Induction chemotherapy followed by surgical resection

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1 Surgical Resection for Residual N 2 Disease After Induction Chemotherapy Jeffrey L. Port, MD, Robert J. Korst, MD, Paul C. Lee, MD, Matthew A. Levin, BS, David E. Becker, MA, Roger Keresztes, MD, and Nasser K. Altorki, MD Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, New York, New York Background. Induction therapy is a common treatment modality for patients with stage IIIA non-small cell lung cancer (NSCLC). Although mediastinal nodal downstaging after induction therapy is generally considered a favorable prognostic feature, the benefit of resection in the presence of residual N 2 disease is controversial. In this study we analyzed our experience with resection after induction chemotherapy in patients with residual N 2 disease to more precisely define the role of surgical resection in this group of patients. Methods. In this retrospective analysis, we reviewed the records of 78 patients with N 2 disease who received induction therapy with preoperative intent between 1990 and All patients had potentially resectable disease. Survival analysis was performed using the Kaplan-Meier method. A Cox proportional hazards regression model was used to evaluate multiple prognostic factors. Results. There were 78 patients (39 men) with a median age of 64 years. Sixty had nonsquamous histology. Resection was performed in 52 patients (47 R 0 ). Hospital mortality was 1.9%. A complete pathologic response occurred in 2 of 52 (3.8%) patients and 19 of 52 (36%) patients had no residual N 2 disease. Overall 5-year survival for resected patients was 23%. Overall 5-year survival was 30% for N 0 -N 1 patients and 19% for those with residual N 2 disease. Multivariable analysis identified clinical response to therapy (p ) and histology (p 0.01), but not residual N 2 disease (p 0.65), as important prognostic variables. Conclusions. Surgical resection may be a viable option for patients with residual N 2 disease after induction chemotherapy, provided an R 0 resection can be performed. (Ann Thorac Surg 2005;79: ) 2005 by The Society of Thoracic Surgeons Induction chemotherapy followed by surgical resection is an increasingly common treatment strategy for patients with potentially resectable IIIA non-small cell lung cancer (NSCLC). The interest in this approach stems from the results of several phase II trials and three small phase III trials [1 13] that have shown that this strategy is both feasible and results in superior survival rates compared with surgery alone. Survival rates are especially improved in those patients in whom the mediastinal nodal disease is eradicated. However, there is some concern about the merits of surgical resection in those patients with persistent N 2 disease. Recent studies [13, 14] have shown that survival for patients with residual N 2 disease may be as low as 10% at 2 years. This has led many to question the role of surgery in this particular group. In this study we analyzed our experience with surgical resection after preoperative chemotherapy in patients with N 2 disease, in order to clarify the role of surgical resection in those patients with persistent mediastinal nodal disease. Accepted for publication Oct 26, Presented at the Poster Session of the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26 28, Address reprint requests to Dr Altorki, Department of Cardiothoracic Surgery, Suite M404, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021; Patients and Methods A retrospective analysis was performed of all patients from 1990 to 2003 who underwent induction chemotherapy for clinically staged IIIA NSCLC at our institution. Data collected included basic demographics, pretreatment clinical staging, induction therapy, and surgical treatment. The Committee on Human Rights in Research (Institutional Review Board) of Weill Medical College approved this study. Clinical Staging Patients underwent preoperative evaluation with a computed tomographic (CT) scan of the chest and abdomen, a bone scan, a brain imaging study, and more recently a positron emission tomographic (PET) scan. The majority of patients (89%) had a staging cervical mediastinoscopy. Chemotherapy All patients received 2 to 3 cycles of induction chemotherapy. The most common chemotherapy doublet was paclitaxel/carboplatin (80%). All patients were restaged with a CT scan of the chest and abdomen within 2 to 4 weeks of their last treatment and had to show a response to therapy or stable disease in order to be considered candidates for resection. Categories of response included a complete response, partial response, minimal response, stable disease, and progression of disease. A complete 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg PORT ET AL 2005;79: N 2 DISEASE AFTER INDUCTION CHEMOTHERAPY 1687 response (CR) was defined as the disappearance of all clinical evidence of tumor by CT scanning. A partial response (PR) was recorded when the product of the tumor s greatest diameter, and that perpendicular to it, was reduced by 50% or more, a minimal response (MR) when there was a reduction between 50% and 25%, and stable disease when that product increased or decreased by less than 25%. Progression of disease was defined as an increase in tumor measurements as described above by at least 25%, or the clear development of new lesions. Surgical Procedure Patients who underwent resection had a thoracotomy with an anatomic lung resection and a complete mediastinal lymph node dissection (levels 2, 4, 7, 8, and 9 for right-sided tumors and levels 5, 6, 7, 8, and 9 for left-sided tumors). A resection was considered complete (R 0 ) when there was no residual gross or microscopic disease at the bronchial or vascular margins and no residual disease in the dissected nodal basins. Disease involving the highest mediastinal node in the right hemithorax was not considered evidence of an incomplete resection if that node was completely resected. An R 1 resection was defined as the presence of microscopic residual tumor at the resected bronchial or vascular margins, while an R 2 resection was defined as the presence of residual gross unresectable disease at the conclusion of the procedure. All operative and pathological reports were analyzed to determine the completeness of resection, stage of disease, and response to treatment. A complete pathological response was defined as no evidence of disease at pathological assessment. Minimal residual microscopic disease was defined as the presence of only 10% or less viable tumor cells in the pathologic specimen. Statistical Considerations Complete outcome information and the status of each patient with respect to survival and the presence of recurrent disease were determined from a prospectively collected database and medical records. Statistical analysis was performed using the SPSS statistical software (SPSS Inc., Chicago, IL). Survival was determined by the Kaplan-Meier method. Overall survival was calculated from the date of surgical resection (for those patients who had a resection) or the date of mediastinoscopy (for those patients with unresectable disease) to the date of death from any cause. A multivariable analysis of independent prognostic factors was calculated with the Cox proportional hazards regression model. The variables considered in the model included the following: gender, age, histology, clinical T-status, residual N 2 disease, and response to therapy. Results Table 1. Patient Characteristics (n 78) Characteristic No. of Patients % Sex Male Female Age, years Median 64 Range Induction chemotherapy Paclitaxel/carbo Other Median no. cycles 2 Mediastinoscopy Positive Not performed Clinical response Complete Partial Minimal Stable disease Disease progression Death Initial histology Squamous Nonsquamous Surgical procedure Explored Resected (% explored) Between 1990 and 2003, 78 patients with histologically proven NSCLC with N 2 disease received induction chemotherapy. The main patient characteristics are listed in Table 1. Fifteen patients had disease progression and there was one chemotherapy-related death. In the remaining 62 patients a clinical response was seen in 25 patients (5 CR, 17 PR, 3 MR) while 37 patients had stable disease (Table 1). The overall objective response rate was 25 of 78 (32.1%). Of the 62 patients eligible for exploratory thoracotomy, two declined surgery, eight proved unresectable on the basis of extensive unresectable mediastinal adenopathy or a T 4 primary tumor, and 52 underwent resection. Resectability was 66% (52 of 78 patients) for the whole group and 86.6% (52 of 60 patients) for those who underwent exploratory thoracotomy. Among the resected patients, 23 of 52 (44%) had a clinical response to preoperative therapy (4 CR, 16 PR, 3 MR). The types of resection are listed in Table 2. An R 0 resection was achieved in 47 of 52 patients (90.4%). Five patients had an R 1 resection due to either a positive microscopic bronchial margin undetected in the operating room (n 4) or extensive extracapsular mediastinal nodal disease involving the trachea with a positive microscopic margin (n 1). All bronchial stumps were covered with autologous tissue using pericardial fat pad or intercostal muscle. There was one hospital mortality (1.9%) (Table 2). Pathology Final histology is shown in Table 2. A complete pathological response was seen in 2 of 52 patients (3.8%) (Table 2). Two additional patients (3.8%) had minimal residual

3 1688 PORT ET AL Ann Thorac Surg N 2 DISEASE AFTER INDUCTION CHEMOTHERAPY 2005;79: Table 2. Surgical Characteristics (n 52) Characteristic No. of Patients % Procedure Lobectomy Pneumonectomy a Bilobectomy Sleeve resection Segmentectomy Completeness of resection R R Hospital mortality Pathological response Complete response Residual microscopic disease No response Final histology Adenocarcinoma Squamous Other Residual N 2 disease Multilevel residual N 2 disease Extracapsular nodal disease a Includes one superior vena cava graft. microscopic disease while 48 (92.3%) had no significant pathological response. Thirty-three (63%) patients had residual N 2 disease and 19 (37%) had downstaging of the Fig 2. Overall 5-year survival for resected versus unresected patients. mediastinum to N 0 or N 1 (13 N 0 ). Multilevel N 2 disease was detected in 17 patients (32.7%) and extracapsular nodal disease was present in 7 (13.5%) (Table 2). Fig 1. Overall 5-year survival (solid line) with 95% pointwise confidence interval (dashed lines). Fig 3. Overall 5-year survival for patients with residual N 2 versus no residual N 2 disease.

4 Ann Thorac Surg PORT ET AL 2005;79: N 2 DISEASE AFTER INDUCTION CHEMOTHERAPY 1689 nodal disease (n 7, p 0.38 vs no extracapsular nodal disease) appeared to impact on survival. The independent effect of several factors including age, gender, clinical response, histology, residual N 2 disease, and tumor status on the survival of resected patients was analyzed using a Cox proportional hazards regression model. Because residual N 2 disease and T-status were highly correlated, two separate regression models were performed with one model containing residual N 2 disease as a predictor variable and the other model containing T-status as a predictor variable (Table 3). Neither model contained residual N 2 disease and T-status together because of multicollinearity between these two regressors. Tumor histology (squamous vs other) and clinical response (responders vs nonresponders) were significant predictors of overall survival (Table 3). Comment Fig 4. Overall 5-year survival for clinical responders versus patients with stable disease. Survival Overall 5-year survival for the entire group (n 78) was 17% (Fig 1) with a median survival of 23.6 months. Overall 5-year survival for resected (n 52) and unresected patients (n 26) was 23% and 12%, respectively (p 0.006), with a median survival of versus months (Fig 2). Overall 5-year survival for patients with residual N 2 (n 33) was 19% versus 30% for patients with no residual N 2 (n 19, p 0.3), with a median survival of 29.7 versus 36.7 months (Fig 3). When resected patients were stratified by response, the overall 5-year survival for responders (n 23) versus patients with stable disease (n 29) was 55% and 12%, respectively (p 0.001), with a median survival of 59.3 months versus 23.6 months (Fig 4). In univariate analysis neither multilevel disease (n 17, p 0.95 vs single level disease) nor extracapsular The optimal treatment for patients with residual N 2 disease after induction chemotherapy remains controversial. Most authors have reported dismal 5-year survival in the range of 5% to 10% for this group after resection and have suggested that efforts be made to identify these patients preoperatively to exclude them from resection [13, 14]. In the current report we analyzed our experience with resection after induction chemotherapy in patients with residual N 2 disease. In contrast to most previous reports we found that 19% of patients with residual N 2 disease may achieve long-term survival after complete surgical resection. Similar results have also been reported by Martin and colleagues [15] and De Leyn and colleagues [8]. In both of these studies resection was carried out after induction chemotherapy for residual nodal disease. Although the best survival was reported in patients in whom mediastinal nodal disease was eradicated, patients with completely resected N 2 had a 5-year survival rate of 20% and 22%, respectively, in these two studies. In the current report the lack of a significant difference in survival between patients with mediastinal disease and those without is almost certainly a reflection of the small number of patients examined rather than a true equivalence in outcome. It would appear reasonable to attempt to identify the large subset of patients with residual N 2 Table 3. Results of Multivariable Analysis Model 1 Model 2 Variable Hazard Ratio 95% CI p Hazard Ratio 95% CI p Age (one year increments) Sex (female vs male) Clinical response (none vs partial/complete) Histology (squamous vs other) Residual N 2 (yes vs no) Tumor stage (T 2 vs T 1 ) CI confidence interval.

5 1690 PORT ET AL Ann Thorac Surg N 2 DISEASE AFTER INDUCTION CHEMOTHERAPY 2005;79: disease that will not benefit from surgical resection in order to avoid futile surgical intervention. Surprisingly, neither multilevel nodal disease nor extranodal disease appear to identify that subset. However, the small sample size in both subsets precludes a definitive conclusion. Interestingly though, clinical response to therapy appeared to be an important predictor of outcome. Survival in patients with any clinical response (major, partial, or minimal) was 55% compared to only 12% for those with stable disease. These results suggest that patients who show a clinical response should be offered surgical resection irrespective of the presence or absence of residual mediastinal nodal disease, provided a complete (R 0 ) resection can be accomplished. The management of patients with stable disease after induction therapy should be carefully individualized with particular attention given to reassessing the mediastinum to determine the presence or absence of residual mediastinal nodal disease. Modalities such as reoperative mediastinoscopy, video-assisted thoracoscopy, and possibly PET scanning may be useful restaging modalities. In those select few patients without apparent mediastinal disease, resection may be justified assuming an R 0 resection is anticipated. Limitations of this study include the retrospective nature of the analysis, the small sample size, and the study span of more than a decade. Nonetheless the inference from this study that patients with residual N 2 disease may benefit from surgical resection warrants further investigation. References 1. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994;86: Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 1998;21: Rosell R, Gomez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 1999;26: Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993;55: ; discussion Cappuzzo F, Selvaggi G, Gregorc V, et al. Gemcitabine and cisplatin as induction chemotherapy for patients with unresectable stage IIIA-bulky N2 and stage IIIB nonsmall cell lung carcinoma: an Italian lung cancer project observational study. Cancer 2003;98: Sugarbaker DJ, Herndon J, Kohman LJ, Krasna MJ, Green MR. Results of cancer and leukemia group B protocol A multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer. J Thorac Cardiovasc Surg 1995;109:473 83; discussion Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002;20: De Leyn P, Vansteenkiste J, Deneffe G, Van Raemdonck D, Coosemans W, Lerut T. Result of induction chemotherapy followed by surgery in patients with stage IIIA N2 NSCLC: importance of pre-treatment mediastinoscopy. Eur J Cardiothorac Surg 1999;15: Nagai K, Tsuchiya R, Mori T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003;125: O Brien ME, Splinter T, Smit EF, et al. Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer: an EORTC phase II study (EORTC 08958). Eur J Cancer 2003; 39: Pisters KM, Ginsberg RJ, Giroux DJ, et al. Induction chemotherapy before surgery for early-stage lung cancer: a novel approach. J Thorac Cardiovasc Surg 2000;119: Pass HI, Pogrebniak HW, Steinberg SM, Mulshine J, Minna J. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992;53: Voltolini L, Luzzi L, Ghiribelli C, Paladini P, Di Bisceglie M, Gotti G. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy. Eur J Cardiothorac Surg 2001;20: Bueno R, Richards WG, Swanson SJ, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000;70: Martin J, Ginsberg RJ, Abolhoda A, et al. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg 2001;72: