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© 1999 American Society for Clinical Oncology Gemcitabine and Cisplatin Versus Mitomycin, Ifosfamide, and Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Randomized Phase III Study of the Italian Lung Cancer ProjectFrom the Department of Medical Oncology, Policlinico Hospital, Perugia; Department of Clinical and Biological Sciences, University of Torino, Torino; Department of Medical Oncology, S Chiara Hospital, Pisa; Department of Pneumology III, Forlanini Hospital, Department of Medical Oncology II, Regina Elena Institute, Department of Medical Oncology I, Regina Elena Institute, and Department of Pneumology VIII, Forlanini Hospital, Rome; Department of Medical Oncology B, National Cancer Institute "G Pascale" and Department of Endocrinology and Molecular and Clinical Oncology, Federico II University, Naples; Department of Medical Oncology, S Maria delle Croci Hospital, and Department of Medical Oncology, Umberto I Hospital, Lugo, Ravenna; Department of Medical Oncology, S Maria Hospital, Terni; Department of Medical Oncology, S Maria Hospital, Reggio Emilia; Department of Radiation Oncology, S Gerardo Hospital, Monza; Department of Medical Oncology, Infermi Hospital, Rimini; Department of Medical Oncology, University of Messina, Messina; Department of Pneumology, Civile Maggiore Hospital, Verona; Department of Pneumology I, "Vincenzo Cervello" Hospital, Palermo; and Department of Pneumology, Infermi Hospital, Biella, Italy. Address reprint requests to Giorgio V. Scagliotti, MD, University of Torino, Department of Clinical and Biological Sciences, Azienda Ospedaliera S Luigi, Regione Gonzole n. 10, 10043 Orbassano, Torino, Italy; email scagliotti{at}ihnet.it
PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non–small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 100 mg/m2 on day 2, every 28 days, or mitomycin 6 mg/m2, ifosfamide 3,000 mg/m2, and mesna on day 1 plus cisplatin 100 mg/m2 on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P = .029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P = .877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P < .001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P < .001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.
NON–SMALL-CELL lung cancer (NSCLC) remains a worldwide health problem. Surgical resection is curative in fewer than 30% of patients with early-stage disease.1 At diagnosis, most NSCLC patients have advanced or metastatic disease that is not amenable to surgery. Consequently, the long-term prognosis is still poor, even though several chemotherapeutic agents and different treatment strategies have been extensively investigated. Cisplatin-based combination therapy is currently considered to be the most active treatment for advanced NSCLC.2,3 A recent meta-analysis has compared chemotherapy versus best supportive care in stage IV NSCLC, showing a 27% relative reduction in mortality rate, which translates into an absolute improvement in median survival time of 2 months and a 10% increase in 1-year survival.4 The conclusion of the meta-analysis was that chemotherapy should be offered to selected patients with stage IV NSCLC and good performance status. Despite this positive information, however, there is still no standard chemotherapy regimen for the treatment of NSCLC. Recently, two clinical trials have demonstrated a survival advantage related to the use of a specific chemotherapy regimen in patients with advanced NSCLC.5,6 In a Pan-European study, the combination of cisplatin and vinorelbine proved to be statistically superior in terms of response rate and survival to cisplatin and vindesine or vinorelbine alone.5 A multicenter, Italian, randomized trial compared cisplatin and etoposide with mitomycin, vindesine, and cisplatin and with mitomycin, ifosfamide, and cisplatin (MIC), with the same cisplatin dose used in all three treatment arms. This study, which included 393 patients and took stage and performance status into account as pretreatment clinical prognostic factors, revealed a superior response rate for the two three-drug combinations and, at the multivariate analysis, a survival benefit in favor of MIC versus cisplatin and etoposide.6 Therefore, vinorelbine and cisplatin or MIC seemed logical reference regimens for the investigation of combination chemotherapy including new agents. Most of these new drugs have distinct mechanisms of action, such as the microtubule inhibitors paclitaxel and docetaxel and the novel antimetabolite gemcitabine,7 and they have shown promising activity in advanced NSCLC. Gemcitabine has demonstrable activity both as a single agent8-14 and in combination with cisplatin.15-20 In six phase II studies in more than 250 patients, the gemcitabine and cisplatin (GC) combination exhibited a response rate ranging from 26% up to 54%, with 1-year survival in the range of 35% to 61%.16,17,20 The good safety profile of gemcitabine, its in vitro–proven synergism of action,21 and its lack of overlapping toxicities with cisplatin make GC an attractive combination to be compared with reference regimens. On the basis of the results of our phase II study of the GC combination,17 we decided to compare in the present phase III study this two-drug regimen with MIC at the same schedule and doses previously tested. The primary end point of the study was the assessment of patient quality of life (QoL). Secondary end points included response rate, toxicity, and survival. In a disease such as NSCLC, in which the impact of chemotherapy on survival is marginal and the value of objective response is limited, other clinical end points, such as symptom control and QoL, have been recently implemented into clinical studies. In addition, testing a two-drug versus a three-drug regimen could potentially induce a reduction of toxicity. It is hoped that this would translate into an improvement in QoL, especially when taking into account the described pulmonary toxicity of mitomycin and hemorrhagic cystitis for ifosfamide. Both of these drugs were included in the reference arm of the study.
Patient Selection Eligible patients had to fulfill the following criteria: histologic or cytologic diagnosis of NSCLC, stage IIIb (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV disease; no prior chemotherapy, immunotherapy, or radiation therapy; age between 18 and 75 years; performance status of  2 according to the Zubrod scale; life expectancy of at least 12 weeks; no active infection; no second primary malignancies except in situ carcinoma of the cervix or adequately controlled basal cell carcinoma of the skin; adequate bone marrow reserve (WBC count 3.5 x 109/L, platelet count 100 x 109/L, hemoglobin level 10 g/L, and hematocrit level 30%); and normal liver and renal function. The presence of at least one unidimensional, measurable lesion was required, although bidimensionally measurable disease was preferred. Patients with brain metastases were included in the study if they did not require emergency therapy. All patients signed written informed consent according to the protocol submitted and approved by local and regional ethical committees. Baseline evaluation included a QoL assessment, a complete history and physical examination, a complete blood cell count and serum chemistry analysis, urinalysis, an ECG, chest x-rays in the posteroanterior and lateral views, and computed tomography scans for tumor measurement according to the investigators' decision. Other imaging modalities, such as magnetic resonance imaging and bone scintigraphy, were performed according to specific clinical indications. All baseline imaging procedures were performed within 4 weeks before the study entry and repeated after two cycles and, in case of response, 4 weeks later. In patients receiving gemcitabine, the whole-blood cell count was repeated before each administration.
Sample Size The sample size was not calculated using more conventional techniques based on objective tumor response rates. However, a sample size of 150 patients per arm allowed the detection of a difference, with at least 80% power, in the tumor response rate of 18%. Both calculations assumed a two-sided significance level of .05 and an estimated nonassessability rate for efficacy analysis of 13%. The sample size was believed to be sufficient in order to assess clinically significant differences in patient QoL using the QLQ–C30-LC13. Differences that could not be detected by this study design and sample size were not considered to be of clinical interest.26 Randomization was centrally performed and patients were stratified by extent of disease (stage IIIB v stage IV), performance status (0 to 1 v 2), and investigational site. Patients were balanced with respect to study treatment in each stratum and for each factor using the algorithm described by Pocock and Simon.27
Treatment Schedule
Dose adjustments within a cycle were made for gemcitabine according to the following guidelines: on days 8 and 15 of each cycle, patients received 75% of the dose if the neutrophil count was 0.5 to 0.99 x 109/L or the platelet count was 50 to 99 x 109/L; treatment was held if the neutrophil count was less than 0.5 x 109/L or the platelet count was less than 50 x 109/L. Dose adjustments for subsequent cycles were made for each treatment group. If the WBC count fell below 3.0 x 109/L and/or the platelet count was With the exception of alopecia and nausea and vomiting, patients who experienced other nonhematologic toxicities greater than WHO grade 2 received either 50% of the scheduled dose or the dose was held. Dose escalation to the original dose was allowed if patients tolerated doses given at the 75% level and did not exhibit toxicities greater than WHO grade 1.
Treatment Evaluation Overall survival was defined as the interval from the date of randomization to the date of death. All randomized patients were included for efficacy and survival analysis according to the intent-to-treat principle. Only the QoL analysis was not based on intent-to-treat principle due to missing data. Staging, responses, and toxicities were discussed and confirmed during regular meetings of all investigators together with external radiologists. A nonparametric paired t test was used to compare changes in QoL within a treatment arm; analysis of variance was used to compare changes between treatment arms. Fisher's exact test was used to compare characteristics in the two treatment arms. Survival curves were estimated by the Kaplan-Meier technique,25 and differences were assessed by both the log-rank test and Wilcoxon's test at the .05 level of significance.
From November 1995 until January 1997, 337 patients were recruited for the trial from 30 Italian centers. Three hundred seven patients qualified for randomization: 155 in the GC arm and 152 in the MIC arm. One patient in the MIC arm refused treatment after randomization. Thirty patients failed to qualify for randomization for a variety of reasons, including misdiagnosis, patient decision, and poor health. The patient characteristics are summarized in Table 1. Prognostic factors were equally distributed across the two treatment arms. Ninety-three percent and 95% of patients had a performance status of 0 or 1 in the GC and MIC arms, respectively, and most patients (79%) in both arms had stage IV disease. The predominant histologic type was adenocarcinoma (44% of patients). Seventeen percent of patients in the GC arm and 15% of patients in the MIC arm had brain metastases at study entry.
Treatment Administration
Early death occurred in eight patients in each treatment arm. All deaths were unrelated to study medications except for three cases, two in the GP arm (one case of acute renal failure after cisplatin administration and one case of heart failure) and one in the MIC arm (sudden death). In the remaining 13 cases, nine deaths were due to the rapid clinical progression of the neoplastic disease (six in the MIC arm and three in the GP arm) and four (all in the GP arm) were due to heart arrest (two cases), sudden death (one case), or respiratory failure (one case). All of these deaths were judged by the investigators to be totally unrelated to study medications. There were 14 adverse events in the GC arm, half of them occurring during the first cycle, and 19 in the MIC arm, with two thirds of them occurring between the second and fifth cycles. The mean dose of gemcitabine delivered to all 155 patients was 722 mg/m2 (median dose, 706 mg/m2), and the mean dose of cisplatin delivered to the same patients was 86.1 mg/m2 (median dose, 86 mg/m2). In the MIC arm, the mean dose of mitomycin delivered to 151 patients was 5.9 mg/m2 (median dose, 6.0 mg/m2), of ifosfamide to the same patients, 2,915 mg/m2 (median, 3,000 mg/m2), and of cisplatin, 91 mg/m2 (median, 99 mg/m2).
QoL
Toxicity
Grade 4 thrombocytopenia was significantly more frequent and severe in the GC arm (38% v 12%, P < .001) and it led more frequently to platelet transfusions (15% v 3%). This considerable thrombocytopenia was the primary cause of gemcitabine dose reduction (23% on day 8 and 31% on day 15) and omission (9% on day 8 and 49% on day 15), which translated into a substantial reduction of planned dose-intensity for gemcitabine (70% of intended dose-intensity) (Table 5). However, on day 29, the hematologic recovery was complete for neutrophils (8% and 2% of patients had persistence of grade 3 or 4 toxicity in the GC and MIC arms, respectively) as well as for platelets (7% v 3%). Clinical manifestations of thrombocytopenia (ie, petechiae, mucosal bleeding) seldom occurred and were usually short-lived.
Grade 3 and 4 nonhematologic toxicities were reported in both arms of the study (Table 6). The main toxicities were nausea/vomiting and alopecia. Despite the prophylactic use of 5-hydroxytryptamine-3 antagonists and corticosteroids, severe nausea and/or vomiting was reported in 18% of patients treated with GC and 22% of patients treated with MIC. Alopecia was reported in both arms, but it affected a significantly greater number of patients in the MIC arm than in the GC arm (39% grade 3 in the MIC arm v 12% in the GC arm, P < .001).
Grade 3 peripheral neuropathy was rare, with reports of cases in one patient treated with GC and in two patients treated with MIC. No grade 4 peripheral neuropathy was observed in either treatment arm. Moderate or severe dyspnea (grades 3 and 4) was reported in six patients (five with grade 3 and one with grade 4) treated with GC and in three patients (all with grade 3) treated with MIC. Some of the peculiar toxicities of gemcitabine, originally reported in phase I and II studies, such as peripheral edema and flu-like syndrome, were never seen in this study. The use of high-dose corticosteroids in the prevention of emesis could have played a role in avoiding these side effects.
Response
Survival
In this large, multicenter, randomized trial, the comparison of MIC, one of the most active "old" regimens developed and used mainly in Europe, to GC, one of the most promising new combinations, showed substantial equivalence in the main end points of the trial, including QoL, median survival time, time to progression, and 1-year survival rate. The GC regimen produced a higher incidence of grade 4 thrombocytopenia (38%) than did the MIC regimen (12%). However, as in our phase II study, myelosuppression was characterized by a sharp but short nadir, with near full recovery on day 29 of each cycle, without any significant clinical relevance.17 It is important to point out that in the present trial, blood samples were collected weekly in the GC arm and only every 4 weeks in the MIC arm, with a possible underestimation of MIC myelotoxicity never checked at its maximum potential nadir. Other toxicities and symptom control, as measured by the self-administered EORTC QLQ–C30-LC13 questionnaire, seem to be equivalent in both arms. Probably most of the toxicities observed in both arms could be reasonably attributed to the high doses of cisplatin used. Despite the in vitro evidence of a steep dose-response relationship for cisplatin in NSCLC cell lines28 and preliminary positive results in the clinical setting,29 this relationship has not been further confirmed by two randomized clinical trials30,31 and, more recently, by the results of the meta-analysis.4 However, the reference arm for the present study was selected on the basis of the results of our previous randomized clinical study,6 in which the hypothesis of the existence of a dose-response relationship was accepted. GC achieved a significantly higher response rate, and this seems to be the only major difference in the study. The MIC regimen showed an activity comparable to that of our previous randomized trial6 in which the overall response rate was 40% in a study population with 58% stage IV patients. In contrast, in the present study, the overall response rate of 26% was reported in a mainly stage IV patient population (79%). The GC regimen confirmed its substantial efficacy in metastatic or poor-prognosis stage IIIB patients (ie, those with pleural effusion or N3 supraclavicular nodal involvement). The gemcitabine schedule used in this trial caused a significant dose reduction and omission, primarily on day 15, with a substantial decrease in the planned dose-intensity. Nevertheless, clinical efficacy and median survival were both at the upper value of historical control, and this is an important step for further clinical development of a GC regimen. As already shown in a previous phase II study,32 brain metastases responded, as did the other disease sites, denying the ineligibility of asymptomatic patients with brain metastases for further clinical trials evaluating chemotherapy. Recently, a randomized clinical trial recruited 522 patients with locally advanced or metastatic NSCLC and showed that gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 100 mg/m2 on day 1, every 28 days, was superior to cisplatin alone in terms of response rate (30% v 11%, P < .0001), time to progression (5.6 v 3.7 months, P = .0013), and median survival (9.1 v 7.6 months, P = .004). In the combination arm, grade 3 and 4 neutropenia and thrombocytopenia were documented in 58% and 51% of the patients, respectively.33 Taken together, the safety and efficacy results of these two randomized studies, both based on a 4-week administration schedule for gemcitabine, are quite consistent. In an attempt to reduce toxicity, an alternative schedule of GC was tested in a phase II randomized study of the Spanish Lung Cancer Study Group that clearly demonstrated the superiority of gemcitabine 1,250 mg/m2 on days 1 and 8 plus cisplatin 100 mg/m2 on day 1, every 21 days, in comparison to cisplatin and etoposide in terms of response rate (41% v 22%, P = .025) and time to progression (6.3 months v 4.3 months, P = .007). The toxicity profile of GC administered every 21 days was quite comparable to that of cisplatin and etoposide.34 A 21-day schedule was also shown to be feasible and active in a phase II randomized study from our group35 evaluating two doses of cisplatin (70 mg/m2 v 100 mg/m2) combined with gemcitabine 1,000 mg/m2 on days 1 and 8. The study showed a comparable activity of the two doses of cisplatin and a reduced toxicity of the lower dose. On the basis of the results of the present trial, of the above-mentioned Spanish clinical trial,34 and of our randomized phase II trial,35 we suggest modifying the gemcitabine administration schedule to maintain the same dose-intensity by withholding gemcitabine on day 15 and shortening the cycle duration to 21 days. This new schedule is being tested in an ongoing randomized trial that compares GC with two currently widely used chemotherapy regimens (ie, carboplatin plus paclitaxel and cisplatin plus vinorelbine) for the treatment of advanced NSCLC. The activity of this GC regimen in metastatic disease should be considered relevant for planning clinical trials in early stages such as the neoadjuvant or adjuvant setting. An example of such strategy is the phase II EORTC trial of neoadjuvant chemotherapy in stage IIIA NSCLC, in which the same schedule for GC was used as induction chemotherapy before radiotherapy or surgery; GC achieved a response rate of 73%, with three complete responses (6%) and a high percentage of surgical resections.36
The following investigators also contributed to the study: M. Mosconi, S. Darwish, and S. Porrozzi (Department of Medical Oncology Department, Policlinico Hospital, Perugia); L. Dogliotti and G. Selvaggi (Department of Clinical and Biological Sciences, University of Torino, Turin); P.F. Conte, C. Tibaldi, and A. Antonuzzo (Department of Medical Oncology, S. Chiara Hospital, Pisa); M.R. Migliorino and A. Cipri (Department of Pneumology III, Forlanini Hospital, Rome); M. Lopez (Department of Medical Oncology II, Regina Elena Institute, Rome); A. Rossi (Department of Medical Oncology B, National Cancer Institute "G. Pascale," Naples); F. Cognetti (Medical Oncology I Department, Regina Elena Institute, Rome); E. Matano and V. Damiano (Department of Endocrinology and Molecular and Clinical Oncology, Federico II University, Naples); F. Zumaglini (Department of Medical Oncology, S. Maria delle Croci Hospital, Ravenna); R. Bartolucci and S. Gasparoni (Department of Medical Oncology, S. Maria Hospital, Terni); C. Boni and L. Savoldi (Department of Medical Oncology, S. Maria Hospital, Reggio Emilia); G. Altavilla (Department of Medical Oncology, University of Messina, Messina); F. Salvati and F. Nunziati (Department of Pneumology VIII, Forlanini Hospital, Rome); R. Canaletti (Department of Medical Oncology, Civile Hospital, Piacenza); L. Morandini (Department of Pneumology, Civile Maggiore Hospital, Verona); M. Raimondi (Department of Pneumology I, "Vincenzo Cervello" Hospital, Palermo); P. Malacarne (Department of General Medicine and Medical Oncology, St Anna Hospital, Ferrara); A. Paccagnella and A. Favaretto (Department of Medical Oncology, Civile Hospital, Padova); E. Recaldin (Department of Medical Oncology, S. Cuore Hospital, Negrar, Verona); M. Clerico (Department of Medical Oncology, Regionale Hospital, Aosta); G. Cocconi and S. Salvagni (Department of Medical Oncology, Parma); V. Fosser (Medical Oncology Service, St Bartolo Hospital, Vicenza); G. Luporini and M. Clerici (Department of Medical Oncology, St Carlo Borromeo Hospital, Milan); F. Figoli (Medical Oncology Service, Arzignano, Vicenza); E. Pasquini (Medical Oncology Service, Civile Hospital, Cattolica, Forli); R. Righi (Department of Pneumology, Villa Ognissanti, Careggi Hospital, Firenze, Italy); B. Nguyen, A. Liepa, A. Hayden, and C. Niyikiza (Eli Lilly, Indianapolis, IN).
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
). The ratio of d/
100 x 109/L on day 1 of each new cycle, the whole cycle was delayed by 1 full week. If patients exhibited febrile neutropenia, World Health Organization (WHO) grade 4 thrombocytopenia, or bleeding associated with thrombocytopenia, they received 75% of the scheduled dose in the subsequent cycle. 
