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© 2001 American Society for Clinical Oncology Phase II Trial of Paclitaxel Plus Gemcitabine in Patients With Locally Advanced or Metastatic Non–Small-Cell Lung CancerFrom the Hospital Clínico Lozano Blesa and Hospital Miguel Servet, Zaragoza; Hospital Germans Trias i Pujol, Badalona; Free University of Madrid and Hospital Clínico, Madrid; Hospital General de Elche and Hospital General, Alicante; Hospital Vall d’Hebrón, Barcelona; and Hospital General, Hospital Clínico, and Hospital Arnau de Vilanova, Valencia, Spain. Address reprint requests to Rafael Rosell, MD, Medical Oncology Service, Hospital Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Barcelona, Spain; email: rrosell{at}ns.hugtip.scs.es
PURPOSE: Given the cisplatin-related myelotoxicity and nonhematologic toxicities, we were prompted to undertake a study of the noncisplatin combination of paclitaxel plus gemcitabine to evaluate the efficacy, tolerance, and survival of this combination in patients with locally advanced and metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received gemcitabine 2,000 mg/m2 and paclitaxel 150 mg/m2 on days 1 and 15 of a 28-day cycle, for a maximum of eight cycles. RESULTS: Between December 1997 and June 1998, 89 untreated NSCLC patients were enrolled; 30 (34%) had stage IIIB disease (23 with malignant pleural effusion and seven without), and 59 (66%) had stage IV disease. Eighty-six percent of patients had a performance status of 0 or 1. The median number of cycles administered was four (range, one to eight cycles). The mean dose-intensity for both paclitaxel and gemcitabine was nearly 100%. Hematologic and nonhematologic toxicities were mild. Thirty-eight patients received second-line chemotherapy after completion of the study. The overall intent-to-treat response rate was 32.2%, with a higher response rate for stage IIIB patients (43.3%) than for stage IV patients (26.3%). Overall median survival was 9.9 months, and 1-year survival was 38.8% (14.2 months for stage IIIB and 7.7 months for stage IV; P = .007). Median survival was 10.2 months for patients with a performance status of 0 or 1 and 4.8 months for patients with a performance status of 2 (P = .007). CONCLUSION: A biweekly paclitaxel/gemcitabine regimen was well tolerated, with an acceptable response rate and a reasonable median survival time, especially in patients with good performance status. It merits further exploration in future studies.
SEVERAL THREADS of evidence from meta-analyses indicate that chemotherapy modestly but significantly increases survival in patients with advanced or metastatic non–small-cell lung cancer (NSCLC). Recently in the United Kingdom, Cullen et al1 reported a randomized trial including 797 patients in which the combination of mitomycin, ifosfamide, and cisplatin 50 mg/m2 (MIC) up to four cycles enhanced survival in comparison with palliative care alone. The median survival for patients with disseminated disease was 6.7 months in the MIC group, in contrast to 4.8 months in the palliative care group (P = .03), and 1-year survival rates were 25% and 17%, respectively. This study1 has reaffirmed the well-known meta-analysis published in 1995,2 in which a hazard ratio of 0.73 in favor of cisplatin-based chemotherapy was detected in comparison with best supportive care. The 1995 meta-analysis had also found a 2-month difference in median survival time (6 v 8 months) and an absolute improvement in 1-year survival of 10% (15% v 26%). Previously, Albain et al3 identified cisplatin as an independent predictor of improved outcome (P < .00005) in a multivariate analysis of 2,290 patients. Recently, Ranson et al4 identified a hazard ratio of 0.70 in favor of paclitaxel as a single agent in comparison with best supportive care in a mixed population (53% with stage IV disease). Median survival was significantly longer in the paclitaxel group (6.8 months) than in the best supportive care group (4.8 months). Ever since, many European oncologists have often used cisplatin-based regimens to treat NSCLC. In fact, however, cisplatin toxicity is even higher with cisplatin-based combinations than with single-agent cisplatin. According to a meta-analysis,5 cisplatin-based combination chemotherapy is linked to a 3.6-fold increase in the risk of treatment-related death. Several recent studies have highlighted the cisplatin toxicity burden. Sandler et al6 have reported a randomized phase III trial of single-agent cisplatin versus gemcitabine plus cisplatin (GC) in 522 assessable patients, of whom 98 (37.7%) treated with the GC regimen and 34 (13%) treated with single-agent cisplatin required packed RBC transfusions. A comparable percentage of patients received packed RBC transfusions both in the Crinò et al7 randomized trial comparing GC with MIC (23% for the GC arm v 19% for the MIC arm) and in the Cardenal et al8 randomized trial of GC versus etoposide plus cisplatin (29% for the GC arm v 21% for etoposide + cisplatin arm). Twenty percent of patients in the Sandler et al6 GC arm and 15% of patients in the Crinò et al7 GC arm required platelet transfusions for grade 4 thrombocytopenia. In the study by Sandler et al,6 other important side effects were also recorded. Asthenia was noted in 40.2% of the patients in the single-agent cisplatin arm. The incidence of grade 3 neurohearing toxicity (hearing loss that interfered with function not correctable with a hearing aid) was 6.1% in the single-agent cisplatin arm. Furthermore, in the study by Crinò et al,7 despite the prophylactic use of 5-hydroxytryptamine-3 antagonists and corticosteroids, severe nausea or vomiting was reported in 18% of patients in the GC arm and 22% of patients in the MIC arm. Paclitaxel/gemcitabine doublets have been analyzed in phase I and II studies. Einhorn et al9 reported a phase I trial in NSCLC combining gemcitabine with paclitaxel, in which each drug was administered weekly for 3 weeks every 4 weeks. The response rate was 40%, with mild grade 3 or 4 neutropenia and thrombocytopenia. Doses were escalated without side effects up to 800 mg/m2 and 80 mg/m2, respectively. De Pas et al10 also carried out a phase I study in NSCLC evaluating the same weekly schedule of paclitaxel/gemcitabine administered weekly for 3 consecutive weeks every 4 weeks. Doses were escalated up to 1,750 mg/m2 and 100 mg/m2, respectively, without reaching the maximum-tolerated dose. The overall response rate was 59%, with no apparent dose-response relationship. Giaccone et al11 conducted a phase I/II study with escalating doses of paclitaxel 150, 175, and 200 mg/m2 on day 1 and a fixed dose of gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks. The paclitaxel/gemcitabine combination was well tolerated, and the mild toxicity allowed an increase of the paclitaxel dose from 150 to 200 mg/m2. Hence, 30 subsequent NSCLC patients were treated at the paclitaxel dose of 200 mg/m2 with gemcitabine 1,000 mg/m2 on days 1 and 8. The overall response rate was 24% in 49 (63% stage IV) assessable patients with almost nil toxicity. In this phase I/II study,11 paclitaxel was given as a 3-hour infusion before gemcitabine. Rothenberg et al12 performed a phase I trial of paclitaxel/gemcitabine administered every 2 weeks in patients with refractory tumors. Both drugs were administered on day 1 of a 14-day cycle. The recommended phase II dose was paclitaxel 150 mg/m2 and gemcitabine 3,000 mg/m2. However, two additional studies using different schedules of paclitaxel and gemcitabine showed an association with severe myelotoxicity. Poole et al13,14 sought different schedules of paclitaxel/gemcitabine in two phase I trials. The administration of paclitaxel on day 1 and gemcitabine days 1, 8, and 15 every 28 days was hampered by a high incidence of grade 4 neutropenia.13 Conversely, the administration of paclitaxel on day 8 and gemcitabine on days 1 and 8 in a 3-week schedule resulted in a lower incidence of grade 3 and 4 neutropenia. On the basis of the clinical activity of gemcitabine and the special action of paclitaxel on beta-tubulin, we decided to evaluate the activity of the paclitaxel/gemcitabine combination in a large phase II trial in advanced or metastatic NSCLC patients, administering paclitaxel as a 3-hour infusion before gemcitabine once every 2 weeks.
Eligibility Patients were required to have documented histologically or cytologically confirmed diagnosis of unresectable stage IIIB (preferably with pleural effusion) or IV NSCLC, including nonsymptomatic CNS metastases. Patients were required to have measurable (lesions that can be accurately measured in at least one dimension) or nonmeasurable (all other lesions) disease. Patients were required to have an Eastern Cooperative Oncology Group performance status of  2, adequate bone marrow reserve (WBC count, 3.5 x 109/L; platelet count, 100 x 109/L; and hemoglobin level, 9.0 mg/dL), and adequate renal function (serum creatinine level 1.5 mg/dL). Exclusion criteria included the presence of prior malignancies (except basal cell carcinoma of the skin or carcinoma-in-situ of the cervix). Prior radiotherapy was allowed as long as the irradiated area was not the only source of measurable disease and the therapy was completed at least 3 weeks before enrollment onto the study. This multicenter protocol was approved by the ethics committees of the participating hospitals. Written informed consent was obtained from all patients.
Pretreatment Evaluation Before each course, we repeated the medical history and physical examination, laboratory assessment (only blood cell count on day 15), weight determination, and toxicity evaluation (Eastern Cooperative Oncology Group criteria,15 except for arthralgia/myalgia and asthenia, which were based on Cancer and Leukemia Group B criteria).
Treatment
Dose Adjustments and Evaluations During Treatment
Determination of Response
Statistics
Eighty-nine patients with locally advanced or metastatic NSCLC were enrolled from 10 Spanish Lung Cancer Group–affiliated institutions between December 1997 and June 1998. Median follow-up was 9.6 months (range, 0.6 to 30 months). Patient characteristics are listed in Table 1. The median age was 67 years (range, 36 to 75 years). Most patients were male (95%) and had a performance status of 0 or 1 (86%). Fifty-nine patients (66%) had stage IV disease. Forty patients (45%) had squamous cell carcinoma, and 23 patients (25%) had lost more than 5% of their usual body weight during the 6 months before study entry. Sixteen patients had undergone prior surgery, and eight had received prior radiation therapy.
The median number of cycles administered was four (range, one to eight cycles). In 20 (5.2%) of 379 cycles, administration was delayed for a median of 13 days. Delay in four cycles (1%) was due to neutropenia. In the other 16 cycles, it was due to other factors, such as asthenia, neurotoxicity (paresthesias and dysesthesia), nausea and vomiting, and temporary elevations in serum transaminase levels. In 29 additional cycles (7.6%), dose reduction was necessary, mainly due to neurologic toxicity, asthenia, diarrhea, and hematologic toxicity. The mean dose-intensity was gemcitabine 966.5 mg/m2/wk (96.6% of planned dose) and paclitaxel 72.9 mg/m2/wk (97.2% of planned dose). No CRs and 28 PRs were observed, for an overall intent-to-treat response rate of 32.2% (95% CI, 22.4% to 42%). The paclitaxel/gemcitabine combination had a higher response rate for stage IIIB patients, with 13 PRs (43.3% [95% CI, 26.3% to 60.3%]), than for stage IV patients, with 15 PRs (26.3% [95% CI, 14.9% to 37.7%]). Toxicity was assessable in 88 patients (one patient died before starting treatment), and no different toxicity patterns were observed according to disease stage ( Table 2). Only two patients required packed RBC transfusions. No febrile neutropenia, severe infections, fatal infections, bleeding, or platelet transfusions occurred. Nonhematologic toxicities are listed in Table 2. No relevant neurologic toxicities were reported. Most patients did not experience pulmonary toxicity. Severe dyspnea could be attributable to lung cancer progression, chronic obstructive pulmonary disease, pneumonia, or pleural effusion.
Overall median survival was 9.9 months (95% CI, 8 to 11.7 months). One-year survival probability was 38.8%, and 2-year survival probability was 20%. Broken down by stage, median survival was 14.2 months (95% CI, 10.5 to 17.9 months) for stage IIIB patients and 7.7 months (95% CI, 4.5 to 10.9 months) for stage IV patients (log-rank test, P = .007) ( Fig 1). Median survival according to performance status was 10.2 months (95% CI, 7.9 to 12.5 months) for patients with a performance status of 0 or 1 and 4.8 months (95% CI, 2.3 to 7.3 months) for patients with a performance status of 2 (log-rank test, P = .007) ( Fig 2).
The use of noncisplatin combinations of gemcitabine with taxanes is a relatively novel approach whose main aim is to diminish cisplatin-related myelotoxicity and other side effects. Dose schedule is still a central issue in this search for a balance between good response rate and low toxicity. The days-1-and-8 schedule for gemcitabine plus taxanes has been recommended.20 Giaccone et al11 administered paclitaxel up to 200 mg/m2 on day 1 with gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks. Grade 2 peripheral neurotoxicity was observed in 14% of patients, but the incidence of grade 3 or 4 neutropenia was minimal (17%). Intriguingly, grade 3 or 4 pulmonary toxicity was reported in 2% of patients. Also on a biweekly schedule,12 pneumonia and interstitial fibrosis were reported in one of 10 cases.21 A phase I study of docetaxel 100 mg/m2 on day 1 and gemcitabine 800 mg/m2 on days 1, 8, and 15 every 28 days attained a 43% response rate in previously treated NSCLC patients. However, toxicity was high, with limiting thrombocytopenia and hepatic dysfunction, and 25% of the patients required RBC transfusions.22 On the other hand, when docetaxel 100 mg/m2 was administered on day 8 and gemcitabine 900 mg/m2 on days 1 and 8 every 3 weeks with prophylactic granulocyte colony-stimulating factor, grade 4 anemia and thrombocytopenia were uncommon (2%), and grade 3 or 4 neutropenia was 8%.23 In a phase I/II trial, the triplet of paclitaxel, carboplatin, and gemcitabine caused a considerable toxicity, including 14% hospitalizations for febrile neutropenia, and fatigue was scored at 41%.24 Less toxicity was observed with a similar triplet of paclitaxel, cisplatin, and gemcitabine administered on days 1 and 15 every 4 weeks. However, grade 4 neutropenia occurred in 58% of patients, with only one episode of febrile neutropenia. Median survival was 11.5 months, with 42% 1-year survival.25 Little efficacy data are available on the paclitaxel/gemcitabine combination, but the 32.2% response rate, 9.9-month median survival time, and 38.8% 1-year survival observed in our study mirror the results commonly reported in phase II trials of cisplatin combinations with vinorelbine, paclitaxel, docetaxel, and gemcitabine and the paclitaxel/carboplatin combination (reviewed in Bunn and Kelly26). Although we must concede that our trial included a number of patients with malignant pleural effusion, which may have influenced outcome, when median survival is broken down by disease stage, our 7.7-month median survival time for the 59 stage IV patients does not differ from other studies combining either cisplatin or carboplatin with paclitaxel. However, in randomized studies of cisplatin combinations, the incidence of grade 3 or 4 neutropenia is high. The Le Chevalier et al27 trial reported 78.7% grade 3 or 4 neutropenia in the vinorelbine/cisplatin arm; the incidence of anemia was not reported. In the Giaccone et al28 trial, RBC transfusions were required in 13% of patients treated with cisplatin 80 mg/m2 and paclitaxel 175 mg/m2. Similarly, Schiller et al29 reported a 64% response rate and 17-month median survival using cisplatin 120 mg/m2 plus weekly vinblastine 5 mg/m2 and amifostine, again with the cost of grade 4 neutropenia in 92% of patients. To date, one of the best combinations in terms of tolerability and compliance is paclitaxel/carboplatin,30 which has been tested in two randomized trials. The Southwest Oncology Group trial attained a 27% response rate, 8-month median survival, and 36% 1-year survival rate.31 Kosmidis et al32 obtained similar results with this combination. Hypothesizing that survival could be influenced by the paclitaxel dose,33 they compared two different paclitaxel doses (175 v 225 mg/m2) with carboplatin dosed to an area under the concentration-time curve of 6. The higher-dose group showed a tendency to higher survival but without statistical significance, but significantly more neutropenia and neurotoxicity were observed. Only two studies have compared cisplatin/taxane or carboplatin/taxane combinations with noncisplatin/taxane regimens. Georgoulias et al34 compared docetaxel 100 mg/m2 plus cisplatin 80 mg/m2 with gemcitabine 1,100 mg/m2 on days 1 and 8 plus docetaxel 100 mg/m2 on day 8; granulocyte colony-stimulating factor was administered to both arms. Overall response rates, survival, and toxicities were similar in both arms. However, docetaxel/gemcitabine yielded a higher response rate in adenocarcinoma. Kosmidis et al35,36 carried out a randomized trial with 329 patients comparing paclitaxel 200 mg/m2 plus carboplatin dosed at an area under the concentration-time curve of 6 with paclitaxel at the same dose plus gemcitabine 1,000 mg/m2 on days 1 and 8. Interestingly, the response rate and median survival time were better in the gemcitabine arm, although the difference was not statistically significant. Grade 3 or 4 neutropenia was similar in both arms (around 10%), and grade 3 or 4 thrombocytopenia was also similar in both groups (1%); grade 3 or 4 anemia was almost nil, and grade 3 neurotoxicity was reported in 6% of patients in the gemcitabine arm. Our results are in line with those reported for recent trials of new drug combinations. As might be expected, survival was related to disease stage and performance status, which supports the decision in many trials not to include patients with poor performance status. The median survival time of 4.8 months for patients with a performance status of 2 concurs with the results reported by Johnson et al30 in the subgroup of patients with poor performance status, which led the investigators to exclude patients with poor performance status from the E-1594 phase III randomized trial. Our biweekly regimen used a lower gemcitabine dose than that recommended by Rothenberg et al,12 without any apparent effects on response rate and with the advantage of the absence of severe hepatic toxicity. One of the most significant findings in our study was the low toxicity reported, with almost null hematologic and neurologic toxicity compared with other commonly used chemotherapy regimens. The choice of the best schedule still remains to be elucidated. However, it seems that the use of a days-1-and-8 schedule halving paclitaxel doses remains an interesting option that merits further exploration.
Supported by Bristol-Myers Squibb and Eli Lilly Laboratories.
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Ranson M, Davidson N, Nicolson M, et al: Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 92: 1074-1080, 2000 5. Lilenbaum RC, Langenberg P, Dickersin K, et al: Single agent versus combination chemotherapy in patients with advanced nonsmall cell lung carcinoma. A meta-analysis of response, toxicity, and survival. Cancer 82: 116-126, 1998[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
