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Prognostic factors and long term results of neo adjuvant therapy followed by surgery in stage IIIA N2 non-small cell lung cancer patients

Prognostic factors and long term results of neo adjuvant therapy followed by surgery in stage... Departments of Pulmonary Medicine, BACKGROUND: Prognosis of stage IIIA N2 non-small cell lung cancer (NSCLC) remains poor despite the changes in therapeutic strategies. Radiation Oncology, Thoracic Surgery, OBJECTIVES: To assess long term results of neo adjuvant therapy followed by surgery for patients with stage Pathology, Affi liated IIIA N2 NSCLC and to analyze factors infl uencing survival. Hospital of Jiangsu MATERIALS AND METHODS: The methods adopted include: Retrospective review of medical records of 91 University, Zhenjiang, patients with stage IIIA N2 NSCLC, who received neo adjuvant therapy followed by surgery; collection of information on demographic information, staging procedure, preoperative therapy, clinical response, type of resection, Jiangsu, China pathologic response of tumor, status of lymph nodes and adjuvant chemotherapy; survival analysis by Kaplan- Meier and calculation of prognostic factors using log-rank and Cox regression model. RESULTS: All patients received a platinum-based chemotherapy and 23 (29.1%) had an associated radiotherapy. Eighty four patients underwent thoracotomy. Median survival was 26 months (95%CI, 22.6-30.8 months) with three and fi ve year survival rates of 31.6 and 20.9%, respectively. Prognostic factors for survival on univariate analysis was clinical response (P = 0.032), complete resection (P = 0.002), pathologic tumor response (P < 0.001), and lymph nodal down staging (P = 0.001). Multivariate analyses identifi ed complete resection, pathologic tumor response and lymph nodal down staging as independent prognostic factors. CONCLUSION: Survival of patients with stage IIIA N2 NSCLC who received neo adjuvant therapy is signifi cantly infl uenced by clinical response, complete resection, pathologic tumor response, and lymph nodal down staging. These results can be helpful in guiding standard clinical practice and evaluating the outcome of neo adjuvant therapy followed by surgery in patients with stage IIIA N2 NSCLC. Key words: Neo adjuvant therapy, non-small cell lung cancer, prognostic factor, stage IIIA, surgery, survival tage IIIA N2 non-small cell lung cancer surgery compared with surgery alone for [8-11] S(NSCLC) with involvement of ipsilateral stage IIIA NSCLC. However, a phase III mediastinal N2 represents a heterogeneous randomized trial reported by Nagai et al. failed group of patients. For patients with this locally to demonstrate any benefit of neo adjuvant advanced disease, five-year survival rate chemotherapy followed by surgery over surgery [12] after surgery or radiotherapy alone is only alone. In another phase III trial in resectable approximately 10%; majority of the patients stages I (except T1 N0), II and IIIA NSCLC [1,2] died of distant metastases. This observation patients, neo adjuvant chemotherapy failed to Address for [13] correspondence: led to attempts to improve survival by adopting improve survival of stage IIIA N2 patients. Prof. Jian Li, combined modality approaches such as neo Inconsistency of results from randomized trials Department of Pulmonary adjuvant chemotherapy followed by surgery assessing neo adjuvant chemotherapy for stage Medicine, Affi liated and/or radiotherapy. The rationale for using IIIA NSCLC is due to small sample sizes, short Hospital of Jiangsu neo adjuvant chemotherapy for the treatment follow-up periods, and unacceptable toxicity University, No. 438 of stage IIIA NSCLC is based on evidence that for certain of the chemotherapy regimens North Jiefang Road, Zhenjiang, 212001, chemotherapy can reduce tumor burden which administered. To date, management of stage Jiangsu, China. could facilitate surgery, improve resectability and IIIA N2 NSCLC is controversial, and there is no E-mail: lijian541226@163. eradicate micrometastases to prevent systemic agreement about the best approach to patients com [3,4] relapse. Several phase II trials show the with involvement of ipsilateral mediastinal role of neo adjuvant chemotherapy in patients lymph node. Because of the demonstrated [5-7] [14] with locally advanced NSCLC. Two small heterogeneity in this patient population, it is S Submission: ubmission: 24-05-09 24-05-09 randomized trials suggest a prolonged survival not yet clear for which subset of these patients A Accepted: ccepted: 26-07-09 26-07-09 D DOI: OI: ***** ***** for neo adjuvant chemotherapy followed by this therapeutic strategy (neo adjuvant therapy Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 201 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients followed by surgery) will be most rewarding. The identifi cation found on fi nal pathologic review, were classifi ed as microscopic of prognostic factors could be useful for better selection of incomplete resection (R1). Gross residual disease after surgical therapy and design of future randomized trials. resection was classifi ed as macroscopic incomplete resection (R2). Pathologic response, status of lymph node, operative In this study, we review our experience between 1998 and 2004, morbidity and mortality and postoperative treatment when to analyze prognostic factors and better defi ne the long-term appropriate were recorded. survival of Chinese patients with stage IIIA NSCLC treated with neo adjuvant therapy followed by surgery. Pathologic response of primary tumor was examined using [16] criteria reported by de Bore et al. Pathologic complete response (pCR) was defi ned as absence of any tumor in the Materials and Methods surgical specimen; partial response (pPR) was defined as the presence of only small residual foci of tumor cells, or the Patients presence of signifi cant areas of tumor necrosis throughout the Medical records of all patients with stage IIIA N2 NSCLC surgical specimen; no change (pNC) was defi ned as the presence who underwent surgery following neo adjuvant therapy at of large area of identifi able tumor cells in the surgical specimen our hospital were reviewed retrospectively for the period with minimal evidence of tumor necrosis. Nodal status from January 1998 to October 2004. We limited our analyses classifi cation was determined from a postoperative pathologic to patients who had been clinically staged as IIIA N2 disease examination. Down staging was defi ned as complete fi brosis, and received platinum-based neo adjuvant chemotherapy (with scar, or granulation of lymph nodes, with neither normal nodal or without radiotherapy) including patients who underwent formation nor cancer cell in the surgical specimen. Patients thoracotomy, had a clinical response and stable disease as well with normal nodal formation in ipsilateral mediastinum were as patients who were not operated upon due to progressive excluded from the study. Operative morbidity was defi ned as disease. Hence the patients who achieved surgical resection any event occurring during the fi rst 30 days following surgery. had completely postoperative pathologic information. Data recorded included demographic information, staging Statistical analysis procedures and pretreatment clinical stage. All patients were Overall survival was calculated from the fi rst cycle of neo staged on the basis of history, physical examination, chest adjuvant chemotherapy to the date of death or date of last X-ray, bronchoscopy, brain and chest computed tomography follow-up. Survival data was last collected in May 2008. (CT) scan, abdominal ultrasound or abdominal CT scan, Survival curve were estimated using the Kaplan-Meier method. radionuclide bone scan. Tumors were staged according to the [15] The following variables were considered potentially prognostic revised version of TNM staging published in August 1997. variables for survival: Sex, initial tumor stage, histology, chemotherapy regimen, adjunction of radiotherapy, clinical Criteria for pretherapy diagnosis of stage IIIA NSCLC with response to neo adjuvant therapy, type of surgery, extent of clinical N2 (cN2) were defi ned as a mediastinal node of short surgical resection, pathologic tumor response, status of lymph axis diameter exceeding 15mm on CT scan. Cases with a node, and adjuvant chemotherapy. diameter between 10 and 14mm were included only of there was more than one node. Patients with N3 disease revealed Log-rank analysis was used for univariate analysis for by CT scan were excluded from this study. This study was signifi cant prognostic factor. Cox regression model was used approved by the Ethics Committee of Affi liated Hospital of for the multivariable analysis of independent prognostic Jiangsu University in China. factor. Statistical analysis was performed using the SPSS V10.0 software package (SPSS Inc., Chicage, Illinois). Patient treatment and assessment Data on chemotherapy regimen, number of cycles, radiotherapy and clinical response to neo adjuvant therapy, surgical Results procedure and site of the fi rst cancer recurrence post-operation was collected. After completion of neo adjuvant therapy, chest Patient characteristics CT scan was repeated for all patients to assess the clinical From January 1998 to October 2004, 105 patients received neo response to therapy and feasibility for surgery. Brain CT adjuvant therapy for stage IIIA N2 NSCLC at our hospital. Of and bone scan were repeated if clinically indicated. Patient’s these, 91 had detailed clinical and follow-up data and were responses to chemotherapy were categorized as complete, assessable and eligible for this study. The remaining patients partial response, stable or progressive disease according to were not assessable for the following reasons: No available World Health Organization (WHO) criteria. data due to loss to follow-up (n=six), use of nonplatinum chemotherapy regime (n=four), patient refusal for surgery Patients who had a clinical response and stable disease received after neo adjuvant therapy (n=four). The patient characteristics thoracotomy. The extent of the performed pulmonary resection and treatment information are listed in Table 1. There were was left to the discretion of the attending surgeon based on the 66 men and 25 women in the group. The median age was intraoperative assessment of the residual disease. All accessible 59 years (range 38-70 years). Thirteen, 40, and 38 cases were hilar lymph nodes were dissected from the specimen, and a classifi ed as T1N2M0, T2N2M0, and T3N2M0, respectively. complete mediastinal lymph node dissection was performed Forty two and 49 cases were identifi ed as single and multiple for all patients. A complete resection (R0) was defi ned as lymph node involvement, respectively, according to pretherapy pathologic demonstration of negative tissue margins and CT scan. Examination of bronchoscopic biopsy and brushing all detectable disease had been removed. Patients who had (73 patients) or percutaneous needle aspiration specimens a complete gross resection, in whom positive margins were (18 patients) were performed to determine the histologic 202 Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients Table 1: Patient characteristics and treatment or cisplatin plus vinorelbine at a 21-day treatment cycles. The following radiotherapy commenced three weeks after the start Characteristic No. of patients % of the second cycles of chemotherapy with a total irradiation (n = 91) dose ranging from 40 to 50 Gy (a dose of 2.0 Gy administered Sex Male 66 72.5 daily, fi ve days per week). The concurrent chemoradiotherapy Female 25 27.5 consisted of two cycles of cisplatin (30 mg/m on days 1, 8, and Age (yr) 2 15) plus etoposide (50 mg/m on days 1 to 5) with concurrent, Median 59 continuous chest radiotherapy, which began on day 1 of Range 38-70 chemotherapy with a dose of 1.8 or 2.0 Gy daily, fi ve days per Initial tumor stage week at the total dose ranging from 40 to 45 Gy. T1N2M0 13 14.3 T2N2M0 40 44 The radiotherapy fi eld included the primary tumor with 1.5 cm T3N2M0 38 41.7 Histology margin, the ipsilateral pulmonary hilum, upper and median Squamous cell carcinoma 40 44 mediastinal lymph nodes. Clinical response to neo adjuvant Adenocarcinoma 44 48.4 therapy is summarized in Table 1. Six patients (6.6%) achieved Large cell carcinoma 4 4.4 a complete response, 36 patients (39.6%) obtained a partial Undifferentiated NSCLC 3 3.2 response, and 42 patients (46.2%) had stable disease, and seven Chemotherapy regimen patients (7.7%) had progressive disease. The overall response EP 12 13.2 rate was 46.2%. NP 45 49.5 GP 34 37.3 Thoracic radiotherapy Surgical treatment Yes 29 31.9 Eighty four patients who had a clinical response and stable No 62 68.1 disease underwent thoracotomy. Seven patients experienced Clinical response progressive disease received radiotherapy and further Complete response 6 6.6 chemotherapy. Type of surgical resection included lobectomy Partial response 36 39.6 (n = 45), bilobectomy (n = 15), and pneumonectomy (n = 24). Stable disease 42 46.1 A complete resection (R0) was achieved in 63 patients (75%), Progressive disease 7 7.7 Type of operation (n = 84) an R1 in 15 patients (17.9%), and an R2 in six patients (7.1%). Lobectomy 45 53.6 The operative mortality rate was 2.4% (2/84). Thirteen patients Biolobectomy 15 17.8 (15.5%) had a non-lethal postoperative complication that Pneumonectomy 24 28.6 included arrhythmia (n is equal to three), pneumonia (n is Pathologic response of tumor equal to three), bronchopleural fi stula (n is equal to two), (n = 84) heart failure (n is equal to two), prolonged air leak (n is Complete response 8 9.5 equal to two), and chylothorax (n is equal to one). Pathologic Partial response 41 48.8 complete response of primary tumor (pCR) was found in eight No change 35 41.7 Pathologic lymph node status patients (9.5%), including fi ve patients with squamous cell (n = 84) carcinoma and three patients with adenocarcinoma, pPR was N2 56 66.7 seen in 41 patients (48.8%), pNC was recorded in 35 patients N1 18 21.4 (41.7%). pathologic responses were not entirely consistent with N0 10 11.9 clinical response. Eighteen patients were down staged to N1, EP-Etoposide and cisplatin; NP-Vinorelbine and cisplatin; GP-Gemcitabine 10 patients were down staged to N0, and 56 patients remained and cisplatin N2 positive at operation. Down staging was seen in 20 (48%) of the 42 patients with single lymph node involvement and eight types. Forty four patients had adenocarcinoma, 40 patients (16%) of 49 patients with multiple lymph node involvement. had squamous cell carcinoma, four had large cell carcinoma, The proportion of down staging in patients with single lymph and three had undifferentiated NSCLC. node involvement was signifi cantly higher than patients with multiple lymph node involvement (P = 0.019). Fifteen patients Neo adjuvant treatment had subcarinal lymph node involvement. Postoperative The neo adjuvant chemotherapy regimen consisted of cisplatin 2 2 radiotherapy was administered on 17 out of 21 patients who (80 mg/m on day 1) plus etoposide (100 mg/m on days 1 either had an incomplete resection (R1 or R2) or involvement to 5) in 12 patients (13.2%), cisplatin (80 mg/m on day 1) of the uppermost mediastinal lymph node. Thirty two patients plus vinorelbine (30 mg/m on days 1 and 8) in 45 patients (38.1%) received two to three cycles of adjuvant chemotherapy (49.5%) and cisplatin (80 mg/m on day 1) plus gemcitabine with cisplatin plus vinorelbine or cisplatin plus gemcitabine. (1000 mg/m on days 1 and 8) in 34 patients (37.3%). Three patients received one cycle of chemotherapy, 76 received Survival two cycles of chemotherapy, 12 received three cycles of chemotherapy. Twenty nine patients (31.9%) with N2-bulky The median follow-up time was 43 months. The median survival disease, defi ned as multiple lymph node involvement on a time from the date of starting neo adjuvant chemotherapy CT scan with a minimal greatest dimension of two cm and for all patients in this study was 26 months (95% CI, 21.6- with radiologic signs of extra capsular extension, underwent 30.8 months), and the one-, three-, and fi ve-year survival rates preoperative sequential (n = 13) or concurrent (n = 16) was 86.1%, 31.6% and 20.9%, respectively. Forty seven (74.6%) chemoradiotherapy. The sequential chemotherapy consisted of 63 patients who achieved a complete resection were known of two cycles of chemotherapy with cisplatin plus etoposide to have experienced a recurrence. The recurrence was loco Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 203 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients regional in 16 patients (34%), distant in 24 patients (51.1%), and Table 2: Univariate analysis of factors infl uencing both loco regional and distant in seven patients (14.9%). Sites of survival by log-rank test distant metastases included brain (n is equal to 12), bone (n is Variables Overall survival P equal to 10), liver (n is equal to fi ve), adrenal glands (n is equal Median 1-year 3-years 5-years (months) (%) (%) (%) to two) and contra lateral lung (n is equal to two). Sex Male 28 86.3 31.4 20.9 0.593 For the purposes of analysis, the squamous cell carcinoma Female 30 90.5 33.3 28.6 patients were considered as one group, and the other patients Initial clinical stage who predominantly had ademocarcinoma were considered T1-2 N2 32 88.9 44.4 29.2 0.324 nonsquamous. The results of univariate analysis of prognostic T3 N2 27 86.7 26.7 22.0 factors for survival are shown in Table 2. Factors correlated with Histology improved survival were clinical response (PR and CR), complete Squamous cell 29 87.9 36.4 23.9 0.772 resection (R0), pathologic response of tumor (pCR and pPR), carcinoma and lymph nodal down staging (N1 and N0). Patients who had Nonsquamous cell 28 84.6 35.9 22.2 carcinoma clinical complete or partial response to neo adjuvant therapy Radiotherapy had a 30-month median survival compared with 23 months for Yes 30 86.4 35.3 29.4 0.164 patients with stable disease and progressive disease [P = 0.032, No 28 81.1 27.7 12.4 Figure 1]. The patients with complete resection had a median Clinical response survival of 30 months compared with 21 months for patients CR and PR 30 92.1 42.1 36.4 0.032 with incomplete resection [P = 0.002, Figure 2]. Pathologic SD and PD 23 71.4 19.2 9.5 complete and partial response was associated with 36 months Type of surgery Pneumonectomy 25 84.2 26.3 10.5 0.129 median survival, compared with 23 months in patients with Lobectomy and 29 88.7 35.8 28.1 pathologic no change in surgical specimens [P < 0.001, Figure 3]. bilobectomy The median survival for patients with N1 and N0 disease was Extent of resection 37 months compared with 27 months for patients with residual Complete resection 30 94.3 41.5 31.8 0.002 N2 disease [P = 0.001, Figure 4]. Survival was not infl uenced Incomplete 21 68.4 21.1 0 by sex, initial clinical stage, histology, chemotherapy regimen, resection adjunction of radiotherapy, type of resection, and postoperative Pathologic response chemotherapy. Factors that demonstrated prognostic pCR and pPR 36 95.2 50.0 40.2 <0.001 pNC 23 76.7 10.0 0 signifi cance by univariate analysis were then examined in a Lymph nodal multivariate analysis. Analysis of Cox regression model showed downstaging that extent of surgical resection (P = 0.001), pathologic response N0 and N1 37 95.5 54.5 49.1 0.001 of tumor (P < 0.001), and lymph nodal down staging (P = 0.048) N2 27 82.0 28.0 11.4 were independent prognostic factors [Table 3]. Adjuvent chemotherapy Discussion Yes 29 96.2 38.5 18.5 0.912 No 27 82.6 34.8 28.1 CR-Complete response; PR-Partial response; SD-Stable disease; Although neo adjuvant chemotherapy is considered a PD-Progressive disease; pCR-Pathologic complete response; pPR-Pathologic standard of treatment in patients with resectable stage IIIA partial response; pNC- Pathologic no change NSCLC in the updated guideline of the European Society [17] of Medical Oncology, there are still many controversial Table 3: Multivariate analysis of prognostic factors by opinions on the optimal approach of locally advanced N2 Cox regression model disease. During the last 10-15 years, many phase II trials Variables Hazard 95%CI P had suggested that neo adjuvant chemotherapy with or radio without radiotherapy followed by surgery was feasible and Clinical response 1.095 0.824-1.372 0.367 tolerable, and can improve surgical resectability and survival (CR and PR versus SD and PD) [5-7,18,19] for stage IIIA N2 NSCLC. Moreover, the response Extent of resection 2.869 1.556-5.288 0.001 rate to neo adjuvant chemotherapy in patients with stage III (Complete versus incomplete and early stage disease as well as good performance status resection) Pathologic tumor response 3.295 1.827-5.943 <0.001 were signifi cantly higher than those patients with advanced [18,19] (pCR and pPR versus pNC) stage IV NSCLC. However, the signifi cant variability in Lymph nodal downstaging 2.074 1.007-4.267 0.048 designs of these trials resulted in discrepancy of results and (N1 and N0 versus N2) variable survival data reported. Recent studies have analyzed CI-Confi dence interval; CR-Complete response; PR-Partial response; prognostic factors for long-term survival in patients with SD-Stable disease; PD-Progressive disease; pCR-Pathologic complete locally advanced NSCLC underwent surgery following neo response; pPR-Pathologic partial response; pNC-Pathologic no change [19-23] adjuvant therapy. In the present study, we examined the [19] [20] by Lorent et al. and Betticher et al. The study by Lorent prognostic factors and the outcome of patients with stage IIIA et al. showed that patients who achieved complete resection N2 NSCLC and treated with neo adjuvant chemotherapy after neo adjuvant chemotherapy had an median survival of with or without radiotherapy followed by surgery. In 58 months, with fi ve-year survival rate of 38.6%, compared univariate analysis, survival was signifi cantly infl uenced by the clinical response (P = 0.032) or surgical complete resection with 17 months and zero per cent, respectively, in those (P = 0.002). These results are consistent with trials reported patients who had incomplete resection (P = 0.004). Pathologic 204 Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients Figure 1: Kaplan-Meier survival curve according to respone to neo adjuvant Figure 2: Kaplan-Meier survival curve according to extent of surgical chemotherapy; (Complete response and partial response versus stable and resection; (Complete resection versus incomplete resection, log rank test: progressive disease, log rank test: P = 0.032) P = 0.002) Figure 3: Kaplan-Meier survival curve according to pathologic response; Figure 4: Kaplan-Meier survival curve according to lymph nodular status; (N0 (Pathologic complete response and partial response versus pathologic no or N1 disease versus N2 disease, log rank test: P = 0.001) change, log rank test: P < 0.001) tumor response (P < 0.001) and lymph nodal down staging advanced NSCLC after neo adjuvant treatment. (P = 0.001) had also been identifi ed as strong predictors of survival on our univariate analysis. The female sex and early tumor stage (smaller tumor size) have been associated with better survival prognosis in previous [23,24] [20] Further, we found that patients with single lymph node studies but not in our analysis. Betticher et al. in a trial show involvement had signifi cantly higher rate of down staging that histology (squamous cell carcinoma) correlated with a better when compared with patients with multiple lymph nodes, pathologic response to neo adjuvant chemotherapy while the which may be due to less tumor burden in the former. impact of histology on survival prognosis remains undefi ned. [21] A study by Thomas et al. demonstrated that the degree of The same results were found in our study. Just like some tumor regression examined in the resection specimens was reports analyzing predictive prognosis factors to neo adjuvant [23,25] predictive for survival, the median survival of 36 months versus therapy, we failed to fi nd substantial difference in survival 14 months for tumor regression >90% compared with tumor rate of patients using combined radiotherapy and chemotherapy regression less than or equal to 90% patients, and three-year as compared with those using neo adjuvant chemotherapy alone. survival rates of 48% versus nine per cene (P = 0.02). The SWOG It is possible that the addition of radiotherapy to neo adjuvant [22] study showed 30-month median survival for patients with chemotherapy may not affect survival because it eradicates loco N0 and N1 disease compared with 10 months for N2 disease regional tumor without treating systemic disease, which is the with a three-year survival rate of 44 versus 18% (P < 0.001). main cause of death in this patient population. Some investigators Though these trials included patients with stage IIIB disease reported that pneumonectomy was signifi cantly associated with and thoracic radiotherapy was given, it indicated that the a shorter survival when compared with other types of resection [23,25] degree of pathologic response and lymph nodal down staging (lobectomy and bilobectomy). However, we did not confi rm can signifi cantly infl uence survival in patients with locally a signifi cant long-term adverse infl uence of pneumonectomy. Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 205 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients The reason for this discrepancy could be patient selection for current knowledge about the outcome of locally advanced performing pneumonectomy and small sample size. NSCLC patients submitted to neo adjuvant therapy, and may help in guiding standard clinical practice. 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Okada M, Tsubata N, Yoshimura M, Migamoto Y, Matsnoka H. cancer: A multicenter phase II trial. J Clin Oncole 2003;21:1752-9. Induction therapy for non-small cell lung cancer with involved 21. Thomas M, Rube C, Semik M, von Eiff M, Freitag L, Macha HN, mediastinal nodes in multiple stations. Chest 2000;118:123-8. et al. Impact of preoperative bimodality induction including 29. Cappuzzo F, Selvaggi G, Gregorc V, Mazzoni F, Betti M, twice-daily radiation on tumor regression and survival in stage Migliorino MR, et al. Gemcitabine and cisplatin as induction III non-small-cell lung cancer. J Clin Oncol 1999;17:1185-93. chemotherapy for patients with unresectable stage IIIA-bulky 22. Albain KS, Rübe VW, Growley JJ, Rice TW, Turrisi AT, Weick JK, N2 and stage IIIB nonsmall cell lung carcinoma. Cancer et al. Concurrent cisplatin/etoposide plus chest radiotherapy 2003;98:128- 34. followed by surgery for stage IIIA (N2) and IIIB non-small cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880-92. 23. Martin J, Ginsberg RJ, Venkatraman ES, Bains MS, Downey RJ, Source of Support: Nil, Confl ict of Interest: None declared. Korst RJ, et al. Long-term results of combined-modality Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 207 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Thoracic Medicine Pubmed Central

Prognostic factors and long term results of neo adjuvant therapy followed by surgery in stage IIIA N2 non-small cell lung cancer patients

Annals of Thoracic Medicine , Volume 4 (4) – May 1, 168

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Pubmed Central
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© Annals of Thoracic Medicine
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1817-1737
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1998-3557
DOI
10.4103/1817-1737.56010
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Abstract

Departments of Pulmonary Medicine, BACKGROUND: Prognosis of stage IIIA N2 non-small cell lung cancer (NSCLC) remains poor despite the changes in therapeutic strategies. Radiation Oncology, Thoracic Surgery, OBJECTIVES: To assess long term results of neo adjuvant therapy followed by surgery for patients with stage Pathology, Affi liated IIIA N2 NSCLC and to analyze factors infl uencing survival. Hospital of Jiangsu MATERIALS AND METHODS: The methods adopted include: Retrospective review of medical records of 91 University, Zhenjiang, patients with stage IIIA N2 NSCLC, who received neo adjuvant therapy followed by surgery; collection of information on demographic information, staging procedure, preoperative therapy, clinical response, type of resection, Jiangsu, China pathologic response of tumor, status of lymph nodes and adjuvant chemotherapy; survival analysis by Kaplan- Meier and calculation of prognostic factors using log-rank and Cox regression model. RESULTS: All patients received a platinum-based chemotherapy and 23 (29.1%) had an associated radiotherapy. Eighty four patients underwent thoracotomy. Median survival was 26 months (95%CI, 22.6-30.8 months) with three and fi ve year survival rates of 31.6 and 20.9%, respectively. Prognostic factors for survival on univariate analysis was clinical response (P = 0.032), complete resection (P = 0.002), pathologic tumor response (P < 0.001), and lymph nodal down staging (P = 0.001). Multivariate analyses identifi ed complete resection, pathologic tumor response and lymph nodal down staging as independent prognostic factors. CONCLUSION: Survival of patients with stage IIIA N2 NSCLC who received neo adjuvant therapy is signifi cantly infl uenced by clinical response, complete resection, pathologic tumor response, and lymph nodal down staging. These results can be helpful in guiding standard clinical practice and evaluating the outcome of neo adjuvant therapy followed by surgery in patients with stage IIIA N2 NSCLC. Key words: Neo adjuvant therapy, non-small cell lung cancer, prognostic factor, stage IIIA, surgery, survival tage IIIA N2 non-small cell lung cancer surgery compared with surgery alone for [8-11] S(NSCLC) with involvement of ipsilateral stage IIIA NSCLC. However, a phase III mediastinal N2 represents a heterogeneous randomized trial reported by Nagai et al. failed group of patients. For patients with this locally to demonstrate any benefit of neo adjuvant advanced disease, five-year survival rate chemotherapy followed by surgery over surgery [12] after surgery or radiotherapy alone is only alone. In another phase III trial in resectable approximately 10%; majority of the patients stages I (except T1 N0), II and IIIA NSCLC [1,2] died of distant metastases. This observation patients, neo adjuvant chemotherapy failed to Address for [13] correspondence: led to attempts to improve survival by adopting improve survival of stage IIIA N2 patients. Prof. Jian Li, combined modality approaches such as neo Inconsistency of results from randomized trials Department of Pulmonary adjuvant chemotherapy followed by surgery assessing neo adjuvant chemotherapy for stage Medicine, Affi liated and/or radiotherapy. The rationale for using IIIA NSCLC is due to small sample sizes, short Hospital of Jiangsu neo adjuvant chemotherapy for the treatment follow-up periods, and unacceptable toxicity University, No. 438 of stage IIIA NSCLC is based on evidence that for certain of the chemotherapy regimens North Jiefang Road, Zhenjiang, 212001, chemotherapy can reduce tumor burden which administered. To date, management of stage Jiangsu, China. could facilitate surgery, improve resectability and IIIA N2 NSCLC is controversial, and there is no E-mail: lijian541226@163. eradicate micrometastases to prevent systemic agreement about the best approach to patients com [3,4] relapse. Several phase II trials show the with involvement of ipsilateral mediastinal role of neo adjuvant chemotherapy in patients lymph node. Because of the demonstrated [5-7] [14] with locally advanced NSCLC. Two small heterogeneity in this patient population, it is S Submission: ubmission: 24-05-09 24-05-09 randomized trials suggest a prolonged survival not yet clear for which subset of these patients A Accepted: ccepted: 26-07-09 26-07-09 D DOI: OI: ***** ***** for neo adjuvant chemotherapy followed by this therapeutic strategy (neo adjuvant therapy Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 201 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients followed by surgery) will be most rewarding. The identifi cation found on fi nal pathologic review, were classifi ed as microscopic of prognostic factors could be useful for better selection of incomplete resection (R1). Gross residual disease after surgical therapy and design of future randomized trials. resection was classifi ed as macroscopic incomplete resection (R2). Pathologic response, status of lymph node, operative In this study, we review our experience between 1998 and 2004, morbidity and mortality and postoperative treatment when to analyze prognostic factors and better defi ne the long-term appropriate were recorded. survival of Chinese patients with stage IIIA NSCLC treated with neo adjuvant therapy followed by surgery. Pathologic response of primary tumor was examined using [16] criteria reported by de Bore et al. Pathologic complete response (pCR) was defi ned as absence of any tumor in the Materials and Methods surgical specimen; partial response (pPR) was defined as the presence of only small residual foci of tumor cells, or the Patients presence of signifi cant areas of tumor necrosis throughout the Medical records of all patients with stage IIIA N2 NSCLC surgical specimen; no change (pNC) was defi ned as the presence who underwent surgery following neo adjuvant therapy at of large area of identifi able tumor cells in the surgical specimen our hospital were reviewed retrospectively for the period with minimal evidence of tumor necrosis. Nodal status from January 1998 to October 2004. We limited our analyses classifi cation was determined from a postoperative pathologic to patients who had been clinically staged as IIIA N2 disease examination. Down staging was defi ned as complete fi brosis, and received platinum-based neo adjuvant chemotherapy (with scar, or granulation of lymph nodes, with neither normal nodal or without radiotherapy) including patients who underwent formation nor cancer cell in the surgical specimen. Patients thoracotomy, had a clinical response and stable disease as well with normal nodal formation in ipsilateral mediastinum were as patients who were not operated upon due to progressive excluded from the study. Operative morbidity was defi ned as disease. Hence the patients who achieved surgical resection any event occurring during the fi rst 30 days following surgery. had completely postoperative pathologic information. Data recorded included demographic information, staging Statistical analysis procedures and pretreatment clinical stage. All patients were Overall survival was calculated from the fi rst cycle of neo staged on the basis of history, physical examination, chest adjuvant chemotherapy to the date of death or date of last X-ray, bronchoscopy, brain and chest computed tomography follow-up. Survival data was last collected in May 2008. (CT) scan, abdominal ultrasound or abdominal CT scan, Survival curve were estimated using the Kaplan-Meier method. radionuclide bone scan. Tumors were staged according to the [15] The following variables were considered potentially prognostic revised version of TNM staging published in August 1997. variables for survival: Sex, initial tumor stage, histology, chemotherapy regimen, adjunction of radiotherapy, clinical Criteria for pretherapy diagnosis of stage IIIA NSCLC with response to neo adjuvant therapy, type of surgery, extent of clinical N2 (cN2) were defi ned as a mediastinal node of short surgical resection, pathologic tumor response, status of lymph axis diameter exceeding 15mm on CT scan. Cases with a node, and adjuvant chemotherapy. diameter between 10 and 14mm were included only of there was more than one node. Patients with N3 disease revealed Log-rank analysis was used for univariate analysis for by CT scan were excluded from this study. This study was signifi cant prognostic factor. Cox regression model was used approved by the Ethics Committee of Affi liated Hospital of for the multivariable analysis of independent prognostic Jiangsu University in China. factor. Statistical analysis was performed using the SPSS V10.0 software package (SPSS Inc., Chicage, Illinois). Patient treatment and assessment Data on chemotherapy regimen, number of cycles, radiotherapy and clinical response to neo adjuvant therapy, surgical Results procedure and site of the fi rst cancer recurrence post-operation was collected. After completion of neo adjuvant therapy, chest Patient characteristics CT scan was repeated for all patients to assess the clinical From January 1998 to October 2004, 105 patients received neo response to therapy and feasibility for surgery. Brain CT adjuvant therapy for stage IIIA N2 NSCLC at our hospital. Of and bone scan were repeated if clinically indicated. Patient’s these, 91 had detailed clinical and follow-up data and were responses to chemotherapy were categorized as complete, assessable and eligible for this study. The remaining patients partial response, stable or progressive disease according to were not assessable for the following reasons: No available World Health Organization (WHO) criteria. data due to loss to follow-up (n=six), use of nonplatinum chemotherapy regime (n=four), patient refusal for surgery Patients who had a clinical response and stable disease received after neo adjuvant therapy (n=four). The patient characteristics thoracotomy. The extent of the performed pulmonary resection and treatment information are listed in Table 1. There were was left to the discretion of the attending surgeon based on the 66 men and 25 women in the group. The median age was intraoperative assessment of the residual disease. All accessible 59 years (range 38-70 years). Thirteen, 40, and 38 cases were hilar lymph nodes were dissected from the specimen, and a classifi ed as T1N2M0, T2N2M0, and T3N2M0, respectively. complete mediastinal lymph node dissection was performed Forty two and 49 cases were identifi ed as single and multiple for all patients. A complete resection (R0) was defi ned as lymph node involvement, respectively, according to pretherapy pathologic demonstration of negative tissue margins and CT scan. Examination of bronchoscopic biopsy and brushing all detectable disease had been removed. Patients who had (73 patients) or percutaneous needle aspiration specimens a complete gross resection, in whom positive margins were (18 patients) were performed to determine the histologic 202 Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients Table 1: Patient characteristics and treatment or cisplatin plus vinorelbine at a 21-day treatment cycles. The following radiotherapy commenced three weeks after the start Characteristic No. of patients % of the second cycles of chemotherapy with a total irradiation (n = 91) dose ranging from 40 to 50 Gy (a dose of 2.0 Gy administered Sex Male 66 72.5 daily, fi ve days per week). The concurrent chemoradiotherapy Female 25 27.5 consisted of two cycles of cisplatin (30 mg/m on days 1, 8, and Age (yr) 2 15) plus etoposide (50 mg/m on days 1 to 5) with concurrent, Median 59 continuous chest radiotherapy, which began on day 1 of Range 38-70 chemotherapy with a dose of 1.8 or 2.0 Gy daily, fi ve days per Initial tumor stage week at the total dose ranging from 40 to 45 Gy. T1N2M0 13 14.3 T2N2M0 40 44 The radiotherapy fi eld included the primary tumor with 1.5 cm T3N2M0 38 41.7 Histology margin, the ipsilateral pulmonary hilum, upper and median Squamous cell carcinoma 40 44 mediastinal lymph nodes. Clinical response to neo adjuvant Adenocarcinoma 44 48.4 therapy is summarized in Table 1. Six patients (6.6%) achieved Large cell carcinoma 4 4.4 a complete response, 36 patients (39.6%) obtained a partial Undifferentiated NSCLC 3 3.2 response, and 42 patients (46.2%) had stable disease, and seven Chemotherapy regimen patients (7.7%) had progressive disease. The overall response EP 12 13.2 rate was 46.2%. NP 45 49.5 GP 34 37.3 Thoracic radiotherapy Surgical treatment Yes 29 31.9 Eighty four patients who had a clinical response and stable No 62 68.1 disease underwent thoracotomy. Seven patients experienced Clinical response progressive disease received radiotherapy and further Complete response 6 6.6 chemotherapy. Type of surgical resection included lobectomy Partial response 36 39.6 (n = 45), bilobectomy (n = 15), and pneumonectomy (n = 24). Stable disease 42 46.1 A complete resection (R0) was achieved in 63 patients (75%), Progressive disease 7 7.7 Type of operation (n = 84) an R1 in 15 patients (17.9%), and an R2 in six patients (7.1%). Lobectomy 45 53.6 The operative mortality rate was 2.4% (2/84). Thirteen patients Biolobectomy 15 17.8 (15.5%) had a non-lethal postoperative complication that Pneumonectomy 24 28.6 included arrhythmia (n is equal to three), pneumonia (n is Pathologic response of tumor equal to three), bronchopleural fi stula (n is equal to two), (n = 84) heart failure (n is equal to two), prolonged air leak (n is Complete response 8 9.5 equal to two), and chylothorax (n is equal to one). Pathologic Partial response 41 48.8 complete response of primary tumor (pCR) was found in eight No change 35 41.7 Pathologic lymph node status patients (9.5%), including fi ve patients with squamous cell (n = 84) carcinoma and three patients with adenocarcinoma, pPR was N2 56 66.7 seen in 41 patients (48.8%), pNC was recorded in 35 patients N1 18 21.4 (41.7%). pathologic responses were not entirely consistent with N0 10 11.9 clinical response. Eighteen patients were down staged to N1, EP-Etoposide and cisplatin; NP-Vinorelbine and cisplatin; GP-Gemcitabine 10 patients were down staged to N0, and 56 patients remained and cisplatin N2 positive at operation. Down staging was seen in 20 (48%) of the 42 patients with single lymph node involvement and eight types. Forty four patients had adenocarcinoma, 40 patients (16%) of 49 patients with multiple lymph node involvement. had squamous cell carcinoma, four had large cell carcinoma, The proportion of down staging in patients with single lymph and three had undifferentiated NSCLC. node involvement was signifi cantly higher than patients with multiple lymph node involvement (P = 0.019). Fifteen patients Neo adjuvant treatment had subcarinal lymph node involvement. Postoperative The neo adjuvant chemotherapy regimen consisted of cisplatin 2 2 radiotherapy was administered on 17 out of 21 patients who (80 mg/m on day 1) plus etoposide (100 mg/m on days 1 either had an incomplete resection (R1 or R2) or involvement to 5) in 12 patients (13.2%), cisplatin (80 mg/m on day 1) of the uppermost mediastinal lymph node. Thirty two patients plus vinorelbine (30 mg/m on days 1 and 8) in 45 patients (38.1%) received two to three cycles of adjuvant chemotherapy (49.5%) and cisplatin (80 mg/m on day 1) plus gemcitabine with cisplatin plus vinorelbine or cisplatin plus gemcitabine. (1000 mg/m on days 1 and 8) in 34 patients (37.3%). Three patients received one cycle of chemotherapy, 76 received Survival two cycles of chemotherapy, 12 received three cycles of chemotherapy. Twenty nine patients (31.9%) with N2-bulky The median follow-up time was 43 months. The median survival disease, defi ned as multiple lymph node involvement on a time from the date of starting neo adjuvant chemotherapy CT scan with a minimal greatest dimension of two cm and for all patients in this study was 26 months (95% CI, 21.6- with radiologic signs of extra capsular extension, underwent 30.8 months), and the one-, three-, and fi ve-year survival rates preoperative sequential (n = 13) or concurrent (n = 16) was 86.1%, 31.6% and 20.9%, respectively. Forty seven (74.6%) chemoradiotherapy. The sequential chemotherapy consisted of 63 patients who achieved a complete resection were known of two cycles of chemotherapy with cisplatin plus etoposide to have experienced a recurrence. The recurrence was loco Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 203 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients regional in 16 patients (34%), distant in 24 patients (51.1%), and Table 2: Univariate analysis of factors infl uencing both loco regional and distant in seven patients (14.9%). Sites of survival by log-rank test distant metastases included brain (n is equal to 12), bone (n is Variables Overall survival P equal to 10), liver (n is equal to fi ve), adrenal glands (n is equal Median 1-year 3-years 5-years (months) (%) (%) (%) to two) and contra lateral lung (n is equal to two). Sex Male 28 86.3 31.4 20.9 0.593 For the purposes of analysis, the squamous cell carcinoma Female 30 90.5 33.3 28.6 patients were considered as one group, and the other patients Initial clinical stage who predominantly had ademocarcinoma were considered T1-2 N2 32 88.9 44.4 29.2 0.324 nonsquamous. The results of univariate analysis of prognostic T3 N2 27 86.7 26.7 22.0 factors for survival are shown in Table 2. Factors correlated with Histology improved survival were clinical response (PR and CR), complete Squamous cell 29 87.9 36.4 23.9 0.772 resection (R0), pathologic response of tumor (pCR and pPR), carcinoma and lymph nodal down staging (N1 and N0). Patients who had Nonsquamous cell 28 84.6 35.9 22.2 carcinoma clinical complete or partial response to neo adjuvant therapy Radiotherapy had a 30-month median survival compared with 23 months for Yes 30 86.4 35.3 29.4 0.164 patients with stable disease and progressive disease [P = 0.032, No 28 81.1 27.7 12.4 Figure 1]. The patients with complete resection had a median Clinical response survival of 30 months compared with 21 months for patients CR and PR 30 92.1 42.1 36.4 0.032 with incomplete resection [P = 0.002, Figure 2]. Pathologic SD and PD 23 71.4 19.2 9.5 complete and partial response was associated with 36 months Type of surgery Pneumonectomy 25 84.2 26.3 10.5 0.129 median survival, compared with 23 months in patients with Lobectomy and 29 88.7 35.8 28.1 pathologic no change in surgical specimens [P < 0.001, Figure 3]. bilobectomy The median survival for patients with N1 and N0 disease was Extent of resection 37 months compared with 27 months for patients with residual Complete resection 30 94.3 41.5 31.8 0.002 N2 disease [P = 0.001, Figure 4]. Survival was not infl uenced Incomplete 21 68.4 21.1 0 by sex, initial clinical stage, histology, chemotherapy regimen, resection adjunction of radiotherapy, type of resection, and postoperative Pathologic response chemotherapy. Factors that demonstrated prognostic pCR and pPR 36 95.2 50.0 40.2 <0.001 pNC 23 76.7 10.0 0 signifi cance by univariate analysis were then examined in a Lymph nodal multivariate analysis. Analysis of Cox regression model showed downstaging that extent of surgical resection (P = 0.001), pathologic response N0 and N1 37 95.5 54.5 49.1 0.001 of tumor (P < 0.001), and lymph nodal down staging (P = 0.048) N2 27 82.0 28.0 11.4 were independent prognostic factors [Table 3]. Adjuvent chemotherapy Discussion Yes 29 96.2 38.5 18.5 0.912 No 27 82.6 34.8 28.1 CR-Complete response; PR-Partial response; SD-Stable disease; Although neo adjuvant chemotherapy is considered a PD-Progressive disease; pCR-Pathologic complete response; pPR-Pathologic standard of treatment in patients with resectable stage IIIA partial response; pNC- Pathologic no change NSCLC in the updated guideline of the European Society [17] of Medical Oncology, there are still many controversial Table 3: Multivariate analysis of prognostic factors by opinions on the optimal approach of locally advanced N2 Cox regression model disease. During the last 10-15 years, many phase II trials Variables Hazard 95%CI P had suggested that neo adjuvant chemotherapy with or radio without radiotherapy followed by surgery was feasible and Clinical response 1.095 0.824-1.372 0.367 tolerable, and can improve surgical resectability and survival (CR and PR versus SD and PD) [5-7,18,19] for stage IIIA N2 NSCLC. Moreover, the response Extent of resection 2.869 1.556-5.288 0.001 rate to neo adjuvant chemotherapy in patients with stage III (Complete versus incomplete and early stage disease as well as good performance status resection) Pathologic tumor response 3.295 1.827-5.943 <0.001 were signifi cantly higher than those patients with advanced [18,19] (pCR and pPR versus pNC) stage IV NSCLC. However, the signifi cant variability in Lymph nodal downstaging 2.074 1.007-4.267 0.048 designs of these trials resulted in discrepancy of results and (N1 and N0 versus N2) variable survival data reported. Recent studies have analyzed CI-Confi dence interval; CR-Complete response; PR-Partial response; prognostic factors for long-term survival in patients with SD-Stable disease; PD-Progressive disease; pCR-Pathologic complete locally advanced NSCLC underwent surgery following neo response; pPR-Pathologic partial response; pNC-Pathologic no change [19-23] adjuvant therapy. In the present study, we examined the [19] [20] by Lorent et al. and Betticher et al. The study by Lorent prognostic factors and the outcome of patients with stage IIIA et al. showed that patients who achieved complete resection N2 NSCLC and treated with neo adjuvant chemotherapy after neo adjuvant chemotherapy had an median survival of with or without radiotherapy followed by surgery. In 58 months, with fi ve-year survival rate of 38.6%, compared univariate analysis, survival was signifi cantly infl uenced by the clinical response (P = 0.032) or surgical complete resection with 17 months and zero per cent, respectively, in those (P = 0.002). These results are consistent with trials reported patients who had incomplete resection (P = 0.004). Pathologic 204 Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients Figure 1: Kaplan-Meier survival curve according to respone to neo adjuvant Figure 2: Kaplan-Meier survival curve according to extent of surgical chemotherapy; (Complete response and partial response versus stable and resection; (Complete resection versus incomplete resection, log rank test: progressive disease, log rank test: P = 0.032) P = 0.002) Figure 3: Kaplan-Meier survival curve according to pathologic response; Figure 4: Kaplan-Meier survival curve according to lymph nodular status; (N0 (Pathologic complete response and partial response versus pathologic no or N1 disease versus N2 disease, log rank test: P = 0.001) change, log rank test: P < 0.001) tumor response (P < 0.001) and lymph nodal down staging advanced NSCLC after neo adjuvant treatment. (P = 0.001) had also been identifi ed as strong predictors of survival on our univariate analysis. The female sex and early tumor stage (smaller tumor size) have been associated with better survival prognosis in previous [23,24] [20] Further, we found that patients with single lymph node studies but not in our analysis. Betticher et al. in a trial show involvement had signifi cantly higher rate of down staging that histology (squamous cell carcinoma) correlated with a better when compared with patients with multiple lymph nodes, pathologic response to neo adjuvant chemotherapy while the which may be due to less tumor burden in the former. impact of histology on survival prognosis remains undefi ned. [21] A study by Thomas et al. demonstrated that the degree of The same results were found in our study. Just like some tumor regression examined in the resection specimens was reports analyzing predictive prognosis factors to neo adjuvant [23,25] predictive for survival, the median survival of 36 months versus therapy, we failed to fi nd substantial difference in survival 14 months for tumor regression >90% compared with tumor rate of patients using combined radiotherapy and chemotherapy regression less than or equal to 90% patients, and three-year as compared with those using neo adjuvant chemotherapy alone. survival rates of 48% versus nine per cene (P = 0.02). The SWOG It is possible that the addition of radiotherapy to neo adjuvant [22] study showed 30-month median survival for patients with chemotherapy may not affect survival because it eradicates loco N0 and N1 disease compared with 10 months for N2 disease regional tumor without treating systemic disease, which is the with a three-year survival rate of 44 versus 18% (P < 0.001). main cause of death in this patient population. Some investigators Though these trials included patients with stage IIIB disease reported that pneumonectomy was signifi cantly associated with and thoracic radiotherapy was given, it indicated that the a shorter survival when compared with other types of resection [23,25] degree of pathologic response and lymph nodal down staging (lobectomy and bilobectomy). However, we did not confi rm can signifi cantly infl uence survival in patients with locally a signifi cant long-term adverse infl uence of pneumonectomy. Annals of Thoracic Medicine - Vol 4, Issue 4, October-December 2009 205 Li, et al.: Prognosis of stage IIIA N2 NSCLC patients The reason for this discrepancy could be patient selection for current knowledge about the outcome of locally advanced performing pneumonectomy and small sample size. NSCLC patients submitted to neo adjuvant therapy, and may help in guiding standard clinical practice. 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A randomized trial comparing induction chemotherapy followed They also used lymph node size on CT scan as staging criteria. by surgery with surgery alone for patients with stage IIIA N2 Furthermore, in the present study, N2 status was determined non-small-cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003;125:254-60. fi nally according to the post-operative pathologic examination 13. Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, of mediastinal lymph nodes. Pathologic fi nding indicating Lebeau B, et al. Preoperative chemotherapy followed by surgery complete fibrosis, scar, or granulation of lymph nodes, compared with primary surgery in resectable stage I (except T1 with neither normal nodal formation nor cancer cell, meant N0) II and IIIa non-small lung cancer. J Clin Oncol 2002;20:247-53. pathologic complete response of lymph nodes (down staging). 14. Andre F, Grunenwald D, Pignon J-P, Dujon A, Pujol JL, Therefore, N2 status can be determined at least in patients who Brichon PY, et al. Survival of patients with resectable N2 achieved surgical resection. non- small-cell lung cancer: Evidence for a subclassifi cation and implication. J Clin Oncol 2000;18:2981-9. The most important factor to judge a study on neo adjuvant 15. Mountain CF. Revisions in the international system for staging therapy is long-term survival. Our results confi rm that clinical lung cancer. Chest 1997;111:171-7. response, surgical complete resection, pathologic response 16. de Boer RH, Smith IE, Pastorino LL, O’Brien MER, Ramage F, of tumor and lymph nodal down staging after neo adjuvant Ashley S, et al. Pre-operative chemotherapy in early stage therapy for stage IIIA NSCLC, are the prognostic factors resectable non-small-cell lung cancer: A randomized feasibility identifi ed as infl uencing survival. 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Annals of Thoracic MedicinePubmed Central

Published: May 1, 168

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