative Procedure There have been a number of published reports of the results of chest wall resection for NSCLC invading the parietal pleura or the chest wall. These were all retrospective studies. In all of these studies, the most important factor influencing survival following resection of T3 (chest wall) tumors was completeness of resection (Table 4). Downey and coauthors 7 ex- Table 4 Complete vs Incomplete Resection of T3 Chest Wall NSCLC Source Patients, No. 5-yr Survival, % Incomplete Resection Complete Resection Pitz et al 41 125 11 29 Ratto et al 42 112 0 16 Downey et al 7 334 4 32 Magdeleinat et al 43 201 13 24 www.chestjournal.org CHEST / 123 / 1/ JANUARY, 2003 SUPPLEMENT 195S

Source Table 5 Morbidity of Operations Patients, No. Operative Mortality, No. of Patients/Total Patients (%) En Bloc Resection Extrapleural Resection Albertucci et al 44 37 2/21 (9.5) 2/16 (12.5) Harpole et al 45 47 0/47 (0) NA Downey et al 7 175 10/175 (6) Magdeleinat et al 43 201 3/79 (4%) 11/122 (9%)* *p 0.2 for the difference in mortality between extrapleural and en bloc resection. Includes 25 patients with superior sulcus tumors. NA no patients in this series underwent extrapleural resection. En bloc, 92 patients; extrapleural, 80 patients; discontinuous, 3 patients; authors noted that en bloc resections and extrapleural resection were associated with similar mortalities. plored 334 patients. Of those, 175 patients had R0 (margins negative on microscopic examination) resections, 94 patients had R1 (margins positive on microscopic examination) or R2 (margins grossly positive) resections, and 65 patients underwent exploration without resection. Overall survival of patients undergoing R0 resections was 32%. The 5-year survival of R0 patients with N0 disease was 49%. The survival of incompletely resected patients was indistinguishable from that of patients undergoing no resection at all, with only 4% of incompletely resected patients and 0% of unresected patients alive after 3 years. The authors concluded that the most striking finding...isthat an incomplete resection, even if only microscopic disease, offers the patient no curative benefit. The type of resection that results in a complete (R0) resection for a specific patient is the one that should be performed. Downey et al 7 based the choice of operation (extrapleural resection vs en bloc resection) on careful intraoperative assessment. If an extrapleural resection was attempted but the extrapleural plane could not be developed easily, suggesting tumor invasion into the chest wall, then en bloc resection was performed. For 175 patients managed in this fashion, and for whom a complete resection was achieved, no survival difference was noted (5-year survival of 36% for both groups, p 0.57). The authors concluded that survival did not depend on the extent of resection (en bloc vs extrapleural) as long as a complete resection was achieved. Others have reported that en bloc resection is associated with better survival than extrapleural resection, even for those T3 (chest wall) tumors whose depth of invasion is limited to the parietal pleura only. 44 These data are not generally supported by the results of larger series. 7,9 Ratto et al 42 reported that 19 patients in their series underwent discontinuous resection, a situation where extrapleural dissection was carried out initially but a portion of chest wall was resected separately during the same operation, usually out of concern that the pleural margin was close or positive for malignant cells. None of the 19 patients survived longer than 30 months. Pitz et al 41 performed discontinuous resection in 7 patients. None of the seven patients survived beyond 18 months. Based on limited data, it would seem that a discontinuous resection does not lead to a complete resection, which is the most important determinant of survival in the treatment of patients with T3 (chest wall) tumors. Many authors (Table 5) have reported that the morbidity of operations incorporating en bloc resection of T3 (chest wall) tumors is similar to that of operations where an extrapleural resection is performed. 7,43 45 Therefore, there should be no reluctance to perform this procedure when intraoperative evaluation of T3 (chest wall) tumors suggests tumor invasion beyond the parietal pleura. In summary, completeness of resection is the most important predictor of survival in patients undergoing resection of T3 (chest wall) tumors. (Lymph node status is the next most important factor; see the next chapter on stage IIIA NSCLC.) The appropriate operation is the one that yields a complete resection (either extrapleural resection or en bloc resection). Limited data suggest that discontinuous resections are not equivalent to complete resections. Data suggest that the mortality rate of operations incorporating en bloc chest wall resection for T3 (chest wall) tumors is similar to that associated with extrapleural resection. Recommendations 9. For patients with T3 (chest wall) NSCLC that, at the time of operation, may extend beyond the parietal pleura, en bloc resection of T3 (chest wall) NSCLC must be performed unless one is confident that extrapleural invasion does not exist. Long-term survival after surgical treatment for T3 (chest wall) NSCLC is highly dependent on the completeness of resection. Level of evidence, poor; benefit, substantial; grade of recommendation, C 10. For patients with T3 (chest wall) NSCLC that does not extend beyond the parietal pleura, an extrapleural resection may be performed. As long as a complete resection is achieved, survival following extrapleural resection is similar to that achieved following en bloc resection. Level of evidence, poor; benefit, substantial; grade of recommendation, C 11. At the time of surgery for T3 (chest wall) NSCLC suspected of invading beyond the 196S Lung Cancer Guidelines

parietal pleura, separation of the tumor from the chest wall followed by resection of that portion of the chest wall that the tumor was originally adherent to (ie, discontinuous or non-en bloc resection) should be avoided. Limited data suggest that a discontinuous resection results in very inferior survival compared to en bloc resection. Level of evidence, poor; benefit, substantial; grade of recommendation, C Postoperative (Adjuvant) Radiotherapy for T3 (Chest Wall) NSCLC No randomized trials have been performed that compare surgery alone to surgery and adjuvant radiotherapy for resected T3 (chest wall) NSCLC. To determine the value of postoperative radiotherapy in patients who have undergone chest wall resection, one should evaluate well-staged patients who have no lymph node involvement. The reported experience is small. 7,46,47 Patterson et al 46 reported 35 patients with T3 (chest wall) tumors. Thirty patients underwent complete resections, and 5 patients had incomplete resections. Postoperative radiotherapy was administered to 22 patients. The authors reported that the patients who received postoperative radiotherapy had a better 5-year survival (56% vs 30%, p value not calculated). However, most recent studies suggest no effect from radiotherapy in patients with completely resected T3 (chest wall) NSCLC. Subsequently, Piehler and colleagues 47 reported 93 patients operated on for lung cancer invading the chest wall. Sixty-six patients underwent complete en bloc resections, and 31 of those had T3N0 disease. Sixteen of those were selected to receive postoperative radiotherapy. The selection criteria were not given. The actuarial survival at 5 years was the same whether or not radiotherapy was administered (53.3% vs 54.4%). Downey and colleagues, 7 in the largest series to date, reported that the 5-year survival after complete resection of T3N0 chest wall NSCLC was not different in 79 patients who underwent surgery alone compared to 21 who received postoperative radiotherapy (48% vs 53%, p 0.63). Of note, these authors could not find any benefit from postoperative radiotherapy in patients with completely resected chest wall tumors who were found to have N1 or N2 metastases at final staging. Based on limited data, there seems to be no survival advantage of postoperative radiotherapy for patients who have undergone complete resection of T3 (chest wall) NSCLC. The few studies that address postoperative radiotherapy in patients who have undergone an incomplete resection of T3 (chest wall) NSCLC did not identify a survival advantage in this group either. 42,48 A meaningful analysis cannot be performed because of the small number of patients to be analyzed. Recommendations 12. For patients who have undergone complete resection of T3 (chest wall) NSCLC, routine postoperative radiotherapy does not provide a documented survival benefit and should not be used in these patients. Level of evidence, poor; benefit, none/negative; grade of recommendation, I 13. In patients who have undergone incomplete resection (or resection with a negative but close margin) of T3 (chest wall) NSCLC, postoperative radiotherapy may provide a survival benefit and can be used. Level of evidence, poor; benefit, small/weak; grade of recommendation, C Treatment of T3 (Mediastinal) NSCLC Approximately one half of patients with T3 tumors have tumors that invade the lateral chest wall or apex of the lung. The other half have tumors that either invade the mediastinum, have grown to within 2 cm of the carina, or less commonly invaded the diaphragm. As noted above, the prognosis for these patients seems to be worse than for patients with more peripheral tumors. Surgical resection provides limited 5-year survival in most instances, with the exception of tumors that invade or contact the mediastinal fat or pericardium over a small area (these are often discovered only at the time of surgery). For patients with resected T3 (mediastinal) NSCLC, the average 5-year survival of reported series is about 25% (range, 9 to 37%). 3,13,16,41 No controlled studies of adjuvant radiotherapy following complete resection of T3 (mediastinal) NSCLC have been reported. Martini et al 16 reported the results of a series of patients (n 15) treated with interstitial brachytherapy following incomplete resection of T3 (mediastinal) NSCLC. They reported a 5-year survival of 20% in the adjuvant radiotherapy group compared to 7% in the group undergoing incomplete resection only and 0% in the group treated with radiation alone. This suggests that patients may derive some benefit from adjuvant radiotherapy after incomplete resection of T3 (mediastinal) NSCLC. There are no data to support its use when a complete resection has been performed. Recommendations 14. For patients with T3 (mediastinal) NSCLC who have undergone incomplete resection, www.chestjournal.org CHEST / 123 / 1/ JANUARY, 2003 SUPPLEMENT 197S

postoperative radiotherapy may be of benefit. Level of evidence, poor; benefit, small; grade of recommendation, C 15. Adjuvant radiotherapy for T3 (mediastinal) NSCLC for completely resected patients should not be performed. Level of evidence, poor; benefit, none/negative; grade of recommendation, I Patients with mainstem bronchial involvement are usually reported in series of sleeve resections, often mixed in with other stages. The range of 5-year survival in reported series varies from 12 to 40%, 43,49,50 with two small series reporting 5-year survival of 80% with T3 mainstem involvement (see previously mentioned recommendations regarding type of resection under treatment of T1-2N1 tumors). 40,51 The presence of N2 lymph node metastases significantly affects survival (Table 6). This seems to be especially true for patients with central T3 tumors, based on the experience of groups operating on patients with tumors classified as T3 because of airway proximity. 41,49,50 Staples et al 52 found that the prevalence of N2 metastases was 54% for central tumors and 27% for peripheral tumors in 151 patients undergoing mediastinoscopy. Since the 5-year survival of patients with T3N2 NSCLC is low, and central tumors are more likely to have occult N2 metastases, mediastinoscopy should be performed in patients with T3 central tumors prior to resection. Recommendation 16. In all patients with centrally located clinical T3 NSCLC, histologic assessment of mediastinal lymph nodes should be performed prior to resection. Preoperative identification of N2 lymph node metastases precludes surgical resection as initial therapy in this setting. Level of evidence, poor; benefit, substantial; grade of recommendation, C Some authors have recommended induction therapy for patients with central T3 NSCLC and N2 metastases. Responders could then undergo resection. No data are available to evaluate this. Summary Stage II NSCLC consists of a number of different groups of patients. Because of this and because only 5 to 10% of all patients with NSCLC are classified as stage II, the quality of the evidence for certain recommendations listed here is limited. Other limitations of these guidelines include the fact that it is not possible to include all of the varied clinical situations that a practicing physician is likely to encounter in a document such as this, and that ongoing research may render sections of these guidelines obsolete not long after they are published. Despite these limitations, several conclusions can be drawn regarding the current treatment of patients with stage II NSCLC and areas for future research. Adjuvant therapy of any sort (radiotherapy, chemotherapy, combined chemotherapy and radiotherapy) has never proven to prolong survival following complete resection of stage II NSCLC. Although a number of randomized clinical trials have been performed, the issue of postoperative radiotherapy is still controversial because of the techniques used in those trials. Modern methods for administering radiotherapy may decrease the toxicity associated with treatment while maintaining effective local control capabilities. Postoperative radiotherapy has a role in treating patients with close or positive margins after resection. Ongoing clinical trials (and some recently completed) will hopefully determine if currently available chemotherapy agents in combination are more effective than previous agents when used in the adjuvant setting. Therefore, we believe that the use of most adjuvant therapies should be limited to patients enrolled in clinical trials. Table 6 Effects of N2 Lymph Node Metastases on Survival Source Type of T3 Tumor % 5-yr Survival T3N2 Magdeleinat et al 43 Chest wall 21 Elia et al 9 Chest wall 0 Downey et al 7 Chest wall 15 Harpole et al 45 Chest wall (18 mo median survival) Pitz et al 41 Chest wall 14 Albertucci et al 44 Chest wall 0 Ratto et al 42 Chest wall 0 Pitz et al 14 Mediastinum/main bronchus 0 Dartevelle et al 48 Main bronchus (0 of 8 patients with paratracheal N2)* Nakahashi et al 40 All types 0 *n 13, subcarinal nodal involvement only, 34% at 3 yr; 3 of 13 patients survived up to 74 mo, 81 mo, and 90 mo, respectively. 198S Lung Cancer Guidelines