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© 2000 American Society for Clinical Oncology Randomized Trial Comparing Cisplatin, Gemcitabine, and Vinorelbine With Either Cisplatin and Gemcitabine or Cisplatin and Vinorelbine in Advanced Non–Small-Cell Lung Cancer: Interim Analysis of a Phase III Trial of the Southern Italy Cooperative Oncology GroupFrom the Division of Medical Oncology A, National Tumor Institute; Divisions of Medical Oncology and Pneumology, Cardarelli Hospital; Division of Medical Oncology, San Gennaro Hospital; Chair of Respiratory Diseases, Second University School of Medicine; Division of Pneumology, Monaldi Hospital, Naples; Division of Medical Oncology, San Carlo Hospital, Potenza; Division of Medical Oncology, Da Procida Hospital, Salerno; Division of Pneumology, City Hospital, Caserta; Division of Medical Oncology, Oncologic Institute; Division of Thoracic Surgery, San Paolo Hospital, Bari; Division of Medical Oncology, Oncologic Hospital, Palermo, Italy. Address reprint requests to Pasquale Comella, MD, Division of Medical Oncology A, National Tumor Institute, via M. Semmola 80131, Naples, Italy; email pcomella{at}sirio-oncology.it
PURPOSE: In our previous phase II study, the cisplatin, gemcitabine, and vinorelbine (PGV) regimen produced a median survival time (MST) of approximately 1 year in advanced non–small-cell lung cancer (NSCLC) patients. The present study was aimed at comparing the MST of patients treated with this triplet regimen with the MSTs of patients receiving cisplatin and vinorelbine (PV) or cisplatin and gemcitabine (PG).
PATIENTS AND METHODS: From April 1997, patients with locally advanced or metastatic NSCLC, an age of RESULTS: The survival data of 180 NSCLC patients (stage IIIB, 76 patients; stage IV, 104 patients) were analyzed in April 1999. Overall, 128 patients had died (PGV, n = 33; PG, n = 42; and PV, n = 53). The MST of patients in the PGV, PG, and PV arms was 51, 42, and 35 weeks, respectively, and the corresponding 1-year projected survival rates were 45%, 40%, and 34%, respectively. When only patients with stage IV disease were considered, an even stronger difference was seen between PGV (MST = 47 weeks) and both PG (34 weeks) and PV (27 weeks). At multivariate Cox analysis, the estimate hazard of death for patients receiving PGV compared with those receiving PV was 0.35 (95% confidence interval, 0.16 to 0.77; P < .01). The response rates were 47% in the PGV arm, 30% in the PG arm, 25% in the PV arm. Both hematologic and nonhematologic toxicities were not substantially worse in patients who received the PGV regimen. CONCLUSION: The PGV regimen is associated with a substantial survival gain (MST > 3 months longer) when compared with the PV combination. Because this difference in survival met one of the early stopping rules, the accrual in the PV arm has been stopped (null hypothesis rejected). Enrollment still continues in the PGV and PG arm to ascertain whether the PGV regimen can also produce a significantly longer survival than that obtained with the PG regimen.
NON–SMALL-CELL lung cancer (NSCLC) represents a major health problem in the Western world. At the time of diagnosis more than 50% of patients have advanced or metastatic disease; thus, a limited number of treatment options are available.1 A number of chemotherapy agents have been shown to be active in NSCLC.2 However, although many chemotherapy regimens have been tested in the last few decades, the long-term prognosis is still poor. Although a standard chemotherapy approach has not yet been defined in these patients, there is quite a widespread agreement about the inclusion of cisplatin in any first-line chemotherapy combination after the results of a recent meta-analysis.3 Among newer active drugs, vinorelbine, gemcitabine, taxanes, and irinotecan are the most promising, in view of their intrinsic cytotoxic activity and of their nonoverlapping toxicity and potential synergism when combined with cisplatin.4 The cisplatin and vinorelbine (PV), cisplatin and gemcitabine (PG), and cisplatin (or carboplatin) and paclitaxel combinations have been widely tested in the last few years.5-18 Although the addition of a new agent to cisplatin has shown a clear improvement of both survival and quality of life when compared with cisplatin alone, there has not yet been clear evidence of a survival gain with these new regimens over older combination chemotherapies. In several large randomized trials, none of these new regimens has produced a major response in more than half of the patients, nor has any succeeded in increasing the median survival time (MST) to more than 1 year.14-18 In view of this, it seems logical to try triplet drug combinations including at least two new agents. The Southern Italy Cooperative Oncology Group has already investigated the cisplatin, gemcitabine, and vinorelbine (PGV) combination in patients with advanced NSCLC. All three drugs were given on days 1 and 8 every 3 weeks; in this way, full doses were delivered at the price of a moderate toxicity.19 This regimen produced a more than 50% objective response rate (ORR) and a 50-week MST.20 As a result, a three-arm phase III trial comparing this new combination with both PV and PG was undertaken. For the PV regimen, we selected the schedule used by Le Chevalier et al,5 because the survival outcome reported in that trial was the best ever reported with this combination. For the PG combination, we chose day 1 administration for cisplatin17 to avoid an additional day of treatment for cisplatin on day 2, as in the Crinò et al11 study, and to prevent the risk of omitting cisplatin administration on day 15 because of cumulative myelosuppression.12 In the present article, the survival outcome of the first 60 patients included in each arm is analyzed.
Eligibility Criteria Chemotherapy-naive patients with histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) NSCLC were eligible for this trial. No prior surgery or thoracic radiotherapy was allowed. They were required to have an age  70 years, adequate bone marrow function (absolute neutrophil count  2 x 109/L, platelet count 100 x 109/L, and hemoglobin level 100 g/L), adequate liver function (bilirubin level two times the upper limit of normal, AST and/or ALT < three times the upper limit of normal, and prothrombin time < 1.5 times control), and creatinine clearance 60 mL/min. The presence of severe cardiac arrhythmia or heart failure, second or third degree heart block, or acute myocardial infarction within 4 months before study entry were considered as exclusion criteria. CNS metastases, if asymptomatic, were not considered as exclusion criteria. A performance status 1 on the Eastern Cooperative Oncology Group (ECOG) scale and a life expectancy of at least 12 weeks were also required. All patients gave their written informed consent, and the trial was approved by the Ethical Committee for the Biologic Research of the National Tumor Institute of Naples (Naples, Italy).
Diagnostic Procedures Physical examination, laboratory tests, and chest x-ray were performed at each chemotherapy course, and all the diagnostic procedures required to evaluate response to treatment were scheduled after a similar time from initial therapy had elapsed for each patient (after the third course in the PGV arm and after the second course in the PG and PV arms). Complete blood cell count was performed weekly.
Treatment Regimens
All patients received an antiemetic prophylaxis consisting of 5-hydroxytryptamine-3–receptor antagonists plus 20 mg of dexamethasone. In the PGV arm, full doses of chemotherapy were given if neutrophil and platelet counts on day of treatment were The doses of each drug were reduced in each arm by 25% if grade 4 neutropenia or thrombocytopenia or grade 3 to 4 nonhematologic toxicity had occurred in the previous cycle. Cisplatin was reduced by 50% for creatinine serum levels of 131 to 180 mmol/L, and suspended for levels greater than 180 mmol/L. The use of granulocyte or granulocyte-macrophage colony-stimulator factor was allowed in the presence of grade 4 neutropenia lasting more than 7 days, neutropenic fever, or if grade 2 or more neutropenia persisted after 2 weeks from the scheduled time of chemotherapy administration. The treatment was definitively discontinued if grade > 1 neutrocytopenia or thrombocytopenia or major nonhematologic toxicity persisted 3 or more weeks after the scheduled time of recycling.
Response and Toxicity Evaluation The World Health Organization grade scale21 was also used to record toxicity. Toxicity was assessed before each cycle of chemotherapy, and hematologic assessments were also performed weekly to determine the toxicity at the nadir. For toxicity analysis the worst data for each patient in all cycles of chemotherapy was used. Performance status and symptom assessment were performed before each cycle of chemotherapy. The assessment of quality of life was also performed by analyzing a 10-item questionnaire derived from the Lung Cancer Symptom Scale,22 which had already been validated in our previous studies.20,23
Statistical Methods and Study Design Randomization was performed centrally at the division of Medical Oncology A of the National Tumor Institute of Naples. Patients were assigned to one of the three arms by a computer-driven minimization procedure that used the center and stage of disease (IIIB v IV) at entry as stratifying variables. For survival analysis, the day of randomization was considered the date of entry. Analysis was conducted on the basis of randomization (intent-to-treat analysis) and on the follow-up data available as of April 15th, 1999. Overall survival was measured from the date of entry to the date of death or date of last follow-up. Survival curves were estimated by the Kaplan-Meier product-limit method.26
Study Flow
Demographics The characteristics of the first 180 assessable patients allocated in the three arms are listed in Table 1. The large majority of patients were men (93%), and the median age was 62 years (range, 32 to 70 years). Approximately 60% of patients had stage IV disease; the remaining patients had stage IIIB disease. Among the 76 patients in stage IIIB, 41 had malignant pleural effusion, 10 had supraclavicular node involvement, and 25 had T4 primary or contralateral mediastinal nodes. The most frequent histology was squamous cell carcinoma, which was diagnosed in half of the patients. At diagnosis, a loss of more than 5% of body weight was registered in approximately 25% of patients. Brain metastases were present in five patients. Baseline characteristics were well-balanced across the three arms.
Survival As of April 15, 1999, 128 patients had died (PGV, n = 33; PG, n = 42; and PV, n = 53). The median potential follow-up was 16 months (range, 6 to 24 months). It was the same in the three arms. The MST was 44 weeks for the whole population (48 weeks for stage IIIB and 40 weeks for stage IV patients; P > .05). Age < 65 years was also associated with a slightly better MST than age > 65 years (47 v 41 weeks, respectively; P > .05). Actuarial survival curves according to the arm of treatment are shown in Fig 1. The MST was 51 weeks in the PGV arm, 42 weeks in the PG arm, and 35 weeks in the PV arm. For stage IV disease, MSTs were 47, 34, and 27 weeks in the PGV, PG, and PV arms, respectively. The 1-year probabilities in the PGV, PG, and PV arms were 45%, 40%, and 34%, respectively. A preliminary assessment of the interaction between treatment and each of the main pretreatment features was performed. No significant interactions resulted. At Cox analysis, including age, stage of disease, ECOG performance status, histology, and weight loss as covariates, the estimated hazard of death for patients receiving PGV compared with those receiving PV was 0.35 (95% confidence interval [CI], 0.16 to 0.77; P < .0058).
Response The response data are listed in Table 2. There were two CRs and 26 PRs in the PGV arm, with an ORR of 47% (95% CI, 34% to 60%). No CRs and 18 PRs and no CRs and 15 PRs occurred in the PG and PV arms, respectively, resulting in ORRs of 30% (95% CI, 19% to 43%) and 25% (95% CI, 15% to 38%), respectively. ORRs, according to stage IIIB versus IV disease, were 54% and 42% in the PGV arm, 36% and 26% in the PG arm, and 29% and 22% in the PV arm. Failures within 3 months occurred in 25%, 33%, and 50% of patients in the PGV, PG, and PV arms, respectively. In particular, five patients (8%) were not reassessed in the PGV arm because of early progression, death, or treatment discontinuation by any cause compared with eight patients (13%) in the PG arm and 20 patients (33%) in the PV arm. All these patients were considered nonresponders. Twelve of 25 stage IIIB patients without pleural effusion or supraclavicular nodes who failed to respond (PGV, n = 1; PG, n = 5; and PV, n = 6) received chest radiotherapy at full dose (60 Gy). An additional 28 patients, either in stage IIIB or in stage IV, received occasional palliative irradiation for symptom control (PGV, n = 11; PG, n = 9; and PV, n = 8). Overall, 95 patients received second-line chemotherapy (PGV, n = 34; PG, n = 31; and PV, n = 30). The same rescue treatment (weekly paclitaxel) was performed in the three arms. Fifteen objective responses (16%) were recorded with second-line chemotherapy, without substantial differences in ORR between patients coming from each of the three arms.
Treatment Compliance and Toxicity Overall, two toxic deaths occurred. Both patients had received the PV regimen. They died after 14 and 18 days from the beginning of chemotherapy; both of them showed grade 4 neutropenia. Chemotherapy was discontinued early because of toxicity in three patients in the PGV arm (one patient because of lack of hematologic recovery, one because of severe emesis, and one patient refused further treatment because of severe fatigue), in three patients in the PG arm (one patient because of lack of recovery from renal toxicity, one because of lack of hematologic recovery, and one because of severe emesis), and in 10 patients in the PV arm (two patients had toxic deaths, one because of severe renal toxicity, two because of severe constipation, three because of severe emesis, and two because of severe fatigue). Other relevant toxic events that did not induce the cessation of treatment and the percentages of patients in which they occurred are listed in Table 3. They were grade 3 to 4 neutropenia (PGV = 45% of patients; PG = 40%, and PV = 75%), severe anemia (PGV = 15%, PG = 13%, and PV = 25%), severe vomiting (PGV = 15%, PG = 30%, and PV = 50%), and grade 1 to 2 peripheral neuropathy (PGV = 18%, PG = 3%, and PV = 20%). A significantly higher occurrence of severe neutropenia (P < .001) and vomiting (P < .0001) was observed in the PV arm compared with the PGV arm.
As a consequence of delay and/or dose reductions, the median relative dose-intensity (actually delivered mg/m2/wk divided by the planned mg/m2/wk) of all drugs in the PGV arm was 84% compared with 87% and 76% for cisplatin and gemcitabine, respectively, in the PG arm, and 81% and 65%, respectively for cisplatin and vinorelbine in the PV arm.
In the last decade, the introduction into clinical practice of several new drugs with proven antitumor activity in NSCLC patients has renewed the interest of clinical oncologists in the treatment of this disease. As a consequence, the number of clinical trials testing new drugs or combinations in this field has been increasing dramatically. In the light of the promising results obtained in phase II studies, the PV, PG, and cisplatin or carboplatin and paclitaxel regimens have become very popular.5-18 Unfortunately, more recent phase III trials have not yet demonstrated that these doublets substantially modify the prognosis of advanced NSCLC patients.14-18 The purpose of the present phase III trial was to evaluate whether the new triplet combination (PGV) we had previously tested in phase I and II studies could provide any meaningful survival gain when compared with the two doublet combinations PG and PV. We chose to exclude patients with an ECOG performance status worse than 1 from the present study because, in a previous study, the possible beneficial effect of an aggressive chemotherapy was restricted to patients without substantial impairment of performance status at diagnosis.27 More recently, an unfavorable survival outcome has also been reported for poor performance status patients included in the ECOG four-arm trial (cisplatin/gemcitabine, cisplatin/paclitaxel, cisplatin/docetaxel, and carboplatin/paclitaxel).28 We want to remark that this is the first report concerning the comparison of a three-drug regimen (including two new drugs) with two-drug combinations. On the basis of the survival data of this interim analysis, it can be stated that the PGV treatment produced a significantly longer MST when compared with the PV regimen. Even though this is an interim analysis, it is unlikely that the results are biased as a result of nonmature follow-up because the median potential follow-up is 16 months in the PGV, PG, and PV arms, and 88% of the patients in the PV arm have died. We also want to point out that the wide difference between survival curves of the PGV and PV arms was not because of an underestimation of the activity of the PV regimen in the present study. Indeed, both the median and 1-year survival rates observed in the present study were superimposable with those reported in the two consecutive Southwest Oncology Group trials.6,18 On the other hand, the survival curve of patients who received PGV in the present study was absolutely identical to the survival curve we previously reported in a phase II study in a similar study population.20 Of course, it must not be forgotten that these results were obtained in case series with good prognosis, because elderly patients or patients with a poor performance status were not included in both these studies. Indeed, we strongly believe that a different therapeutic approach should be considered for these frail patients. Therefore, in the last 2 years, the Southern Italy Cooperative Oncology Group has been conducting a parallel phase III trial in elderly or unfit patients, evaluating a less aggressive approach with a single-agent chemotherapy (vinorelbine) or a two-drug regimen (gemcitabine and vinorelbine) not including cisplatin.29 Although the higher percentage of patients with locally advanced disease enrolled onto our study, as compared with the Southwest Oncology Group trials, might have given us more favorable results, this is improbable because the superiority of the triplet combinations is most evident when only patients with stage IV disease are considered. Indeed, PGV yielded a longer MST than PV by more than 4 months in these patients. Although this trial did not aim to directly compare the PG and PV regimens, PG seems to have a higher antitumor activity, given that PG showed a longer MST than PV by 2 months. As a matter of fact, the 10-month MST observed in the PG arm at the interim analysis compared favorably with those recently reported by Crinò et al14 and Sandler et al,17 who studied similar regimens. A short comment should be made about the other end points of the study, ie, response rate and toxicity. A wide difference in the ORR between the triplet and the doublet regimens was evident. To achieve a similar treatment duration (8 to 10 weeks) before the first restaging, we planned only two cycles of PV in comparison with three cycles of PGV. Because we chose to stop treatment in patients not showing an objective response at the first restaging, whereas other investigators continued the treatment until the occurrence of progression, our management may have underestimated the probability of response to the PV regimen, although the ORRs previously reported with the PV regimen5,6 were not substantially higher than that reported in the present study. Moreover, we want to point out that, at first restaging, the vinorelbine cumulative dose in the PV arm was much higher than the cumulative dose intended in the PGV regimen. In any case, we are absolutely sure that the policy we adopted did not impair the survival outcome of our patients. Indeed, it has recently been reported that even in responding patients the addition of three further cycles of chemotherapy did not result in a clear survival gain.30 In general, the toxicity of the PGV regimen was manageable. Only one patient in the PGV arm had to suspend the treatment early because of toxicity. That compares favorably with the compliance of patients in the PV arm. Indeed, both the high dosage of cisplatin given in a single day and the weekly administration of full doses of vinorelbine produced frequent refusal to continue the treatment in this arm. Severe emesis, constipation, fatigue, and sometimes renal toxicity were the main reasons for this noncompliance. In addition, the occurrence of severe neutropenia was significantly less frequent in the PGV arm compared with the PV arm. The PGV regimen was associated with a moderate nonhematologic toxicity, that involved emesis, neuropathy, and renal toxicity that was similar or even lower than the toxicity observed in the doublet regimens. In conclusion, according to the results of the present interim analysis, the PGV combination produced a highly significant survival gain in patients with advanced NSCLC when compared with the PV treatment. In view of these data, the accrual of patients in the PV arm has been closed, whereas the other arms will stay open until the final sample size is reached, allowing the evaluation of whether the PGV regimen can also produce a significant survival gain when compared with the PG regimen.
The Southern Italy Cooperative Oncology Group conducted this study with the cooperation of the following investigators and institutions: Pasquale Comella, Giuseppe Frasci, Adriano Gravina, and Giuseppe Comella (Division of Medical Oncology A, National Tumor Institute, Naples); Nicola Panza, Gianpaolo Nicolella, and Giovanni Pacilio (Division of Medical Oncology, Cardarelli Hospital, Naples); Michele Natale (Division of Pneumology, Cardarelli Hospital, Naples); Luigi Manzione, Domenico Bilancia, and Angelo Di Nota (Division of Medical Oncology, San Carlo Hospital, Potenza); Giuseppe De Cataldis and Pietro Carnicelli (Division of Medical Oncology, Da Procida Hospital, Salerno); Vito Lorusso and Mario De Lena (Division of Medical Oncology, Oncology Institute, Bari); Franco Carpagnano and Gaetano Di Rienzo (Division of Thoracic Surgery, San Paolo Hospital, Bari); Riccardo Cioffi (Division of Pneumology, City Hospital, Caserta); Luigi Maiorino (Division of Medical Oncology, San Gennaro Hospital, Naples); Enrico Micillo and Paolo Marcatili (Chair of Respiratory Diseases, Second University School of Medicine, Naples); Gianfranco Filippelli and Salvatore Palazzo (Division of Medical Oncology, Oncologic Hospital, Cosenza); Bruno Massidda (Medical Oncology, University School of Medicine, Cagliari); Vittorio Mascia (Division of Medical Oncology, Oncology Hospital, Cagliari); Guido Pusceddu (Division of Pneumology, Bisaghi Hospital, Cagliari); Alfredo Lamberti and Franco Piantedosi (Division of Pneumology, Monaldi Hospital, Naples); Mario Belli and Filomena Del Gaizo (Division of Medical Oncology, City Hospital, Avellino); Antonio Contu (Division of Medical Oncology, City Hospital, Sassari); and Alessandra Mangiameli (Musumeci Clinic, Catania, Italy).
We thank Dr John Perchard for the statistical analysis of this trial, Sabrina Caiazzo for the data management, and Liliana Gallifuoco for her secretarial assistance.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
