Journal of Clinical Oncology, Vol 17, Issue 1
(January), 1999: 12
© 1999 American Society for Clinical Oncology
Randomized Phase III Study of Gemcitabine-Cisplatin Versus Etoposide-Cisplatin in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer
Felipe Cardenal,
M. Paz López-Cabrerizo,
Antonio Antón,
Vicente Alberola,
Bartomeu Massuti,
Alfredo Carrato,
Isidoro Barneto,
María Lomas,
Margarita García,
Pilar Lianes,
Joaquín Montalar,
Catalina Vadell,
José Luis González-Larriba,
Binh Nguyen,
Angel Artal,
Rafael Rosell
From the Hospital Duran i Reynals, Barcelona; Hospital Germans Trias i Pujol, Badalona; Hospital Miguel Servet, Zaragoza; Hospital Arnau de Vilanova, Valencia; Hospital General de Alicante, Alicante; Hospital General de Elche, Elche; Hospital Universitario Reina Sofia, Cordoba; Hospital Infanta Cristina, Badajoz; Hospital 12 de Octubre, Madrid; Hospital La Fe, Valencia; Hospital del Mar, Barcelona; Hospital Clínico, Madrid, Spain; and Lilly Research Laboratories, Indianapolis, IN.
Address reprint requests to Rafael Rosell, MD, Medical Oncology Service, Hospital Germans Trias i Pujol, Crtra. Canyet s/n, 08916 Badalona, Barcelona, Spain; Email rrosell{at}ns.hugtip.scs.es
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ABSTRACT
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PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate.
PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response.
RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm.
CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.
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INTRODUCTION
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THE OUTCOME OF CHEMOTHERAPY in patients with advanced non–small-cell lung cancer (NSCLC) was controversial until recently.1 Four meta-analyses addressed the question of whether chemotherapy increases survival time in cases of advanced NSCLC,2-5 and all four studies showed a benefit with chemotherapy.
Recent American Society of Clinical Oncology Clinical Practice Guidelines state that chemotherapy, ideally a platinum-based regimen, is appropriate for selected patients with advanced NSCLC who have a good performance status.6 The development of new drugs with different mechanisms of action has raised expectations for further improvement. One of these new agents, gemcitabine (Gemzar; Lilly, Louvain, Belgium), has consistently shown activity as a single drug in small7,8 and large multicenter9 phase II studies. The response rates seen in single-arm phase II studies have been confirmed in two randomized phase II studies.10,11
The combination of gemcitabine and cisplatin was synergistic in preclinical models.12 Several phase II studies,13-17 including a previous study conducted by our group that was based on response rate, median survival time, and a 1-year survival rate,17 showed activity for the combination that compared favorably with standard cisplatin-based regimens.
In multicenter, randomized studies published during the 1980s, none of the extensively studied regimens were associated with better results. Splinter18 reviewed a total of 27 phase III trials including 3,937 NSCLC patients receiving combination chemotherapy and found that only one of these 27 studies showed a significant difference in results between the two arms. Etoposide-cisplatin was one of the most widely used regimens, so we chose this combination as the standard treatment arm for this study.
We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced NSCLC. Response rate was chosen as the primary end point of the comparison, and toxicity, quality of life (QOL), time to disease progression, and survival time were selected as secondary end points.
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PATIENTS AND METHODS
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Patient Selection
Patients eligible for this study had histologic or cytologic diagnosis of NSCLC, stage IIIB or IV (according to the American Joint Committee on Cancer, 1992); were at least 18 years of age; had a Karnofsky performance status greater than or equal to 60; had a life expectancy of more than 12 weeks; and had adequate bone marrow, renal, and hepatic function. Patients had not previously received chemotherapy. At least 3 weeks had elapsed since patients received prior radiation therapy. Patients who had received previous radiotherapy were accepted if their assessable disease was outside the radiation portal. Patients had at least one measurable lesion. Measurable lesions were bidimensionally measurable, with discrete margins evident on computed tomographic scans, magnetic resonance imaging, ultrasound, x-rays, or physical examinations. Patients who had the following characteristics were not eligible: only nonmeasurable disease, hypercalcemia, severe concomitant disease, pregnancy, symptomatic CNS metastases, a history of further malignancy in the last 5 years other than basal cell carcinoma of the skin, or carcinoma-in-situ of the cervix. The protocol was approved by the ethics and human investigation committee of each participating institution. Written informed consent was obtained from all patients before randomization.
Treatment Schedule
Patients were stratified according to sex, performance status, disease stage, and treatment center and were randomized to receive either gemcitabine or etoposide along with cisplatin.
Gemcitabine 1,250 mg/m2 was administered intravenously over 30 minutes on days 1 and 8 of each 21-day cycle. Etoposide 100 mg/m2 was administered intravenously over 60 minutes on days 1, 2, and 3 of each 21-day cycle. Cisplatin 100 mg/m2 was administered by a 60-minute infusion of 5% glucose in normal saline on day 1 in both treatment arms before gemcitabine or etoposide. Cycles were repeated on day 22.
Supportive care could include blood-product transfusions and the administration of antibiotics, antiemetics, and analgesics, as appropriate. Hematopoietic growth factors were permitted in the case of prolonged neutropenia. Palliative radiotherapy to a previous painful lesion was allowed, as long as the patient could not be qualified as having progressive disease and the irradiated lesion would not be the only measurable lesion. No other antineoplastic therapy was permitted during the study. Patients received the assigned therapy for as long as they remained stable or responded to treatment, for a maximum of six cycles. Treatment was discontinued if the patient requested it, if the toxicity from the drug regimen was considered to be unacceptable, or if the attending physician thought that a change of therapy would be in the best interest of the patient. Twenty-one patients in the gemcitabine arm and 14 patients in the etoposide arm received radiotherapy during or after the completion of the study. For 11 patients in each treatment arm, the intent was clearly palliative.
Dosage adjustments for every drug, which were made on the basis of hematopoietic and renal function, were made before each administration. Patients who required a treatment delay of more than 3 weeks for any drug were to be withdrawn from the study.
Treatment Evaluation
The primary end point of this study was response rate. Toxicity, QOL, time to disease progression, and survival time were secondary end points.
A complete response was defined as the complete disappearance of all objective disease. A partial response was defined as a 50% or greater reduction in the size of all measurable tumor areas from baseline (as measured by the sum of the products of the longest perpendicular diameters of all measurable lesions) without the appearance of any new disease and no individual tumor increase of more than 25% in the product of the bidimensional measurements. Progressive disease was defined as an increase of at least 25% in the size of one or more measurable lesions or the appearance of any new lesions. Stable disease was defined as an evaluation that failed to qualify for any of the responses noted. Complete and partial responses had to be confirmed by a second evaluation at least 4 weeks later. All tumor responses were submitted to a peer-review process by two independent radiologists.
Toxicity was graded according to World Health Organization toxicity criteria. The ototoxicity of cisplatin was graded by common toxicity criteria.
Patients were screened not more than a week before randomization, and the following assessments were made: medical history, physical examination, Karnofsky performance status, laboratory assessments, electrocardiogram, chest x-ray, and a self-administered QOL questionnaire.
Complete blood counts were repeated every week on patients in the gemcitabine arm and on days 1 and 15 of each 21-day cycle on patients in the etoposide arm. Symptoms and toxicities were recorded before every scheduled treatment, regardless of treatment delays. Blood chemistry, urine analysis, and a physical examination were repeated at the beginning of every new treatment cycle. The QOL questionnaire was completed at the end of every cycle. A chest x-ray was repeated before every other cycle. Indicated measurable lesions on an imaging study were measured no more than 3 weeks before randomization and just before every other cycle.
The QOL questionnaire completed by patients was the European Organization for Research and Treatment of Cancer QLQC30-LC13 questionnaire, a 30-item core questionnaire with a specific subscale for lung cancer patients that explores functional status, physical and psychological symptoms, social situation, and lung cancer symptoms.19,20
Statistical Considerations
Since the primary end point of the study was to compare response rates between the two treatment arms, the sample size was estimated at 62 patients per treatment arm to provide a power of 0.80 to detect a 25% difference in response rates between the two groups at the 5% level (45% response rate for the gemcitabine arm and 20% for the etoposide arm). Treatment assignments were randomized centrally within four separate strata on the basis of sex, stage, treatment center, and performance status. Response rates were compared using Fisher's exact test. Logistic regression was used to analyze group differences according to prognostic factors.
The QOL analysis consisted of the comparison of mean scores to baseline values. Within-treatment analysis was conducted with a non-parametric two-sided paired t test, and between-treatment analysis was conducted with analysis of variance.
Time to disease progression was defined as the time from the date of randomization to the date the patient was assessed as having progressive disease. Survival was defined as the interval between the date of randomization to the date of death. Kaplan-Meier curves were used to display the survival data. The log-rank test was used to compare the survival curves. A Cox proportional hazards model was used to study the influence of prognostic factors on time to disease progression and survival.
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RESULTS
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Patient Characteristics
Between July 1995 and June 1996, 135 patients from 12 Spanish centers were enrolled in this study. Of the 135 patients randomized, two patients did not meet the eligibility criteria for efficacy analysis as stated in the protocol: one because of nonmeasurable disease and one who had received less than one cycle of therapy. Both patients were in the etoposide group. The characteristics of all randomized patients are listed in Table 1. The median age of the patients was 59 years (range, 33 to 76). Most of the patients were male (93%). By histologic type, as determined by the institutional pathologist at the time of registration, 45% had squamous cell carcinoma, 34% had adenocarcinoma, 10% had large cell carcinoma, 10% had undifferentiated carcinoma, and 1% had adenosquamous carcinoma. Male sex and squamous cell carcinoma predominance are epidemiological features of lung cancer in Spain. Fifty percent of the patients had stage IIIB or unresectable local recurrence; 85% of the patients had a good or excellent performance status (Karnofsky score, 80–100). The two groups were well balanced for all of these baseline characteristics (Table 1). Four patients had local (chest) radiotherapy prior to entry onto the study: three in the gemcitabine arm and one in the etoposide arm. Four patients in each treatment arm had undergone curative surgery prior to entry onto study.
Treatment Administration
Only one patient did not receive a single dose of the assigned treatment (etoposide-cisplatin) because he died of a thromboembolic complication the day before he was scheduled for treatment. Thirty patients of 69 in the gemcitabine arm (43%) and 17 patients of 66 in the etoposide arm (26%) received up to six cycles of treatment. The median duration of treatment was 4.1 months in the gemcitabine arm and 3.1 months in the etoposide arm. The median number of cycles administered per patient was five for the gemcitabine arm and four for the etoposide arm. The mean dose per infusion of each drug was close to the planned dose. The mean dose for gemcitabine was 1,117 mg/m2 (range, 612 to 1,293 mg), with a median dose of 1,161 mg/m2 (93% of planned dose). The mean dose for cisplatin in the gemcitabine arm was 91.6 mg/m2 (range, 33 to 101 mg/m2). The chemotherapy schedule in the etoposide arm included etoposide 100 mg/m2 days 1 to 3 with cisplatin 100 mg/m2 on day 1 of every 21-day cycle. The mean dose for etoposide was 95.6 mg/m2 (range, 60 to 100.8 mg/m2), and that for cisplatin in the etoposide arm was 96.2 mg/m2 (range, 60 to 108 mg/m2).
Response
Analysis was performed according to intent-to-treat; therefore, response rates were based on all eligible patients. No patient achieved a complete response. There were 28 responders of the 69 patients in the gemcitabine arm, for a response rate of 40.6% (95% confidence interval [CI], 29% to 53%). There were 14 responders of the 64 patients in the etoposide arm, for a response rate of 21.9% (95% CI, 13% to 34%) (P = .02; two-sided, Fisher's exact test). Table 2 lists the response rates by age, gender, performance status, and disease stage for each treatment arm. In the gemcitabine arm, the response rates were 36% for stage IIIB patients and 44% for stage IV patients; in the etoposide arm, the response rates were 26% for stage IIIB patients and 17% for stage IV patients. The majority of responders had a performance status of 80 to 100, and only 21.4% of the gemcitabine arm responders and 14.3% of the etoposide arm responders had a baseline performance status of 70.
Toxicity
Hematologic toxicities are listed in Table 3. Myelosuppression was the main toxicity. Grades 3 and 4 neutropenia were common in both treatment arms. Additional blood cell counts, differential and platelets, were performed on day 15 for both treatment arms. Grades 3 and 4 neutropenia and febrile neutropenia were more pronounced in the etoposide arm. Grade 4 neutropenia was seen in twice as many patients in the etoposide arm as in the gemcitabine arm (P = .0009). Five patients in the gemcitabine arm were hospitalized for a total of 18 days for febrile neutropenia, compared with eight patients for a total of 71 days in the etoposide arm (P = .386).
Grades 3 and 4 thrombocytopenia occurred more often in the gemcitabine arm (P = .0457). However, this difference was not clinically relevant because patients in the gemcitabine arm did not receive more platelet transfusions or have more bleeding events. In fact, two patients in the gemcitabine arm received platelet transfusions, compared with five patients in the etoposide arm. Grade 4 hemorrhage occurred in two patients in each treatment arm. All four of these patients developed hemoptysis, and only one patient (in the etoposide arm) had grade 4 thrombocytopenia at the time of the event.
Grades 3 and 4 anemia were seen in a comparable number of patients in each treatment arm, and the overall number of patients who received red blood cell transfusions was also comparable in both arms.
Table 4 shows the principal nonlaboratory toxicities. The main symptomatic toxicities were nausea and vomiting and alopecia. Reporting of nausea and vomiting was more frequent in the gemcitabine arm, but the difference was not statistically significant. Alopecia was significantly less pronounced in the gemcitabine arm. Five patients in the gemcitabine arm had abnormal renal function, including two patients with acute renal failure, whereas only one patient in the etoposide arm had abnormal renal function. One patient in the gemcitabine arm died of shock associated with pneumonia, bronchospasm, febrile neutropenia, thrombocytopenia, sepsis, and atrial fibrillation. One patient in the gemcitabine arm had grade 4 dyspnea due to superior vena cava syndrome from his primary lung cancer, for which radiation therapy was initiated.
Quality of Life
Sixty-eight patients in the gemcitabine arm and 63 patients in the etoposide arm completed at least one QOL questionnaire. The median number of questionnaires completed was 5.5 in the gemcitabine arm and four in the etoposide arm, with overall on-study compliance rates of 88.1% and 84.5%, respectively. No clinically significant differences in change from baseline within treatment arm or between treatment arms in functional domains (ie, physical, role, cognitive, emotional, social) or global QOL were observed. In both groups, there was significant improvement in pain, insomnia, cough, hemoptysis, chest pain, and shoulder pain, but no improvement in dyspnea and fatigue. Peripheral neuropathy did not worsen significantly in either treatment arm. Both arms noted significant worsening of nausea/vomiting and alopecia. The only statistically significant between-treatment arm difference in change from baseline was that for alopecia, which was worse in the etoposide arm.
Time to Disease Progression and Response Duration
Time to disease progression curves for all randomized patients are shown in Fig 1. The median time to progression for patients in the gemcitabine arm was 6.9 months (95% CI, 5 to 8.1 months), compared with 4.3 months (95% CI, 3.5 to 4.7 months) for patients in the etoposide arm. The log-rank test showed a statistically significant difference between the two curves (P = .01). The probability of the tumor response lasting at least 6 months was estimated to be 79% for patients in the gemcitabine arm and 57% for patients in the etoposide arm. The administration time of radiotherapy in stage IIIB patients did not significantly affect the difference between the two treatment arms (data not shown).
Cox proportional hazards exploratory analysis was performed using the potential prognostic factors of age, sex, disease stage, performance status, prior radiation therapy, liver metastases, and time since diagnosis as covariates. The proportional hazards assumption was not met for any of these factors, and none was found to be a significant prognostic factor (P  .05) for survival time or time to progressive disease.
Survival Time
Overall survival time curves for all randomized patients by treatment arm are shown in Fig 2. Patients in the gemcitabine arm had an estimated median survival time of 8.7 months (95% CI, 7.7 to 10.2 months), compared with an estimated median survival time of 7.2 months (95% CI, 6.1 to 9.8 months) for patients in the etoposide arm.
The 1-year survival probability is estimated to be 32% for gemcitabine-cisplatin patients and 26% for etoposide-cisplatin patients. The difference between the two treatment arms is not statistically significant (log-rank test, P = .19).
At the time of this analysis (January 15, 1998), the censoring rates for the survival curves were 16% for the gemcitabine-cisplatin arm and 11% for the etoposide-cisplatin arm. The minimum follow-up time was 16 months.
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DISCUSSION
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Gemcitabine-cisplatin treatment provided a significantly higher response rate than did etoposide-cisplatin (40.6% v 21.9%, P = .02) in this randomized study of patients with advanced NSCLC. The difference in response rate could not be attributed to an imbalance of other response predictors, such as performance status and stage, because a logistic regression model showed that the single predictor of response was treatment. All tumor responses were confirmed through a peer-review process by two independent radiologists.
Gemcitabine-cisplatin treatment provided a significantly longer time to disease progression than did treatment with etoposide-cisplatin, as determined by Wilcoxon and log-rank tests. In a Cox proportional hazards model, the risk of progression was significantly reduced for patients receiving gemcitabine-cisplatin treatment (response rate = 0.80; 95% CI, 0.65 to 0.99). In this model, there was no significantly increased risk in time to disease progression for other factors studied (stage, performance status, and age).
Grades 3 and 4 neutropenia and thrombocytopenia were commonly detected but were not life-threatening. There was no statistically significant difference in the incidence of neutropenic fever, although grade 4 neutropenia was significantly more frequent in the etoposide arm. There were no statistically significant differences in the frequency of clinically significant (grades 3 and 4) hemorrhagic events between treatment arms.
After myelosuppression, grades 3 and 4 nausea and vomiting were the second most common toxic events overall despite the liberal use of 5-hydroxytryptamine type 3 antagonists and corticosteroids as antiemetics. Nausea and vomiting were more frequently observed in the gemcitabine arm, while alopecia was more frequently found in the etoposide arm. Single-agent gemcitabine is associated with a much lower incidence of nausea and vomiting, so it is likely that it was the association with cisplatin that caused this adverse effect. Therefore, it could be worth investigating noncisplatin combinations or other schedules for cisplatin. In another study,21 cisplatin was given weekly along with gemcitabine, resulting in less gastrointestinal toxicity, but unfortunately this schedule had to be abandoned because of a disappointingly lower response rate. Quality of life was maintained during treatment in both arms.
The higher response rate achieved with gemcitabine-cisplatin did not translate into a statistically significant survival time benefit in the study presented here. Whether response rate is a good surrogate for survival time in advanced cancer is still a matter of controversy.22 Furthermore, the sample size in this study was not chosen to demonstrate a survival time difference, and with the number of patients enrolled, we had no statistical power to detect a difference in survival time. Consequently, a large trial with survival time as the primary end point is necessary for the investigation of this issue.
Time to disease progression is a measure of the quality of response, which takes into account both objective response and stable disease qualifications. Although it is not generally regarded as an interesting outcome in advanced cancer,23 it usually precedes the observation of survival time differences in larger studies. We believe that the longer time to disease progression in the gemcitabine arm might be an indication of the activity of the combination of gemcitabine and cisplatin.
The gemcitabine-cisplatin regimen used in this study was based on a 21-day schedule. In phase II studies of this combination,13-16 based on a 28-day cycle, gemcitabine was given at a dose of 1,000 mg/m2 on days 1, 8, and 15, and cisplatin was given at a dose of 100 mg/m2 on days 1, 2, or 15. However, the number of omissions and reductions of the day 15 gemcitabine dose was quite high in these trials. Our previous study17 was based on a 28-day cycle, and cisplatin was given on day 15. In the study presented here, we changed to a 21-day schedule to achieve the same dose intensity of cisplatin in both arms. We omitted the day 15 dose of gemcitabine and increased it to 1,250 mg/m2 on days 1 and 8. Our theoretical dose intensity for gemcitabine was 833 mg/m2 week, which is higher than that of other treatment schedules. We achieved an actual dose intensity that compares favorably with that of other trials. Our response rate was inside the range of response rates obtained in phase II trials, and the toxicity level was similar,13-17 despite a less strictly selected patient population.
In conclusion, this was the first comparative study of the gemcitabine-cisplatin treatment combination for NSCLC. The objective response rate for treatment with gemcitabine-cisplatin was confirmed in a randomized multi-institutional setting. Furthermore, a 21-day schedule was demonstrated to have the same objective response rate as that observed with a 28-day schedule. When compared with that of etoposide-cisplatin, gemcitabine-cisplatin treatment provides a significantly higher response rate and longer time to disease progression, without impairing QOL in patients with advanced NSCLC. Studies with a larger number of patients are needed to demonstrate whether the gemcitabine-cisplatin combination improves survival time.
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ACKNOWLEDGMENTS
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Ramón Garcia-Gomez, MD, and Enrique Aranda, MD, also participated in this study. We would like to thank Anders Pedersen, MD, Medical Director of Lilly Research Laboratories, Javier Corral, MD, also of Lilly Research Laboratories, and Eva López, MD, for technical assistance and Renée O'Brate for assistance with the manuscript.
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NOTES
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This study was supported by grant 17222 from Eli Lilly and Company.
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Submitted July 8, 1998;
accepted September 28, 1998.
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TOP
ABSTRACT
INTRODUCTION
