The expanding role of systemic treatment in non-small cell lung cancer neo-adjuvant therapy

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1 17 (Supplement 10): x108 x112, 2006 doi: /annonc/mdl247 The expanding role of systemic treatment in non-small cell lung cancer neo-adjuvant therapy E. Felip & E. Vilar Oncology Department, Vall d Hebron University Hospital, Barcelona, Spain introduction Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80 85% of lung carcinomas. Approximately one-third of NSCLC patients are diagnosed of early-stage disease and for these patients surgery is the most effective treatment with intent to cure. However, even for those patients who undergo surgery, survival remains dismal, with more than 50% relapsing mainly at distant sites. Efforts to improve the outcome of patients with resectable NSCLC have focused on adjuvant and neoadjuvant approaches. At present adjuvant chemotherapy following complete resection could be considered standard of care in stage II-III NSCLC patients. It may be reasonable now to look again to neo-adjuvant chemotherapy to improve survival by the early treatment of micrometastatic disease. Neo-adjuvant chemotherapy followed by surgery and/or radiotherapy has become a standard approach for stage III NSCLC patients and has also been recently explored as an option in stage IB-II NSCLC. randomized trials of surgery versus neo-adjuvant chemotherapy plus surgery in stage IIIA NSCLC Stage IIIAN2 NSCLC includes a heterogeneous group of patients [1]. Andre et al. identified two stage IIIAN2 NSCLC prognostic subgroups, those with nodal lymph node enlargement detected by computer tomography (CT) scan (clinical N2), and those without preoperative detection but diagnosed after lymph node dissection (minimal N2) [2]. In this study, preoperative chemotherapy was associated with a better prognosis for those with clinical N2. Randomized controlled trials have assessed the role of neoadjuvant chemotherapy plus surgery compared with surgery alone in stage III NSCLC patients (Table 1). However there are considerable differences regarding homogeneity in the extension of disease and mandate for N2 histological confirmation of lymph nodes involvement. Pass et al. published an interim analysis of the National Cancer Institute (NCI) trial in 1992 [3]. Twenty-seven patients with histologically confirmed N2 disease were randomized to receive surgery alone or preoperative etoposide and platinum for two cycles plus surgery and then four further cycles. Threeyear survival rate for both the preoperative chemotherapy and the surgery-alone arm were 46% and 21%, respectively (P = 0.12). Although a trend toward increased median survival was observed in the experimental arm (28.7 versus 15.6 months), these results did not reach statistical significance, probably due to small sample size. The Spanish Lung Cancer Study Group (SLCG) and the MD Anderson Cancer Center conducted two small randomized trials, which were stopped early due to strongly positive results in favor of neo-adjuvant chemotherapy. In the SLCG trial, 60 patients with IIIAN2 stage disease based on CT scan findings were randomized to receive surgery alone or neo-adjuvant chemotherapy followed by surgery [4]. Chemotherapy consisted of 3 cycles of mitomycin-c, ifosfamide and cisplatin. Median survival and 3-year survival rate in the chemotherapy plus surgery group was 26 months and 30% compared with 8 months and 0% in the surgery group (P <0.001). These differences remain significant in the 7-year follow-up report [5]. Roth et al. from the MD Anderson Cancer Center conducted a prospective randomized controlled phase III trial that compared surgery alone with perioperative chemotherapy plus surgery [6]. Sixty patients were assigned to surgical resection alone or 3 cycles of preoperative cyclophosphamide, etoposide and cisplatin followed by surgery. Those patients in the experimental arm who achieved response received 3 additional cycles after surgery. In both groups, radiation therapy was added in case of unresectable lesions or incomplete resection. Median survival and 3-year survival rate in the perioperative-chemotherapy group was 64 months and 56% compared with 11 months and 15% for the surgery group (P =0.008 for median survival). After median follow-up of 82 months the results continued to favor those patients who had received neo-adjuvant chemotherapy [7]. A large phase III trial was conducted by the French Thoracic Cooperative Group which included 373 patients with stage I (except T1 N0), II and IIIA resectable NSCLC [8]. Patients were randomized to receive either surgery alone or two cycles of preoperative mitomycin-c, ifosfamide and cisplatin chemotherapy and two further postoperative cycles in responding patients. Post-operative radiotherapy was indicated in case of pt3 or pn2 and/or incomplete resection. Staging was clinical and mediastinoscopy was not mandatory. In this study, a total of 167 patients (47%) with stage IIIA were included. Median survival was 37 months in the perioperative arm and 26 months in the surgery arm; the 3-year survival rate was 51.6% and 41.2%, respectively. These differences did not ª 2006 European Society for Medical Oncology

2 reach statistical significance despite their clinical relevance. In the analysis of stage I and II patients, chemotherapy was found to improve survival with statistically significant differences. Single agent docetaxel has been evaluated as induction treatment in a phase III trial reported by Mattson et al. [9]. Patients with stage IIIA or IIIB were randomized to surgery or curative-intention thoracic irradiation in the control arm (n =140) or to receive 3 cycles of chemotherapy before local treatment in the experimental arm (n =134). In the docetaxel arm, overall response rate was 25%. Only 14% of patients in the docetaxel arm and 18% in the control group underwent surgery. Median survival times in the docetaxel arm and in the control group were 14.8 and 12.6 months, respectively. These results were not statistically significant. A recent meta-analysis of neo-adjuvant chemotherapy in patients with resectable disease has been reported. It analyzes six randomized studies including a total of 590 patients which were published between 1990 and 2003 [10]. The meta-analyses showed that the hazard ratio (HR) of the combined results was 0.66 (95% CI ) in favor of adding neo-adjuvant chemotherapy to a standard procedure. phase II trials of neo-adjuvant chemotherapy using third-generation chemotherapy agents Third generation drugs have been tested in doublet or triplet combinations as neo-adjuvant treatment in several phase II trials (Table 2). The Swiss Group for Clinical Cancer Research enrolled 90 patients with mediastinoscopically proven stage IIIAN2 disease [11]. Neo-adjuvant chemotherapy consisted of 3 cycles of docetaxel and cisplatin. Postoperative radiotherapy was administered to patients with positive resection margin and/or involvement of the uppermost mediastinal lymph node. The overall clinical response rate was 66% and complete resection was feasible in 48% of patients of the entire sample. Median overall survival, event-free survival and 3-year survival rate were 27.6, 11.7 months and 33%, respectively. A multivariate analysis was performed in order to identify prognostic factors for patients survival. Mediastinal downstaging was the most powerful prognostic factor for survival; patients with N2 disease at surgery had a 3-year survival rate of 11% compared to 61% for patients with N0 N1 downstaging (P =0.0003). Complete resection (margin-free resection of the primary tumor and no involvement of the uppermost mediastinal lymph node) was another significant prognostic factor, which correlated with better survival (P=0.0006). After an observation time of 5 years, the median overall survival was 2.9 years for all patients who underwent surgery and 5.2 years for patients who underwent complete resection. The incidence rates for relapse at 5 years were 3% with local disease, 8% distant disease, and 53% local and distant disease. An impressive 28% of patients were relapse-free at 5 years. The Italian Lung Cancer Project performed a phase II trial in patients with clinically unresectable, bulky N2 or stage IIIB NSCLC [12]. Induction treatment consisted of four cycles of gemcitabine and cisplatin. Patients who responded were evaluated for surgery or radiotherapy and those with stable disease received radiation therapy. Fifty-eight patients with stage IIIA NSCLC were included and 21 patients were eligible for resection after induction chemotherapy, with complete resection being carried out in all patients. The median survival for stage IIIA disease group was 16.5 months. Table 1. Reported randomized phase III trials of surgery alone versus neoadjuvant chemotherapy plus surgery in stage IIIA NSCLC. 1 3 year survival Investigators Stage subset Chemotherapy n No ChT ChT P National Cancer Institute IIIA (N2) by biopsy EP 2 cycles Preop EP 4 cycles Postop Spanish Lung Cancer Study Group IIIA (N2) by CT scan MIP 3 cycles Preop <0.05 MD Anderson Cancer Center IIIA (N2) not required, some IIIB CEP 3 cycles Preop and postop <0.05 French Thoracic Cooperative Group Clinical T2N0, II, IIIA resectable MIP 2 cycles preop and postop Mattson et al. IIIA, IIIB by CT Scan D 3 cycles preop NS ChT, chemotherapy; NS, not significant; E, etoposide; P, platinum; M, mitomycin; I, ifosfamide; D, docetaxel; n, number. Table 2. Phase II trials of neoadjuvant chemotherapy using third-generation chemotherapy agents Investigators Stage subset Chemotherapy n RR R0 msv Swiss Group for Clinical Cancer Research IIIA (N2) by biopsy PD 3 cycles The Italian Lung Cancer Project IIIA (bulky N2), IIIB PG 4 cycles EORTC IIIA (N2) by biopsy PG 3 cycles EORTC IIIA (bulky N2) by biopsy TCb 3 cycles De Marinis et al. IIIA (N2) by biopsy PTG 3 cycles Spanish Lung Cancer Study Group IIIA (N2) by biopsy and T4N0 D 3 cycles RR, response rate (%); R0, complete resection rate (%); msv, median survival (mo); P, platinum; D, docetaxel; G, gemcitabine; T, Paclitaxel; Cb, Carboplatin; n, number. Volume 17 Supplement 10 September 2006 doi: /annonc/mdl247 x109

3 The European Organisation for Research and Treatment in Cancer (EORTC) has conducted a phase III trial (EORTC 08941) that addresses the matter of the best local control for stage IIIA and whose results are included elsewhere in this review. Within this setting, two phase II trials have been carried out with two different induction combination regimens [13, 14]. Van Zandwijk et al. published the results of the first study (EORTC 08955) in which 3 cycles of gemcitabine and cisplatin were used as induction chemotherapy in 47 patients [13]. An overall response rate of 70% was observed. Seventeen patients were randomized to resection and 71% were judged to be complete. The median survival for all recruited patients was 18.9 months. In the second trial, published by O Brien et al. (EORTC 08958), the induction chemotherapy combination used was paclitaxel and carboplatin. Of the 52 eligible patients, overall response rate was 64%, 35 patients underwent surgery and median survival was 20.5 months [14]. De Marinis et al. reported the activity and safety of three cycles of a triplet combination of gemcitabine, paclitaxel and cisplatin in 46 pathologically confirmed stage IIIAN2 patients [15]. Postoperative radiotherapy was scheduled for those with pathologic lymph node involvement, incomplete resection or those considered being unresectable. This combination treatment was well tolerated, reporting grade 3 4 neutropenia and thrombocytopenia in 32.7% and 12.2% of the patients as the most common toxicities. Overall response rate was 73.5%; 59% of patients were eligible for surgery and 57% underwent complete resection. Median survival and 1-year survival were 23 months and 85%, respectively. Garrido et al. presented the results of a SLCG phase II trial using three cycles of docetaxel, gemcitabine and cisplatin followed by surgery in stage III patients [16]. In this trial, 136 patients were included. Response was observed in 56% of patients and median survival for all patients included was 15.9 months. neo-adjuvant chemotherapy for early-stage NSCLC The increasing number of trials of preoperative chemotherapy in the locally advanced stage encouraged investigators to study the role of this approach in the early-stage setting. The Bimodality Lung Oncology Team (BLOT) conducted a phase II trial to explore perioperative chemotherapy in patients with stage IB, II and selected IIIA (not N2) [17]. In all patients nodal stage was assessed by CT scan and a negative biopsy by mediastinoscopy. In this study, 94 patients were included and received two cycles of neo-adjuvant chemotherapy with paclitaxel and carboplatin and those who underwent complete resection received 3 additional cycles of the same chemotherapy regimen. Overall response rate to chemotherapy was 53%, and 3- and 5-year survival rate were 58% and 45%, respectively. This study concludes that in early-stage NSCLC induction chemotherapy with paclitaxel and carboplatin is feasible and produces a high response rate with acceptable morbidity and mortality rates. The Southwest Oncology Group designed a phase III trial (S9900) based on the results of the BLOT phase II study [18]. Stage IB-II-T3N1 NSCLC patients were randomized to surgery alone or preoperative chemotherapy with carboplatin and paclitaxel plus surgery. A total of 354 patients were accrued (70% stage IB/IIA). Response rate to preoperative chemotherapy was 40%. The results of this trial, although not statistically significant, seemed to favor the preoperative arm since median survival was 47 months for patients receiving preoperative chemotherapy and 40 months for those in the surgery alone arm (HR = 0.84; P=0.32). This trial was closed earlier than planned because investigators considered that having a surgery alone arm could no longer be considered ethical. Therefore, results of this trial should be interpreted with caution. From the current data, more than 90% of patients receiving neo-adjuvant chemotherapy undergo the planned surgical resection. The superiority of neo-adjuvant or adjuvant chemotherapy in early-stage NSCLC remains an open question and will require randomized studies. One such study is the NATCH trial, which was designed to evaluate the effect of carboplatin and paclitaxel in early-stage NSCLC patients. Since 2000, 555 stage I, II, T3N1 NSCLC patients of a planned 628 have been included in this 3-arm randomized trial comparing surgery alone versus three cycles of neo-adjuvant paclitaxel and carboplatin versus surgery followed by three cycles of the same regimen. The primary objective here is the comparison of disease-free survival times. Furthermore, subanalyses of several genetic abnormalities in paraffin-embedded tumor samples are being carried out. role of surgery in locally advanced NSCLC Surgical resection is used with curative intent in early-stage NSCLC (stage I and II). The role of surgery in more advanced stages, however, is not well established. Two phase III randomized controlled trials which were communicated during 2005 ASCO meeting addressed the role of surgery after induction treatment in advanced disease. Albain et al. presented updated results of the Intergroup 0139 trial [19]. In this study, patients with IIIAN2 NSCLC received induction treatment with cisplatin and etoposide plus concurrent radiotherapy [45 Gray (Gy)]. A total of 396 patients without evidence of progression were then randomized to resection or to continue radiotherapy to 61 Gy. The longer follow-up confirmed significantly improved progression-free survival (P =0.0017), but no overall survival (P =0.24), when surgery follows chemotherapy and radiotherapy. Subgroup analysis revealed that patients without regional lymph node metastasis at surgery (pn0) have longer survival times. Treatment-related mortality rates were 7.9% in the surgical arm and 2.1% in the chemoradiotherapy arm. An exploratory analysis that matched patients on the surgical arm with those on the chemoradiotherapy arm was presented, with regard to patient and disease characteristics. This revealed a significant survival benefit in patients who underwent lobectomy compared with their counterparts in the non-surgical arm (5-year survival: 36% versus 18%, P=0.002), but a detriment to long-term survival if a pneumonectomy was performed. When pneumonectomy was the surgical option following induction, completed thoracic radiotherapy should be considered. x110 Felip & Vilar Volume 17 Supplement 10 September 2006

4 Another phase III trial conducted by the EORTC, mentioned earlier, included unresectable stage IIIA patients who received three cycles of platinum-based induction chemotherapy [20]. Those achieving complete or partial response were randomized to either radical radiotherapy or surgical resection. In the trial design, surgery was expected to increase 5-year survival rate by 10%, compared with radiotherapy. Of the 579 patients registered, 62% had response to induction chemotherapy. A total of 332 patients were randomly assigned to receive either radical surgery (167 patients) or thoracic radiotherapy (165 patients). Among the 154 patients who underwent surgery, complete resection was performed in 51%; operative mortality was 4%. Overall survival was 17.5 months for patients receiving radiotherapy and 16.4 months for patients who underwent surgery (P =0.60). Progression-free survival was 11.3 months for patients receiving radiotherapy and 16.4 months for patients who underwent surgery (P =0.61). After a median follow up of 72 months, surgical resection failed to show improvement in either overall survival or progression-free survival. The conclusion of this study was that unresectable disease remains unresectable after induction chemotherapy. These results seem to suggest that surgical resection after induction treatment in the locally advanced setting may not be the best option for all patients. Any decision about the preferred loco-regional treatment should take into account such factors as planned extent of surgery, resection of right lung, stage after induction therapy, and performance status. future challenges In stage III NSCLC patients, the possibility of developing brain metastases is considerable. Records of 177 surgically staged IIIAN2 patients who were consecutively treated from 1988 to 2000 at Dana-Farber were reviewed [21]. In this series the median survival calculated from surgery was 21 months, with a 3-year survival of 34%. As in other studies, downstaging to N0 disease correlated with longer overall survival and progression-free survival (P <0.001). The most common site of recurrence was the brain, with 34% of patients recurring in the brain as the first site of failure, and 40% developing brain metastases at some point. In patients with non-squamous histology and residual nodal involvement after neo-adjuvant chemotherapy, the risk of brain metastases was 53% at 3 years. Since brain metastases constitute the most common site of failure in stage III NSCLC patients, future studies focusing on prophylaxis of brain metastases may improve the outcome in this group of patients. Additional research will enable us to customize neo-adjuvant therapy on the basis of the biology of the tumor. The SLCG group reported that in stage II-III patients treated with neoadjuvant platinum and gemcitabine, those patients with the lowest BRCA1 or RRM1 mrna levels after chemotherapy treatment were found to have better outcome [22, 23]. Further trials analyzing customized neo-adjuvant chemotherapy are warranted. New chemotherapy agents active in NSCLC should also be incorporated in the neo-adjuvant setting. An ongoing SLCG phase II trial using the pemetrexed and cisplatin combination in resectable stage III disease will include a total of 50 patients. All patients will undergo positron emission tomography (PET)-scans both before starting chemotherapy and prior to surgery. Any correlation between standard uptake value (SUV) decrease and the pathologic findings at surgery will be determined. Microarray techniques will be performed in pre-treatment and surgery samples in order to determine a genetic profile of patients who are likely to respond to this combination. Despite the introduction of improved chemotherapeutic agents, it appears that a survival plateau has been reached. The introduction of biological agents, which target specific intracellular pathways related to the distinctive properties of cancer cells are obviously needed to overcome chemotherapyresistant disease. Among these agents, epidermal growth factor receptor targeting agents (erlotinib and gefitinib) and those, which target vascular endothelial growth factor (bevacizumab) have proven activity in metastatic NSCLC patients. Further neo-adjuvant chemotherapy trials should therefore involve platinum-based combinations plus targeted agents. references 1. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111: Andre F, Grunenwald D, Pignon JP et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000; 18: Pass HI, Pogrebniak HW, Steinberg SM et al. 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