A Phase II Single-Institution Study of Neoadjuvant Stage III A/B Chemotherapy and Radiochemotherapy in Non-Small Cell Lung Cancer

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1 A Phase II Single-Institution Study of Neoadjuvant Stage III A/B Chemotherapy and Radiochemotherapy in Non-Small Cell Lung Cancer Andreas Granetzny, MD, Eberhard Striehn, MD, Ulrich Bosse, MD, Wolfgang Wagner, MD, Olaf Koch, MD, Ulf Vogt, PhD, Peter Froeschle, MD, and Folker Klinke, MD Department of Thoracic Surgery, Ostercappeln, Institute of Pathology, Osnabrueck, Department of Radiation Therapy, Osnabrueck, Department of Hematology and Oncology, Osnabrueck, European Laboratory Association, Ibbenbueren, and Department of Thoracic Surgery, Duisburg, Germany GENERAL THORACIC Background. The relevance of a trimodal strategy in the treatment of lung cancer, consisting of neoadjuvant radiochemotherapy followed by surgery, is a subject of ongoing clinical trials. We tested whether improvement of long-term survival can be achieved for patients with stage III non-small cell lung cancer by this therapeutic approach. Methods. We performed a retrospective analysis of a single-institution phase II study. Of 33 patients enrolled in the protocol between 1992 and 1995, we reviewed the clinical outcomes of 26 patients with locally advanced non-small cell lung cancer (stage III A and III B ), which had been resected after combined chemotherapy and radiochemotherapy. Results. After neoadjuvant therapy, resection of the tumor was accomplished in all patients, and R0 resection was achieved in 92%. Histologic remission was found in 76% of these patients. Involvement of mediastinal lymph nodes was crucially important for the outcome. First, histologic clearance of the mediastinal compartment by neoadjuvant therapy resulted in a 27% 5-year survival rate. Second, patients with viable tumor in any of the mediastinal lymph nodes removed had a poor outcome (median survival 11.4 and 34.7 months in patients with and without viable tumor cells in the specimens, respectively; p 0.01). Conclusions. Histopathologic regression after neoadjuvant multimodal therapy including chemotherapy and radiotherapy was an important prognostic factor in a selected group of patients with locally advanced lung cancer. (Ann Thorac Surg 2003;75: ) 2003 by The Society of Thoracic Surgeons For a long time patients with bulky non-small cell lung cancer (NSCLC) or extensive nodal involvement (stage III) were considered ineligible for surgical intervention. Consequently, those patients were treated exclusively with radiation therapy as a definitive treatment. By introducing the concept of neoadjuvant therapy, chemotherapy and irradiation were adopted to shrink gross mediastinal tumor masses thus allowing complete resection of all of the initial manifestations of the tumor [1]. As emphasized by Green and Barkley [2], preoperative (or induction) therapy may have the advantage of being more effective before the emerging of clonal selection, thus preventing the occurrence of tumor cells not responding to chemotherapy. However, neoadjuvant therapy has been controversial. First, tumor progression can occur because of delayed surgery. Second, systemic toxicity might reduce the physical tolerance of the patients for subsequent resection; and third, intraoperative preparation may be affected by fibrosis, especially related to Accepted for publication Nov 1, Address reprint requests to Dr Granetzny, Department of Thoracic Surgery, Evangelisches Krankenhaus Duisburg-Nord, Fahrner Str. 133, Duisburg 47169, Germany; andreas.granetzny@ejk.de. radiation therapy [1]. Despite the well known disadvantages of multimodal therapy, surgery alone for treating stage III lung cancer can be justified only for highly selected patients [3]. As a result of these controversial issues, addressed by several investigators, ongoing trials are definitely required to define the most suitable sequence of multimodal therapy. Patients and Methods In a phase II study, between 1992 and 1995, 33 patients were treated by a protocol evaluating the feasibility of two courses of platinum-based chemotherapy, followed by radiochemotherapy and subsequent surgery. All patients were enrolled in the study according to the declaration of Helsinki. All patients underwent staging procedures, including radiologic imaging, bronchoscopy, and cervical mediastinoscopy. Patients with tumor involvement of the supraclavicular lymph nodes were excluded. Only patients with histologically proven NSCLC in stage III A und III B were eligible. Chemotherapy consisted of two courses of ifosfamide (1500 mg/m 2, days 1, 3, and 5), carboplatin (300 mg/m 2, 2003 by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Science Inc PII S (02)

2 GENERAL THORACIC 1108 GRANETZNY ET AL Ann Thorac Surg MULTIMODAL TREATMENT OF STAGE III A/B NSCLC 2003;75: Table 1. Preoperative and Postoperative Formula of the Primary Tumor (n 26) Tumor Classification Preoperative (c) Postoperative (p) T0 0 8 T T T3 8 0 T4 7 1 c clinical; p pathohistological. Fig 1. Postoperative tumor stage (n 26). day 1), and etoposide (100 mg/m 2, days 1, 3, 5), followed by combined radiochemotherapy with a total dose of 45 Gy applied twice daily (with a single dose of 1.5 Gy each), carboplatin (100 mg/m 2, days 1, 8, and 15), and vindesine (3 mg, days 1, 8, and 15) within a 3-week interval. After radiologic restaging, revealing at least a no change status, patients underwent thoracotomy. If surgery was not feasible because of insufficient tumor remission (7 patients) or in case of residual tumor burden (R2 resection; n 2), subsequent irradiation up to a total dose of 60 Gy was completed by conventional fractionation. The nonresponders to neoadjuvant therapy were treated further off-study. The 26 patients operated on were evenly distributed to stages III A and III B. Twenty-five patients were male, with a median age of 57 years (range, 43 to 69 years), and the only female patient was 64 years old. At the beginning of therapy, the Karnowsky index of all patients exceeded 70%. Histologic examination showed squamous cell carcinoma (n 12), adenocarcinoma (n 7), large cell carcinoma (n 5), and other types of NSCLC (n 2). With regard to the Union Internationale Contre le Cancer staging system [4], after computed tomographic imaging, bronchoscopy, and mediastinoscopy, lung cancers were staged as follows: T2N2 (n 7), T2N3 (n 3), T3N2 (n 6), T3N3 (n 3), T4N2 (n 5), and T4N3 (n 2). All of the patients with T4 tumors had tumor invasion of the mediastinum. The following operations were performed: pneumectomy (n 8, six of these extended pneumectomies including one right-sided sleeve pneumectomy), bilobectomy (n 5, two extended), and lobectomy (n 12, seven sleeve resections, two cases with additional segmentectomy, and one case with partial replacement of the superior vena cava). In a patient with poor pulmonary function, only segmental resection with additional partial Table 2. Preoperative and Postoperative Nodal State (n 26) Lymph Node Classification Preoperative (c) Postoperative (p) N N1 0 5 N N3 7 0 c clinical; p pathohistological. removal of the chest wall was feasible. In 24 patients, R0 resections with radical mediastinal lymph node dissection were accomplished. Two patients were left with macroscopic residual tumor (R2 resection). Change of T stage after operation was shown for 24 patients (Table 1). The same observation was made concerning nodal status: 26 patients had N2 or N3 disease preoperatively and only 10 patients postoperatively (Table 2). According to our inclusion criteria, all patients enrolled in the study had been classified preoperatively as stage III, but only 9 patients were classified postoperatively as stage III A (n 8) or III B (n 1), as shown in Figure 1. Complete histopathologic remission was observed in 8 patients (30.7%, tumor), 10 patients (38.5%, lymph nodes), and 6 patients (23%, tumor and lymph nodes). Classification of remission rates was performed according to a modified Salzer-Kuntschik technique, originally developed for the evaluation of neoadjuvant chemotherapy in osteogenic sarcoma [5]. Grades 1 to 3 were classified as responders, whereas grades 4 to 6 were considered nonresponders to neoadjuvant therapy. Seventy-six percent (n 25) were responders and 24% (n 8) were classified as nonresponders (Table 3). Using the Kaplan-Meier method [6] survival was estimated from date of operation. Comparison of survival of different discriminative factors was tested for significance by the log rank test [7]. Results The median survival time for all patients has been 15.4 months (range, 2.8 to months). The difference in survival of patients who had an operation compared with Table 3. Histopathological Remission Rate According to the Salzer-Kuntschik Classification [5] Grade Responder I 10 II 7 76% III 8 Nonresponder IV VI 1 Tumor progress, no surgery 7 n 24% Grade I no vital tumor cells; Grade II single tumor cells; Grade III less than 10 % vital tumor tissue; Grade IV 10% 50% vital tumor tissue; Grade V more than 50% vital tumor tissue; Grade VI no effect of chemotherapy. } }

3 Ann Thorac Surg GRANETZNY ET AL 2003;75: MULTIMODAL TREATMENT OF STAGE III A/B NSCLC 1109 GENERAL THORACIC Fig 2. Cumulative survival in clinical stage III A (solid line) and stage III B (dotted line). The difference between the two curves is not significant. those treated off-protocol with only chemotherapy and radiation was statistically significant (19.5 versus 8.4 months, respectively, p ). Of the 26 patients who had an operation after combined radiochemotherapy, 18 (69%) survived for 1 year, 11 (42%) for 2 years, and 7 (27%) for 5 years. The median survival time for patients with stage III A status was 24 months and for patients with stage III B status, 13 months. The difference between the two groups was not statistically significant (p 0.675) (Fig 2). In a multivariate analysis, we searched for factors that might affect survival of the patients who were operated on. No influence on survival was documented for age, histology, grading, or T status. The most important effect on survival was the extent of histopathologic regression of the mediastinal lymph nodes (p ). If the patient s mediastinal lymph nodes were free of tumor cells, these patients had a significantly better prognosis than the ones with remnant tumor (Fig 3). The remission rate of lymph nodes was scored according to the method of Salzer-Kuntschik and coworkers [5]. The median survival time for patients with grade I status postoperatively was 34.7 months (n 10). In contrast, patients with grade II status had a median survival time of 12.6 months (n 7). Patients with a grade III lymph node status (remaining viable tumor cells less than 10%) had a median survival time of 8.9 months (n 8). Only 1 patient was confirmed to have a grade IV status at the time of operation after combined trimodal treatment. At the time of investigation (accrual for protocol until May 1, 2001) with a median follow-up time of 32 months, 7 patients (27%) are still alive without any evidence of tumor relapse or metastatic disease, and all of them have an excellent performance status. For this subgroup, the Fig 3. Long-term survival and remission rates in mediastinal lymph nodes. The difference between the groups with and without malignant cells in the mediastinal lymph nodes was significant (log rank p ). Solid line no malignant cells in mediastinal lymph node (n 10); evenly dotted line malignant cells in mediastinal lymph node (n 16); and unevenly dotted line no operation (n 7). median survival time currently exceeds 90 months. Seven patients (27%) had a long-term survival of more than 60 months (stage III A n 4; stage III B n 3), and four patients (15%) had a long-term survival of more than 90 months. In 5 of those 7 patients there were no viable tumor cells in the mediastinal lymph nodes after dissection (grade I status). In 1 patient some residual tumor cells (grade II) were found, and in another patient less than 10% of tumor cells could be traced in the lymph nodes (grade III). Severe adverse effects during chemoradiotherapy included leucopenia in 4 patients (World Health Organization [WHO] grade III/IV) and thrombopenia in 3 patients (WHO grade III/IV). After radiotherapy, 3 patients had esophagitis (WHO grade III/IV), and 4 patients had clinical signs of pneumonitis. One patient died of pneumonitis resulting from irradiation on the 50th postoperative day. Another patient died on postoperative day 105 because of bronchial stump insufficiency, presumably as a result of postoperative irradiation. Two patients died of cardiac failure on day 32 and day 60. Neoadjuvant multimodal therapy affects the performance status of the patient and induces local inflammatory reactions of the tumor bed and surrounding tissues. Therefore surgical therapy of these patients remains a challenge.

4 GENERAL THORACIC 1110 GRANETZNY ET AL Ann Thorac Surg MULTIMODAL TREATMENT OF STAGE III A/B NSCLC 2003;75: Comment For most patients with advanced lung cancer the advent of multidisciplinary approaches has dramatically changed the treatment of these tumors. Long-term survival is conceivable for certain patients, who already have been identified and whose characteristics still have to be determined by multidisciplinary studies. At present, the most reliable predictor remains the TNM tumor stage [8]. Recently, a further prognostic factor, response to therapy, for combined modality treatment regimens has been evaluated [1]. The standard induction regimen, ie, the chemotherapy protocol and the schedule and type of fractionation of radiotherapy, have not been agreed upon yet. Several ongoing studies were performed with the aim of improving survival in locally advanced NSCLC [9 12]. Published data from clinical trials are difficult to analyze because of the heterogeneity of the different inclusion criteria of these multicenter studies. Several studies have been restricted either to stage III A or III B. The Southwest Oncology Group trial included both stage III A and III B [12], whereas the Rush-Presbyterian trial included patients with T3N0 tumors (now II B ) [13], and at the Dana Faber Institute patients with T3N0 tumors as well as N2 disease were enrolled [14]. Threeyear survival rates between 18% and 33% have been reported, and long-term survivors (more than 5 years) hardly exist [1]. Histopathologic Examination The two-dimensional evaluation of histopathologic remission according to Salzer-Kuntschik and colleagues has been modified (by U.B.) to a three-dimensional method. The remission rate was 76% (complete remission of tumor and lymph nodes in 23%). Histopathologic absence of tumor was also observed in 22% of resected specimens in the Rush-Presbyterian trial. The authors emphasized that this result did not correlate with the disappearance of disease shown by radiologic imaging [15]. That finding is in accordance with our own experience [16]. Consequently all patients without progression of disease on radiologic imaging should be considered for operation. Thus, staging thoracotomy is recommended to decide on tumor resectability. The strongest prognostic factor in our study is the histopathologic remission rate of mediastinal nodes. This finding is in accordance with the data of one of the largest phase II trials, the Southwest Oncology Group 8805 study, published by Albain and associates [9] and Rusch and colleagues [12]. They applied induction chemotherapy and concurrent irradiation therapy to 154 patients with stage III A and III B disease. Patients with a histologically complete response by the lymph nodes had a median survival of 30 months, compared with 10 months for those with persistent lymph node disease (p ). According to Albain and coworkers [9] the strongest predictor of long-term survival was the absence of tumor involvement in mediastinal nodes at the time of operation, with a 3-year survival rate of 44% versus 18% in those who had persistent nodal disease (p ). In our study, 26 patients were operated on, and complete resection was achieved in 24 (92%) patients. Twenty-seven percent of all resections were performed as parenchymal sparing sleeve resections because of poor pulmonary function. As in our institution, the rate of this type of operation does not exceed more than 10% even in large centers. It is well known to thoracic surgeons that radiation-induced vascular obliterations are likely to cause delayed healing of the bronchial anastomosis. For this reason, we performed histologic examinations of the small vessels at the resection margins of the bronchi. We found blood vessels without any structural damage (data not shown). Obliteration of blood vessels has been observed only in the bed of the primary tumor. Consequently it is mandatory to perform the bronchial anastomosis away from the region of the primary tumor. The 5-year survival rate reported in our study (27%) exceeds survival rates for stage III A and III B reported in the literature. This discrepancy might be related to our selection of patients for surgical resection, because only patients with at least no progression of disease were operated on. Resectability and Long-Term The rates of complete resection have varied considerably between 23% [17] and 88% [14]. In the second trial at the Dana Faber Institute, only 44% of the tumors could be resected completely [18]. The high resectability rate in the first trial at the Dana Faber Institute [14] can be explained by the fact that patients with T3N0 tumors (actually stage II B ) were included, as well as patients with N2 mediastinal metastases; stage III B patients were excluded from the study. The resectability rate in our study (100%) with 92% R0 resections could explain the excellent outcome of our patients. The favorable effect of complete resection on median survival rate was also found by Elias and coworkers (second trial at the Dana Faber Institute [18]). The median survival time was 17.9 months overall and 33.5 months when the tumor could be removed completely. It is evident that the unsatisfying data (median survival 11 months, 2-year survival rate 8%) of one of the first trials of combined chemoradiation therapy [19] are a consequence of the low resectability rate. This should also be considered in the Lung Cancer Study Group (LCSG) trial, which had a median survival of 13 months after thoracotomy with only 34% complete resections [20]. Only a few studies with preoperative radiochemotherapy reported long-term results of 5 years or more (Table 4). The 5-year survival rates were between 13% and 37%. In our study, 7 of the 26 patients who were operated on were alive after 5 years (27%); among them are 4 patients in stage III A and 3 patients in stage III B. Three patients (15%) are alive at more than 90 months postoperatively.

5 Ann Thorac Surg GRANETZNY ET AL 2003;75: MULTIMODAL TREATMENT OF STAGE III A/B NSCLC Table 4. Long-Term Rates for Neoadjuvant Chemoradiation Therapy for Non-Small Cell Lung Cancer Reference Patients (n) Median (mo) 5-Year (%) 6-Year (%) Year (%) GENERAL THORACIC Spain [17] Skarin and colleagues [14] Taylor [13] Favaretto [11] Choi and colleagues [21] Present study Complications Aggressive trimodal treatment is associated with significant morbidity in our study. Many patients had severe side effects during radiochemotherapy (4 patients with leucopenia WHO grade III/IV, 3 patients with thrombopenia WHO grade III/IV, 3 patients with esophagitis, and 4 patients with pneumonitis). In the late postoperative period, 1 patient died of cardiac failure on the 32nd postoperative day, and 1 patient succumbed to a bronchial stump leak and pneumonitis. At autopsy of the patient with cardiac failure, complete occlusion of the coronary arteries was found. Based on this experience, we decided to exclude patients with severe peripheral arteriosclerosis from recruitment in the subsequent phase III study. The Southwest Oncology Group investigators [9, 12] noted substantial toxicity as well: 13% of patients had grade IV acute toxicity, and there were two treatmentrelated deaths (1.6%) during the induction therapy period. During the postoperative period 11 (8.4%) additional deaths occurred. An overall treatment-related mortality rate of 15% was found in the neoadjuvant study by Burkes and associates from Toronto [10]. The results of this study and our experience with neoadjuvant therapy in NSCLC have shown that patients with stage III A and III B NSCLC enjoy long-term survival with tolerable therapy-induced morbidity and mortality. Among all known prognostic factors the histopathologic regression of mediastinal lymph nodes has had the most effect on survival. Additionally, the experience of this study showed that 1. Grade of remission of the primary tumor cannot be analyzed exclusively by roentgenogram or computed assisted tomography. 2. Staging thoracotomy is recommended in most cases to evaluate the chance for radical resection. 3. The primary tumor bed must be radically resected, irrespective of histologic evidence of tumor tissue. 4. Resection of the primary tumor bed must be performed beyond the margins of fibrotic tissue resulting from radiochemotherapy, and sleeve resections are feasible without a significant complication rate. References 1. Singhal S, Kaiser LR. Multimodality therapy for non-small cell lung cancer. In Shields TW, Locicero J, Ponn RB, eds. General thoracic surgery. Philadelphia: Lippincott, 2000: Green MR, Barkley JE. Intensity of neoadjuvant therapy in resectable non-small cell lung cancer. Lung Cancer 1997; 17(Suppl 1):S Rocmans P, Capello M, de Franquen P. Exclusive surgery for stage III disease: is it still ethical?. In: van Houtte P, Klastersky J, Rocmans P, eds. 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6 GENERAL THORACIC 1112 GRANETZNY ET AL Ann Thorac Surg MULTIMODAL TREATMENT OF STAGE III A/B NSCLC 2003;75: Riesenbeck D, Rübe C, Thomas M, et al. Korrelation von Bildgebung, Resektabilität und histologischem Therapieansprechen nach präoperativer, kombinierter Radiochemotherapie beim NSCLC. Strahlenther Onkol 1997;1: Spain RC. Neoadjuvant mitomycin C, cisplatin, and infusion vinblastine in locally and regionally advanced non-small cell lung cancer: problems and progress from the perspective of long-term follow-up. Semin Oncol 1998;15(Suppl 4): Elias AD, Skarin AT, Gonin R, et al. Neoadjuvant treatment of stage IIIA non-small cell lung cancer. Long-term results. Am J Clin Oncol 1994;17: Eagan RT, Ruud C, Lee RE. Pilot study of induction therapy with cyclophosphamide, doxorubicin and cisplatin (CAP) and chest irradiation prior to thoracotomy in initially inoperable stage III M0 non-small cell lung cancer. Cancer Treat Res 1987;71: Weiden PL, Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small cell lung cancer. A phase II study of the LCSG. Chest 1994;106(Suppl): Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol 1997;15(2): Notice From the American Board of Thoracic Surgery Regarding Trainees and Candidates for Certification Who Are Called to Military Service Related to the War on Terrorism The Board appreciates the concern of those who have received emergency calls to military service. They may be assured that the Board will exercise the same sympathetic consideration as was given to candidates in recognition of their special contributions to their country during the Vietnam conflict and the Persian Gulf conflict with regard to applications, examinations, and interruption of training. If you have any questions about how this might affect you, please call the Board office at (847) Peter C. Pairolero, MD Chairman The American Board of Thoracic Surgery 2003 by The Society of Thoracic Surgeons Ann Thorac Surg 2003;75: /03/$30.00 Published by Elsevier Science Inc