Journal of Clinical Oncology, Vol 18, Issue 1
(January), 2000: 122
© 2000 American Society for Clinical Oncology
Phase III Trial of Gemcitabine Plus Cisplatin Versus Cisplatin Alone in Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer
By A. B. Sandler,
J. Nemunaitis,
C. Denham,
J. von Pawel,
Y. Cormier,
U. Gatzemeier,
K. Mattson,
Ch. Manegold,
M. C. Palmer,
A. Gregor,
B. Nguyen,
C. Niyikiza,
L. H. Einhorn
From the Hoosier Oncology Group, The Walther Cancer Institute, and the Department of Medicine, Indiana University, Indianapolis; and Eli Lilly and Company, Indianapolis, IN; Physicians Reliance Network, Dallas, TX; Zentralkrankenhaus, Gauting; Grosshansdorf Hospital, Hamburg; and Thoraxklinik, Heidelberg, Germany; Centre de Pneumonologie de Laval, Quebec; and Cross Cancer Institute, Alberta, Canada; Helsinki University Hospital, Helsinki, Finland; and Western General Hospital, Edinburgh, Scotland.
Address reprint requests to Alan Sandler, MD, Indiana University Indiana Cancer Pavilion, Room 473 535 Barnhill Dr, Indianapolis, IN 46202-5286; email asandler{at}iupuie.edu
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ABSTRACT
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PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non–small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC.
PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m2 intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m2 intravenously on day 1) plus gemcitabine (1,000 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle).
RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25.4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P < .0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P = .0013), and overall survival (9.1 months compared with 7.6 months, respectively; P = .004).
CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.
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INTRODUCTION
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NON–SMALL-CELL lung cancer (NSCLC) remains a malignancy that is moderately chemosensitive to most currently available chemotherapeutic agents. Of the more commonly used oncolytics, the most active agents are cisplatin, mitomycin, vinblastine, and etoposide, with response rates in the 15% to 25% range.1
Cisplatin is one of the most extensively studied agents in the treatment of metastatic NSCLC. Pooled data from 10 phase II trials revealed an overall response rate of 21%.1 Combination chemotherapeutic regimens containing cisplatin are considered to be the most active regimens currently available, with response rates in the 25% to 30% range.2 The impact of such regimens on overall survival is less clear. Five major controlled trials have been conducted that compare cisplatin-based chemotherapy with best supportive care.3-7 Only two trials (Rapp et al,6 with 172 assessable patients, and a small French study by Quoix et al,5 with only 49 patients) have shown a statistically significant improvement in median survival from the use of chemotherapy (approximately 6 to 8 months) compared with best supportive care (approximately 3 to 4 months). A recent meta-analysis demonstrated that cisplatin-based regimens produce a modest improvement in the metastatic disease setting. The hazard ratio for patients treated with cisplatin-based regimens compared with best supportive care is 0.73. This translates into an absolute improvement in 1-year survival of 10% (from 15% to 26%) and a median survival improvement from 6 to 8 months.8 Clearly, newer and more active agents are needed in the treatment of advanced or metastatic NSCLC.
Newer agents with initial response rates greater than 20% include the taxanes (paclitaxel and docetaxel), vinorelbine (a new vinca alkaloid), and the camptothecins (of which irinotecan is the most actively studied agent9 ). Another new and exciting agent is gemcitabine, a nucleoside analog that is structurally related to cytarabine.10
Gemcitabine has been studied extensively as a single agent in patients with previously untreated NSCLC. Such studies have involved nearly 600 assessable patients.11-14 Doses in these studies have ranged from 800 to 1,200 mg/m2, administered once weekly for 3 of 4 weeks. Gemcitabine was well tolerated, with the principal hematologic toxicity being grade 3/4 neutropenia (10% to 20% of patients). Nonhematologic toxicities were also mild, consisting of transient rashes, peripheral edema, malaise, and reversible transaminase elevations. The overall response rate was 21%.
Gemcitabine, by its mechanisms of action, was felt to be potentially synergistic with cisplatin. Two recent abstracts from the Netherlands support this finding. Peters et al15 studied the combination of gemcitabine and cisplatin in human ovarian cancer cell lines and noted synergy with long-term (24 to 72 hours) simultaneous exposure. Braakhuis et al16 studied cisplatin plus gemcitabine in two human xenografts (head/neck squamous cell carcinoma) and a murine colon carcinoma transplanted in nude mice. This study also reported a synergistic effect with simultaneous administration.
Thus, it was logical to combine cisplatin with gemcitabine in the treatment of patients with NSCLC. There have been four completed phase II trials of gemcitabine plus monthly cisplatin in patients with NSCLC that explore different schedules of cisplatin (day 1, 2, or 15). The results of these four trials have been fairly consistent, with response rates ranging from 32% to 54% and median survivals of 8.4 to 15.1 months.17-20 We recently reported on the results of our Hoosier Oncology Group phase II trial of cisplatin 100 mg/m2 administered on day 1 with gemcitabine 1,000 mg/m2 administered on days 1, 8, and 15 of each 28-day cycle.17 In this trial, there were 27 assessable patients, with responses occurring in nine patients for an overall response rate of 33%. The overall median survival was 8.4 months, and 37% of patients were alive at 1 year. Toxicities were predominantly hematologic, with grade 3/4 neutropenia and thrombocytopenia occurring in 50% and 50% of patients, respectively.
This phase III international trial was designed to compare the efficacy, primarily in terms of overall survival, of the combination therapy of gemcitabine and cisplatin with cisplatin monotherapy in patients with locally advanced or metastatic NSCLC.
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PATIENTS AND METHODS
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Eligibility
Patients were required to have documented histologically or cytologically confirmed diagnosis of unresectable stage IIIA, IIIB, or IV NSCLC. Patients were required to have measurable or assessable disease and to have received no prior chemotherapy or prior biologic response modifier therapy. Prior radiation therapy 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. Patients were required to have a Karnofsky performance status of 70 to 100; adequate bone marrow reserve (WBC count 3.5 x 109/L, platelets 100 x 109/L, and hemoglobin 9.0 mg/dL); and adequate renal function (serum creatinine  1.5 mg/dL). Four weeks must have passed after major surgery, and patients must have recovered from all toxicity. Patients with prior malignancies were eligible provided they had been disease-free for 5 or more years. Women patients of childbearing potential were required to use an approved form of contraception during the period of study and could not be pregnant at the time of study entry. All patients gave informed consent before study enrollment.
Pretreatment Evaluation
Before initiation of chemotherapy, all patients underwent a history and physical examination, determination of performance status, and measurement of bidimensionally measurable disease (when present). A complete blood cell count, with differential and platelet count, and serum levels of creatinine, transaminases, bilirubin, and calcium were all obtained before entry. A chest x-ray and chest and abdominal computed tomography scans were performed as required to evaluate bidimensionally measurable disease. Health-related quality of life (HRQoL) was assessed with the self-administered Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire.21 Only patients from Canada, the United Kingdom, and the United States participated in the HRQoL assessment because translations of the FACT-L for the other participating countries were not available at the time this trial was initiated.
Treatment
Patients were randomized to one of two treatment regimens, either gemcitabine plus cisplatin or single-agent cisplatin. On the gemcitabine plus cisplatin treatment arm, gemcitabine was administered intravenously (IV) at 1,000 mg/m2 over 30 to 60 minutes on days 1, 8, and 15 followed by 1 week of rest; cisplatin was administered IV at 100 mg/m2 over 30 to 120 minutes on day 1 after the gemcitabine dose. On the single-agent cisplatin treatment arm, cisplatin was administered IV at 100 mg/m2 over 30 to 120 minutes on day 1 of each 4-week (28-day) cycle. Patients received pretreatment IV hydration according to institutional guidelines for cisplatin administration. These 4-week schedules defined a cycle of treatment. Patients may have received a maximum of six cycles.
Dose Adjustments and Evaluations During Treatment
Hematologic toxicity.
Complete blood cell counts with differential and platelet count were performed on days of treatment. Intracycle dosage adjustments were made based on absolute granulocyte count and platelet count as listed in Table 1. Patients who developed either granulocytopenic fever that required antibiotic therapy or bleeding associated with thrombocytopenia received a 25% dose reduction of both cisplatin and gemcitabine for subsequent treatment cycles. A cycle was not started until the absolute granulocyte count was greater than 1.5 x 109/L and platelet count was greater than 100 x 109/L.
Nonhematologic toxicity.
Within a cycle, patients with nonhematologic toxicities grade 0 to 2 (and grade 3 nausea/vomiting) received the full dose of gemcitabine on days 8 and 15. For grade 3 nonhematologic toxicity, other than nausea/vomiting and alopecia, patients received either 75% of the full dose of gemcitabine or no treatment at the discretion of the physician/investigator. For grade 4 nonhematologic toxicities, the gemcitabine dose was held.
Serum creatinine was evaluated on the first treatment day of each cycle. Cisplatin dose was reduced by 25% for a serum creatinine level of 1.6 to 2.0 mg/dL and held for serum creatinine  2.0 mg/dL. The treatment cycle was also delayed for grade 3 or 4 neurotoxicity. Before each course, past history, a physical examination, and determination of performance status was documented, as were measurements of serum creatinine, hepatic transaminases and bilirubin, and urinalysis. If a chest x-ray was adequate to document bidimensionally measurable disease, this was repeated before each cycle of therapy. However, if chest or abdominal computed tomography scans were required to document bidimensionally measurable disease, these were repeated at the beginning of every other cycle of therapy. The FACT-L was completed at the end of each cycle of therapy.
Determination of Response
A complete response (CR) was defined as the complete disappearance of all clinically detectable malignant disease and the return of all abnormal tests to normal values for a period of at least 4 weeks. A designation of partial response (PR) required a decrease of at least 50% of the sum of the cross-sectional areas of all measured lesions in the absence of progression of any existing lesions for at least 4 weeks or the appearance of any new lesions within that time. Progressive disease (PD) was defined as any of the following: (1) a 50% increase or an increase of 10 cm2 in the sum of the products of all measurable lesions over smallest sum observed; (2) clear worsening of any assessable disease; (3) reappearance of any lesion that had disappeared; (4) or appearance of any new lesion/site. Stable disease (SD) was defined as that which did not satisfy the criteria for either CR, PR, or PD. Both the time to disease progression and survival time were measured from the time of randomization.
Statistics
Comparison of tumor response rates between the treatment arms was performed using Fisher’s exact test. Kaplan-Meier analysis was performed using LIFETEST procedure in SAS (SAS/STAT User’s Guide, Version 6; SAS Institute, Cary, NC). Cox proportional hazard analyses of data from time to event variables (survival time, time to PD, and so on) were performed using PHREG procedure in SAS.21,22 Comparison of changes in FACT-L scores between arms was performed using a nonparametric paired t test and analysis of variance.
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RESULTS
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Patient Characteristics
A total of 522 patients were enrolled onto the study; 154 (29.5%) were women, and 368 (70.5%) were men. The greatest number of patients were white (90.2%). Two hundred-sixty patients (78 women and 182 men) were enrolled onto the gemcitabine plus cisplatin treatment arm, and 262 patients (76 women and 186 men) were enrolled onto the cisplatin monotherapy treatment arm. Patient ages ranged from 35 to 88 years, with a median age of 62 years on the gemcitabine plus cisplatin treatment arm, and a median age of 63 years on the cisplatin single-agent treatment arm. Both treatment arms were well balanced with respect to baseline disease characteristics (Table 2). On the gemcitabine plus cisplatin treatment arm, most patients had adenocarcinoma (36.5%), followed by squamous cell carcinoma (30.4%); this compares with 47.7% and 25.2%, respectively, for patients in the single-agent cisplatin arm. Approximately two thirds of patients had stage IV cancer, one fourth had stage IIIB cancer, and less than one tenth had stage IIIA cancer. Most patients had high performance status scores; 82% of patients on the combination arm and approximately 90% of patients on the cisplatin monotherapy arm had a Karnofsky performance status of 80 to 100. Approximately 14% of all patients received prior radiotherapy; most of the previously irradiated (approximately 10% of patients enrolled) had received thoracic radiotherapy, and the remainder had received palliative radiotherapy to either bone or brain.
Hematologic Toxicity
As expected, bone marrow suppression (anemia, leukopenia, and thrombocytopenia) was more pronounced with the combination gemcitabine plus cisplatin regimen compared with single-agent cisplatin (Table 3). In the gemcitabine plus cisplatin treatment arm, World Health Organization (WHO) toxicity criteria grade 3 and 4 anemia was observed in 21.8% and 3.2% of patients, respectively. In the single-agent cisplatin treatment arm, grade 3 and 4 anemia toxicity was observed in 5.7% and 0.8% of patients, respectively. Ninety-eight patients (37.7%) treated with the combination regimen and 34 patients (13.0%) treated with single-agent cisplatin received packed RBC transfusions, with an average of 4 units per patient.
Grade 3 and 4 thrombocytopenia was seen more frequently in the gemcitabine plus cisplatin arm (25.0% and 25.4%, respectively) compared with the single-agent cisplatin arm (2.8% and 0.8%, respectively). Fifty-three patients (20.4%) in the combination regimen had platelet transfusions compared with one patient (0.4%) in the single-agent cisplatin treatment arm. No patient in either arm suffered a significant hemorrhagic event associated with grade 4 thrombocytopenia.
Grade 3 and 4 granulocytopenia also occurred more frequently in the gemcitabine plus cisplatin combination regimen (21.7% and 35.3%, respectively) than in the single-agent cisplatin arm (3.3% and 1.2%, respectively). Twelve patients (4.6%) in the gemcitabine plus cisplatin arm were hospitalized for febrile neutropenia compared with two patients (1.3%) in the single-agent cisplatin arm.
Nonhematologic Toxicity
Grades 3 and 4 toxicities are listed in Table 4. No significant differences between the two treatment arms were reported of serious nonhematologic toxicities. The incidences of grade 3 or 4 nausea and vomiting were similar in both treatment groups. Asthenia and malaise (no grading scale reported) was reported for 58% and 4.2% of patients on the combination arm, respectively, and for 40.2% and 3.8% of the patients on the single-agent cisplatin arm, respectively. Grade 4 creatinine toxicity was noted in one patient on each treatment arm. Grade 3 creatinine toxicity was seen in 4.4% of patients treated with gemcitabine plus cisplatin and in 1.6% of patients treated with single-agent cisplatin. Most patients did not experience pulmonary toxicity. Sixteen patients (6.4%) treated with gemcitabine plus cisplatin and 12 patients (4.9%) treated with single-agent cisplatin experienced grade 3 or 4 pulmonary toxicity. In only two patients (one in each treatment group), drug causality could not be dismissed. Eleven of the 16 patients in the combination treatment arm and 10 of the 12 patients in the single-agent treatment arm had pre-existing dyspnea attributable to lung cancer and/or other significant cardiopulmonary diseases, such as chronic obstructive pulmonary disease, congestive heart failure, pneumonia, or pleural effusion. Grade 3 neuromotor toxicity was higher in the combination regimen (11.5% of patients) compared with single-agent cisplatin (2.5% of patients). One patient on the cisplatin plus gemcitabine arm reported grade 4 neurohearing toxicity in this study. The incidences of grade 3 neurohearing toxicity (hearing loss that interfered with function but was correctable with a hearing aid) were similar in both groups, 5.6% of patients in the gemcitabine plus cisplatin arm and 6.1% in the single-agent cisplatin arm. No grade 4 neurosensory toxicity was reported, and only two patients in each arm (0.8%) had grade 3 neurosensory toxicity. Minimal liver function abnormalities were noted, and more than 90% of all patients had normal or mild (grade 1) transaminase and bilirubin elevation.
Delivered Dose-Intensity
The median number of cycles of gemcitabine plus cisplatin administered was four, and the median number of cycles of single-agent cisplatin administered was two. For the first four cycles of treatment, at least 36% of all patients in the gemcitabine plus cisplatin treatment arm received full doses of gemcitabine, 16.6% to 19.7% of patients had at least one reduced dose, and 24.6% to 42.0% of patients had at least one dose omitted within a cycle (Tables 5 and 6). The main reasons for gemcitabine dose reductions and omissions were thrombocytopenia (40.1% and 47.9%, respectively) and leukopenia (26.9% and 17.4%, respectively). In the gemcitabine plus cisplatin treatment arm, most patients received the full dose of cisplatin, with only 4.5% to 13.9% dose reductions in the first four cycles. In the single-agent cisplatin arm, most patients also received the full dose of chemotherapy. In the first four cycles of treatment, only up to 5.4% of patients had dose reductions, primarily because of creatinine elevation (49.0%). For the combination treatment arm, the mean dose-intensity of gemcitabine was 796.3 mg/m2 for the 4-week schedule (3 weeks on and 1week off), and the mean dose-intensity of cisplatin was 97.0 mg/m2 every 4 weeks. For the single-agent cisplatin treatment arm, the mean dose-intensity for cisplatin was 98.0 mg/m2 every 4 weeks.
Response
Gemcitabine plus cisplatin had a statistically higher overall response rate than single-agent cisplatin, 30.4% versus 11.1%, respectively (two-tailed test, P < .0001) (Table 7). The combination treatment arm yielded three CRs and 76 PRs, for an overall intent-to-treat response rate of 30.4%. The cisplatin treatment arm yielded one CR and 28 PRs, for an intent-to-treat response rate of 11.1%. Each treatment arm also yielded one PR in nonmeasurable disease (per SWOG response criteria).
Time to PD
The estimated median time to PD was 5.6 months (95% confidence interval [CI], 4.6 to 6.1) for gemcitabine plus cisplatin patients compared with 3.7 months (95% CI, 3.3 to 4.2) for cisplatin patients (log-rank test, P = .0013) (Fig 1).
Survival
The estimated median survival was 9.1 months (95% CI, 8.3 to 10.6) for gemcitabine plus cisplatin patients compared with 7.6 months (95% CI, 6.5 to 8.2) for cisplatin patients (log-rank test, P = .004) (Fig 2). The 1-year survival probability was estimated at 39% for gemcitabine plus cisplatin patients, and 28% for cisplatin patients.
HRQoL
Three hundred seventy-eight of the randomized patients (72.4%) participated in the HRQoL assessment. One hundred sixty-one patients in the gemcitabine plus cisplatin treatment arm and 149 patients in the single-agent cisplatin treatment arm met the criteria of completing both a baseline and at least one other FACT-L questionnaire. The median number of questionnaires completed by these patients was four in the combination treatment arm and three in the single-agent cisplatin treatment arm. Baseline scores and median changes at last observation for each patient were not different between the treatment arms (Table 8). Patients in both treatment arms noted decreases in physical and functional well-being and total FACT-L scores but no differences in the other subscales; these changes were not statistically different. Both treatment arms noted a decreased HRQoL, which is not surprising considering the toxic effects of chemotherapy. However, no differences were noted between the treatment arms.
Second-Line Chemotherapy
A total of 27% of patients on the cisplatin monotherapy arm and 18% of patients on the combination arm received second-line chemotherapy. Most of these patients received vinorelbine as second-line therapy (40% of patients on cisplatin arm; 37% on gemcitabine plus cisplatin arm). Taxanes (docetaxel or paclitaxel) were also used for second-line chemotherapy (31% of patients on cisplatin arm; 46% on gemcitabine plus cisplatin arm). Gemcitabine was used as second-line therapy for patients on the cisplatin arm (14%); no patients on the gemcitabine and cisplatin arm received gemcitabine as second-line therapy.
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DISCUSSION
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The results of this large, multicenter, randomized clinical trial reveal a significant survival advantage for the combination of gemcitabine plus cisplatin when compared with cisplatin monotherapy in the treatment of patients with previously untreated advanced or metastatic NSCLC.
Cisplatin was chosen as the control arm because at the initiation of this study, no prior randomized trial had ever shown a survival advantage for combination chemotherapy when compared with cisplatin monotherapy in patients with NSCLC.23,24 In one randomized study, 162 patients were randomized to either single-agent cisplatin (120 mg/m2 every 3 weeks) or the same dose of cisplatin in combination with etoposide (100 mg/m2 on days 1, 2, and 3 of each cycle). In the study, no statistically significant differences were seen in survival; the median survival was 26 weeks for single-agent cisplatin and 22 weeks for cisplatin plus etoposide. The response rate, however, was slightly higher for combination therapy than cisplatin monotherapy (26% v 19%, respectively).24 The results of patients treated with cisplatin in our study (response rate of approximately 11% and survival of 7.6 months) are comparable with other studies conducted with single-agent cisplatin as the control arm.25-28
In this study, both response rate and survival favored the combination arm. This trial randomized approximately 30% of patients with stage IIIA or IIIB to each arm, and, as such, it is worthwhile to examine the results in the context of stage of disease. The response rates for the combination therapy were superior to that of cisplatin alone in patients with both stage III (38% and 22%, respectively; P = .027) and stage IV (27% and 7%, respectively; P < .001) disease. Survival was also superior for patients with stage III disease treated with cisplatin plus gemcitabine compared with cisplatin monotherapy, with a median survival of 13.7 months versus 8.1 months, respectively (log-rank test, P = .0108). For patients with stage IV NSCLC, the differences in survival again favored the combination arm over single-agent cisplatin (8.3 months v 6.8 months, respectively) but did not reach statistical significance (log-rank test, P = .1162).
Hematologic toxicity was seen more commonly in the combination arm. Such toxicity is not surprising given the comparison of a two-drug combination with that of single-agent cisplatin (known to be minimally myelosuppressive). Although there was a 57% incidence of grade 3/4 neutropenia (35% grade 4) in the combination arm, no significant difference was noted in neutropenic fevers between the combination therapy and monotherapy arms (4.6% v 0.8%, respectively). The increased incidence of grade 3/4 anemia may be explained by the increased number of cycles received by patients on the combination arm (median number of cycles, four) compared with the single-agent cisplatin arm (median number of cycles, two). The incidence of thrombocytopenia is intriguing and may be multifactorial. Thrombocytopenia resulted in a large percentage of patients experiencing dose reductions or omissions of gemcitabine and occurred most commonly on day 15. Nearly one half of the gemcitabine dose reductions and two thirds of the gemcitabine dose omissions on day 15 were a result of thrombocytopenia. Such reductions/omissions dictated by thrombocytopenia have not been seen with single-agent gemcitabine. This may be explained by (1) the additional thrombocytopenic effects of cisplatin that occur around day 14; and (2) synergy between cisplatin and gemcitabine. This theory may explain the relative infrequency of thrombocytopenia seen when cisplatin is administered on day 15 of this 28-day regimen. The thrombocytopenia was readily reversible, as evidenced by the virtual absence of serious hemorrhagic events.
In summary, this randomized phase III trial proves that the addition of gemcitabine to cisplatin is superior, in terms of response rate, time to progression, and most importantly, survival, to single-agent cisplatin in the treatment of previously untreated patients with advanced or metastatic NSCLC. In the study by Wozniak et al,27 432 patients with advanced or metastatic NSCLC were randomized to receive either monthly cisplatin or the combination of monthly cisplatin and weekly vinorelbine. The combination therapy was superior to the single-agent therapy with respect to response rate (26% v 12%, respectively) and median survival (8 v 6 months, respectively; P = .0001). Von Pawel et al28 reported on a study of 408 patients with advanced or metastatic NSCLC randomized to receive cisplatin administered every 3 weeks with or without the bioreductive agent, tiripazamine. Again, the combination arm was superior to single-agent therapy in terms of response rate (27.5% v 13.7%, respectively; P < .001) and median survival (8.9 v 6.9 months, respectively; P = .0076). Given the results of this trial, gemcitabine plus cisplatin should be considered as a standard regimen for the first-line treatment of advanced NSCLC, and single-agent cisplatin should no longer be considered an appropriate control arm in future randomized studies of patients with advanced or metastatic NSCLC.
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ACKNOWLEDGMENTS
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Supported in part by Eli Lilly and Company, the Hoosier Oncology Group, and the Walther Cancer Institute (Indianapolis, IN).
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NOTES
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Presented in part at the 34st Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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Submitted February 22, 1999;
accepted August 12, 1999.
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TOP
ABSTRACT
INTRODUCTION
