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© 2002 American Society for Clinical Oncology Long-Term Results of Combined-Modality Therapy in Resectable Non–Small-Cell Lung CancerByFrom the Thoracic Service, Department of Surgery, the Biostatistics Service, Department of Epidemiology and Biostatistics, and the Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Valerie W. Rusch, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: ruschv{at}mskcc.org
PURPOSE: Assessment of long-term results of combined-modality therapy for resectable non–small-cell lung cancer is hampered by insufficient follow-up and small patient numbers. To evaluate this, we reviewed our collective experience. PATIENTS AND METHODS: This study was a retrospective chart review recording demographics, tumor stage, treatment, and outcome of consecutive patients undergoing surgery. Survival was analyzed by Kaplan-Meier, and prognostic factors were analyzed by log-rank and Cox regression. RESULTS: From January 1993 to December 1999, 470 patients were treated, with follow-up in 446: 27 stage I, 55 stage II, 316 stage III, 43 stage IV (solitary M1), and five uncertain. Chemotherapy was mitomycin/vinblastine/cisplatin (174 patients [39.0%]), carboplatin/paclitaxel (148 [33.2%]), and other combination (124 [27.8%]); 75 patients (16.8%) received induction radiation. Resection was complete in 77.4%, incomplete in 8.3%, attempted but with gross residual disease afterward in 1.8%, and not performed in 12.6%. Pathologic complete response occurred in 20 patients (4.5%). With median follow-up of 31.0 months for patients still alive, median and 3-year survival for pathologic stages 0, I, II, III, and IV were more than 90 months, 73%; 42 months, 52%; 23 months, 35%; 16 months, 28%; and 16 months, 23% (P < .001). In a multivariate analysis, age, complete resection, pathologic stage, and pneumonectomy, but not induction regimen, significantly influenced survival. CONCLUSION: Although pathologic complete response outside the protocol setting is low, survival of this large patient cohort is comparable to that of patients in published combined-modality trials. Survival is significantly influenced by patient age, complete resection, pathologic stage, and pneumonectomy. These results can help guide standard clinical practice and emphasize the need for novel induction regimens.
LUNG CANCER IS the second most common malignancy in both men and women. In 2000, lung cancer was diagnosed in an estimated 164,100 patients in the United States.1 Of these new cases, approximately 80% have non–small-cell lung cancer (NSCLC), and half of those patients present with disseminated disease generally not amenable to surgery. Another 20% present with disease locally too advanced to be treated by surgical resection alone. Even in early clinical stages, surgical resection alone offers poor long-term survival. For pathologic stages IA, IB, IIA, and IIB, 5-year survivals are approximately 70%, 60%, 55%, and 40%, respectively.2 When the tumor has spread to the ipsilateral mediastinal lymph nodes (N2 disease, stage IIIA), 5-year survival is about 13%, and when contralateral lymph nodes (N3 disease, stage IIIB) are involved, it is approximately 5%. Although the disease is presumed to be confined to the chest in all those cases, it recurs in the majority of patients undergoing resection, and they die of metastases. Trials evaluating postoperative chemotherapy, radiation, or both in resectable NSCLC have shown limited or no survival benefit.3-6 In contrast, trials have demonstrated improved survival for patients with locally advanced disease (stages IIIA and IIIB) treated with chemotherapy or concurrent chemoradiation before surgical resection.7-10 A multicenter phase III trial is currently in progress to explore the effect of preoperative chemotherapy compared with surgery alone in patients with earlier stage NSCLC (stages IB to selected IIIA) on survival.11 However, the assessment of long-term results of combined-modality therapy is still hampered by insufficient follow-up and small numbers of patients studied. The main objective of this study is to review our collective surgical experience to better define the long-term survival of patients with NSCLC treated by induction therapy followed by surgery, and to determine factors that predict survival.
Subjects and Data Collected Clinical information was obtained through a detailed retrospective review of the medical records of all patients who received induction chemotherapy or chemoradiation for potentially resectable NSCLC either at Memorial Sloan-Kettering Cancer Center (MSKCC) or elsewhere and then underwent thoracotomy at MSKCC. The data recorded included demographic information, staging procedures, and prechemotherapy clinical stage. Details about the neoadjuvant treatment and the surgical procedure were collected. Because of the retrospective nature of the study, information about the clinical response to induction therapy was not consistently available and was not recorded. Final pathologic stage was classified according to the International System for Staging Lung Cancer,2 and the completeness of resection was defined using standard criteria. A complete resection (R0) was defined as pathologic demonstration of negative tissue margins and an assessment by the surgeon that all detectable disease had been removed. Patients who had a complete gross resection in whom positive margins were found on final pathologic review were classified as having undergone microscopically incomplete resection (R1). Gross residual disease after attempted resection was classified as R2. Downstaging was defined as any decrease in the final pathologic stage when compared with the clinical stage before induction therapy. The following data about recurrence and survival were also retrieved from the charts: the site of first recurrence, the disease status at last follow-up, and the date and cause of death. Survival data were last collected in March 2001. The Social Security Death Index Interactive Search Web site was also consulted to check the status of patients lost to follow-up (http://ssdi.genealogy.rootsweb.com).
Statistical Methods Kaplan-Meier log-rank and Cox regression analyses were used for univariate analysis for significant prognostic factors.14,15 The following variables were considered as potentially prognostic variables for survival: age, sex, clinical stage, type of induction therapy received, type of surgery, pathologic stage, and completeness of resection. Cox regression analysis was used for the multivariate analysis of factors found significant on univariate analysis.
From January 1, 1993, through December 31, 1999, 470 patients underwent a thoracotomy after induction chemotherapy for NSCLC at the MSKCC. Follow-up data are available for 446 patients (246 men and 200 women) with a median age of 59 years (range, 25 to 81 years), and analyses were performed on those patients. Their initial clinical stage distribution is listed in Table 1. Clinical stage was determined on the basis of the initial computed tomographic scan of the chest obtained for all patients and the results of mediastinoscopy when performed. Positron emission tomography was not commonly performed during the study period and was not used to stage the patients. The majority of patients (70.8%) had clinical stage III NSCLC before induction therapy. Of the 317 patients (71.1%) who had a mediastinoscopy, N2 disease was proven in 227 (50.9%) of 446 and N3 in eight (1.8%) of 446. All the mediastinoscopies were performed before the beginning of the induction treatment. The sites of solitary metastasis for the 43 clinical M1 patients, all proven by histopathology, were the brain (16 patients); the lung (nine patients); the adrenals (seven patients); bone (seven patients); and colon, inguinal node, spleen, and subcutaneous (one patient each).
Induction Therapy Regimens The majority of patients (424 [95%] of 446) were treated off protocol and more than half were referred for surgical resection after receiving induction therapy at other hospitals. The various treatment regimens used are listed in Table 1. The chemotherapy regimen consisted of mitomycin/vinblastine/cisplatin in 174 patients (39.0%), carboplatin/paclitaxel in 148 (33.2%), and other combinations in 124 (27.8%). Seventy-five patients (16.8%) also received preoperative radiation, with a median dose of 50 Gy (range, 15 to 72 Gy). In 16 patients, documentation of the dose delivered could not be obtained. The median time between the end of the chemotherapy and surgery was 43 days (range, 6 to 453 days).
Surgical Resection Information
Survival The univariate analyses of overall survival according to age, sex, clinical stage, type of induction therapy, pathologic stage, extent of resection, and type of resection are listed in Table 2. Because of the small numbers of patients in each tumor-node-metastasis category, patients were grouped by stages I through IV only. Age, sex, pathologic stage, extent of resection, and type of resection significantly influenced overall survival. Overall survival was not influenced by the type of induction regimen, and clinical staging was a poor predictor of survival.
As seen in Table 2, the addition of radiation therapy does not significantly increase survival. However, radiation is associated with pCR. In fact, 66.6% of p0 patients received induction radiation treatment compared with 19.5% of all other pathologic stage patients (Fisher’s exact test P = .013). No association was found between the type of chemotherapy and pCR (P = .432). Figure 1 shows the overall survival by pathologic stage. Median and 3-year survival for pathologic stages 0, I, II, III, and IV were more than 90 months, 73%; 42 months, 52%; 23 months, 35%; 16 months, 28%; and 16 months, 23%. Clinical stages IIIA and IIIB had a median survival of 23.9 and 15.9 months, respectively. The survival curves are not statistically different, with P = .18 by the log-rank test. Pathologic stages IIIA and IIIB were associated with median survival times of 21.3 and 12.5 months, respectively (P < .001). Survival of patients with initial clinical M1 disease was statistically longer than survival of patients with M1 disease detected at surgery, with median survival of 18.8 and 7.0 months, respectively (P = .02).
Survival by pathologic nodal status is depicted in Fig 2. The median survival for patients with N0/N1 disease was 27.8 months, compared with 15.6 months for patients with residual N2 disease (P < .001). The 3-year survival for N0/N1 patients is 43.3%, and 25.5% for N2 patients. The extent of resection also significantly influenced survival (Fig 3). There is a significant difference in survival between patients with R0 v R1 resection (log-rank = 10.86, P = .001) but not between R1 and R2/no resection (log-rank = 1.07, P = .30). Among our 198 patients known to have residual N2 disease at surgery (T0 to T4, N2, M0 to 1), the resection was R0 in 144 patients, R1 in 16, and R2/no resection in 38. Patients with residual N2 disease with R0 resection had a median survival of 20.7 months (95% confidence interval [CI], 14.8 to 26.5) and 3- and 5-year survivals of 31% and 19%, respectively; with R1, the median survival was 17.2 months (95% CI, 2.0 to 32.4); and for R2/no resection, 9.2 months (95% CI, 6.8 to 11.6). There is a statistically significant increased survival for patients having a complete resection when compared with R2/no resection (P = .0001); there is also an increased survival for R0/R1 v R2/no resection (P = .0002).
Factors that demonstrated prognostic significance by univariate analysis were then examined in a multivariate analysis. In a Cox regression model that included age, sex, pathologic stage, extent of resection, and pneumonectomy, all of these except sex had a significant impact on survival (Table 3).
Recurrence Data about recurrence were analyzed for patients who had a complete resection (R0), excluding those with stage IV disease and those who died of the surgery (n = 289). Among those 289 patients, 197 (68.2%) are known to have experienced a recurrence, 90 did not, and recurrence status is unknown for two patients. Details about the site of first recurrence are complete for 129 patients (129 [65.5%] of 197). The first recurrence was locoregional in 51 patients (39.5%), distant in 54 (41.9%), and both locoregional and distant in 24 (18.6%). The locoregional recurrence was not associated with the type of surgical procedure, the pathologic node status, the type of chemotherapy received, or the use of preoperative radiation (exact P = .69, .70, .94, .19, and .63, respectively).
Reported 3-year survival rates for patients with resected pathologic stage IIIA lung cancer without induction therapy vary from 28% to 32%.2,17 With induction treatment, survival data usually reported for clinical stages IIIA and IIIB are variable among clinical trials. Table 4 lists the median and 3-year survival rates reported. As calculated from the date of surgery, our clinical stage III patients had a median survival of 22 months and a 3-year survival rate of 34%. Those results are consistent with the literature and represent the reality of clinical practice outside the clinical trial setting. Survival does not appear to be substantially different in studies using combined radiation and chemotherapy as compared with those using induction chemotherapy alone (Table 4).
Complete resectability at operation has already been shown to improve survival.18,19 Our study confirms those results, the median survival for R0 resection being 27.8 months (95% CI, 22.4 to 33.2) compared with 11.4 months (95% CI, 8.9 to 13.9) for R1/R2 resections. Female sex has also been associated with better survival prognosis in previous studies.20,21 In our analyses, when controlling for age, stage, extent of resection, and type of resection, the statistical difference in survival disappeared. In subanalysis, female patients in our study group had slightly fewer pneumonectomies (17.5% v 24.4%, P = .08), and more R0 resections (83.5% v 72.4%, P = .006). The absence of tumor in the mediastinal nodes at surgery has been reported as a strong predictor of survival. The Southwest Oncology Group study10 showed a median survival of 30 v 10 months for N0/1 compared with N2 patients and 3-year survival rates of 44% v 18%, respectively. Our study supports those results. Bueno et al22 also showed 21.3-month median survival for patients with N0 disease compared with 15.9 months for N1 and N2 disease. Our patients known to have residual N2 disease at surgery and who had a complete resection (R0) had an opportunity of achieving long-term survival (31% at 3 years and 19% at 5 years). Therefore, our data suggest that it may be appropriate to proceed with resection in patients who have residual N2 disease when the resection is likely to be complete. Assessment of the clinical response to induction therapy was not possible because of the difficulty retrieving these data accurately in a retrospective study. On the other hand, surgical and pathologic data are very accurate. We found a pCR in only 4.5% of the cases. After careful revision of published studies assessing the effect of induction chemotherapy only followed by surgery for stage III NSCLC, pCR proportions (number of complete responses over the number of patients explored) generally range from 0% to 9.5%8,9,18,19,23,24 (Table 4). Two phase II studies showed higher complete response rates: one by Martini et al7 published in 1993 (16.7% pCR) and one by Kumar et al25 in 1997 (15% pCR). More recently, a phase II trial assessed the effect of paclitaxel and carboplatin in patients with early-stage lung cancer, and a pCR was seen in 6.8% of patients (six of 88).11 This low rate of pCR emphasizes the importance of developing more effective induction therapy regimens. Studies assessing the effect of preoperative chemotherapy combined with radiation therapy consistently show better complete response rates10,26-30 (Table 4). Only one study, reported by Fleck et al31 in abstract form, specifically addressed the question of whether radiation augments the benefit of induction chemotherapy before resection. Their resection rate was significantly higher in the chemoradiation group but, unfortunately, the definitive results of this trial have never been published. Only 75 patients in our group received induction radiation in addition to chemotherapy. Our analyses show that a greater proportion of patients treated with radiation were in the p0 group, and that p0 was associated with a longer survival. This finding is similar to that of the Southwest Oncology Group study.10 We have not been able to demonstrate a direct relationship between the addition of radiation to the induction regimen and survival, but might have found this given a larger sample size. Conversely, it is possible that the addition of radiation to induction chemotherapy may not affect survival because it eradicates locoregional tumor without treating systemic disease, which is the main cause of death in this patient population. After controlling for stage, age, and completeness of resection in a multivariate analysis, pneumonectomy is significantly associated with an increased risk of death. Even after removing the operative mortalities and the two deaths known to be from a cause other than cancer from this analysis, pneumonectomy is still associated with a shorter survival when compared with other types of resection (relative rate = 1.593, P = .005). The reason for this finding is unclear. A study from Japan comparing survival after sleeve lobectomy with survival after pneumonectomy also reported shorter survival after pneumonectomy in a multivariate analysis.32 However, Ferguson and Karrison33 did not find a significant long-term adverse influence of pneumonectomy. Overall, these results suggest that sleeve resection should be considered and pneumonectomy avoided whenever sleeve resection is a technically safe option offering an R0 resection.34 The survival of all our solitary M1 patients is relatively favorable, with a median survival of 15.6 months. When we categorized the M1 patients, we found that preinduction M1 patients were those with the best prognosis (median survival of 18.8 months). Those patients are obviously highly selected patients for whom it was possible to treat their distant metastasis with a curative intent. Conversely, patients who were discovered to be M1 at the time of the surgery (eg, metastatic nodule in another lobe) fared poorly, with a median survival of 7.0 months. This survival difference remains significant even when controlling for node status and for pneumonectomy. It is likely that patients found to be M1 at the time of surgery had persistent subclinical metastases and/or progression of their disease despite induction therapy, and thus probably had a biologically more aggressive tumor. In conclusion, the rate of pCR outside the protocol setting is similar to that reported in trials using induction chemotherapy only, but lower than that reported in trials using both induction chemotherapy and radiation. Despite the low pCR rate, the survival of this large cohort of patients, representative of general clinical practice, is comparable to that reported in prospective trials. The survival of highly selected patients with clinical solitary M1 disease who come to resection after induction therapy is relatively favorable. Age, complete resection, pathologic stage, and pneumonectomy were the prognostic factors identified as significantly influencing survival. These results can guide standard practice. However, the low pCR rate emphasizes the importance of continuing to search for novel and more effective induction regimens.
Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Fisher’s exact test.
