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© 2001 American Society for Clinical Oncology Topotecan Versus Observation After Cisplatin Plus Etoposide in Extensive-Stage Small-Cell Lung Cancer: E7593—A Phase III Trial of the Eastern Cooperative Oncology GroupFrom the University of Wisconsin Hospital and Clinics, Madison, WI; Dana-Farber Cancer Institute, Boston, MA; Evanston Northwestern Healthcare and Northwestern University, Evanston, IL; and Vanderbilt University Medical Center, Nashville, TN. Address correspondence to Joan H. Schiller, MD, University of Wisconsin Hospital and Clinics, 600 Highland Ave, Rm K4/636, Madison, WI 53792; email: jhschill{at}facstaff.wisc.edu
PURPOSE: To determine the efficacy of topotecan in combination with standard chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer (SCLC), the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial. PATIENTS AND METHODS: Eligible patients had measurable or assessable disease and an ECOG performance status of 0 to 2; stable brain metastases were allowed. All patients received four cycles of cisplatin and etoposide every 3 weeks (step 1; PE). Patients with stable or responding disease were then randomized to observation or four cycles of topotecan (1.5 mg/m2/d for 5 days, every 3 weeks; step 2). A total of 402 eligible patients were registered to step 1, and 223 eligible patients were registered to step 2 (observation, n = 111; topotecan, n = 112). RESULTS: Complete and partial response rates to induction PE were 3% and 32%, respectively. A 7% response rate was observed with topotecan (complete response, 2%; partial response, 5%). The median survival time for all 402 eligible patients was 9.6 months. Progression-free survival (PFS) from date of randomization on step 2 was significantly better with topotecan compared with observation (3.6 months v 2.3 months; P < .001). However, overall survival from date of randomization on step 2 was not significantly different between the observation and topotecan arms (8.9 months v 9.3 months; P = .43). Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2. Grade 4/5 infection was observed in 4.6% of PE patients and 1.8% of topotecan patients. Grade 3/4 anemia developed in 22% of patients who received topotecan. No difference in quality of life between topotecan and observation was observed at any assessment time or for any of the subscale scores. CONCLUSION: Four cycles of PE induction therapy followed by four cycles of topotecan improved PFS but failed to improve overall survival or quality of life in extensive-stage SCLC. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC patients with good performance status.
SMALL-CELL LUNG cancer (SCLC) is responsible for approximately 20% to 25% of all lung cancer deaths in the United States every year. Although much more sensitive to chemotherapy than non–small-cell lung cancer, with response rates of up to 80% among patients with limited-stage disease, the cancer is almost uniformly fatal, particularly in patients with advanced, extensive-stage disease. Clearly, identification of new, more active drugs is crucial. Topotecan is a water-soluble, semisynthetic analog of the alkaloid camptothecin, which is a specific inhibitor of topoisomerase I. Inhibition of this enzyme results in lethal DNA damage during the course of DNA replication and RNA transcription. In preclinical models, topotecan has been shown to be effective in a number of solid tumors.1 Topotecan has single-agent, first-line activity in SCLC. The Eastern Cooperative Oncology Group (ECOG) administered topotecan at 2.0 mg/m2 daily for 5 days to 48 previously untreated patients with extensive-stage SCLC. The response rate was 39% (19 of 48 patients); all were partial responses, with a median overall survival time of 10 months.2
Topotecan also has activity as a second-line therapy for SCLC.1,3,4 In phase II studies involving refractory SCLC (progression during first-line therapy or within In preclinical studies, exposure to topoisomerase I or II inhibitors can upregulate topoisomerase levels, resulting in synergistic antitumor effects when administered sequentially.6-10 To determine the efficacy of combining topotecan with the topoisomerase II inhibitor etoposide, ECOG conducted a phase III trial of topotecan versus observation after treatment with cisplatin plus etoposide in previously untreated patients with extensive-stage SCLC. The objectives of the study were to determine whether the addition of topotecan to cisplatin and etoposide prolonged the survival of this group of patients and to compare the quality of life (QOL) in patients who received topotecan instead of observation. Because a modest additional effect of topotecan on response rate and survival (disease-free and overall) was anticipated, and given the of added toxicity and cost, a QOL evaluation was considered important to evaluate the aggregate impact of tumor response and toxicity on the patients’ health and well-being.
Eligibility Patients were required to have histologically confirmed, measurable, or assessable small-cell carcinoma of the lung, defined as disease beyond the hemithorax and adjacent nodes, supraclavicular node involvement, or pleural effusion with positive histology. Patients were required to be over 18 years old and have a performance status of 0, 1, or 2, measurable or assessable disease, and adequate hematologic (WBC count  4,000/mm3, platelet count 100,000/mm3), hepatic (bilirubin level  1.5 mg/dL), and renal (creatinine concentration 1.5 mg/dL) function. No prior chemotherapy or biologic therapy was allowed; prior radiation therapy was permitted to any symptomatic site provided the indicator sites were not irradiated and that radiation therapy was completed before chemotherapy was initiated. Patients with CNS metastases were eligible, provided that the attending physician ascertained that the metastases were controlled before initiation of chemotherapy. All patients gave informed consent. After treatment with four cycles of cisplatin and etoposide, patients who had not progressed were eligible to be randomized to either observation or further chemotherapy with topotecan. A computed tomography scan to confirm response after induction chemotherapy had to be completed within 2 weeks before randomization to step 2.
All patients received four cycles of intravenous (IV) cisplatin 60 mg/m2 over 30 minutes to 2 hours on day 1 and etoposide 120 mg/m2 over 1 to 2 hours on days 1, 2, and 3 of a 21-day cycle (step 1) ( Fig 1). After four cycles of therapy, patients with stable or responding disease were stratified for weight loss in the previous 6 months (< 5% v
The Functional Assessment of Cancer Therapy–Lung (FACT-L)11 QOL instrument was administered at randomization to step 2, on day 1 of week 7 after randomization (day 1 of cycle 3 for patients receiving topotecan), and on day 1 of week 16 after randomization to step 2 (4 weeks after completion of topotecan for those patients randomized to that arm). Only patients who were randomized to step 2 completed the questionnaire. Etoposide was reduced 25% for febrile neutropenia, a nadir absolute neutrophil count (ANC) of 750 to 999/mm2 with an ANC of more than 2,000/mm3 on day 1, or a nadir platelet count of 50,000 to 99,999/mm3 with a platelet count of more than 100,000 on day 1. It was reduced 50% if the day-1 ANC was 1,500 to 2,000/mm3 or the platelet count was 75,000 to 99,999, or if the day-1 ANC was more than 2,000/mm3 with a nadir ANC of less than 750/mm3, or if the nadir platelet count was less than 50,000/mm3. It was held for a day-1 ANC of less than 1,500/mm3 or platelet count of less than 75,000/mm3, or a nadir ANC less than 750/mm3 with a day 1 ANC of 1,500 to 2,000/mm3, or nadir platelet count of less than 50,000/mm3 with a day-1 platelet count of 75,000 to 100,000/mm3. Cisplatin was reduced 50% if the day-1 creatinine level was 1.5 to 2.5 mg/dL and was held if it was more than 2.5 mg/dL. Granulocyte colony-stimulating factor was used at the discretion of the treating physician. Topotecan was reduced 25% and 50% for an ANC of less than 2,000/mm3 or an ANC between 1,500 and 2,000/mm3 on day 1 with a nadir ANC of less than 500/mm3 for 5 days or longer, respectively. It was also reduced 25% for an ANC of 1,500 to 2,000/mm3 with a nadir count of less than 500/mm3 for less than 5 days. It was held for a day-1 ANC of less than 1,500/mm3. Topotecan was held for a nadir platelet count of less than 25,000/mm3 if the day-1 platelet count was less than 100,000/mm3 and reduced 50% if the day-1 platelet count was more than 100,000/mm3. It was held for a day-1 platelet count of less than 75,000/mm3 and reduced 50% for a day-1 platelet count of 75,000 to 100,000 mm3. Standard ECOG response criteria were used. Briefly, all known sites of disease had to be completely gone for at least 4 weeks to qualify as a complete response (CR). Partial response (PR) was defined as a 50% or greater reduction in the sum of the areas of all sites of disease, lasting at least 4 weeks. Progressive disease was defined as a 25% or greater increase in the area of any one lesion over the prior measurement or the development of new lesions.
QOL The 21 questions relating to physical well-being, functional well-being, and lung cancer symptoms were combined and designated as the Trial Outcome Index (TOI), which, based on previous studies, is considered to be the best summary indicator of the physical component of QOL.11 Patients were asked to complete the FACT-L at randomization to step 2 and 6 and 16 weeks later. The numeric values for each item were added to give the total score and the scores for subsets of questions, such as the TOI. Higher scores are associated with better QOL.11
Statistical Considerations
Statistical Methods Statistical significance was set at a two-sided level of .05, and all P values reported from the Fisher’s exact test were two-tailed. The Wilcoxon rank sum test14 was used to compare the two study arms with respect to continuous outcomes (eg, age, albumin, LDH). For patients on step 1, survival time was the time from the date of registration on step 1 to date of death; patients who were alive were censored at the date last known alive. For patients on step 1, PFS was the time from the date of registration on step 1 to date of progression/death without progression, if the patient had progressed or died without evidence of progression; patients who were alive and relapse-free were censored at the date of last known follow-up. For patients on step 2, survival time was calculated from the date of randomization on step 2 to date of death; patients who were alive were censored at the date last known alive. For patients on step 2, PFS was calculated from the date of randomization on step 2 to date of progression or death without progression; patients who were alive and relapse-free were censored at the date of last known follow-up. Separate analyses of survival data were carried out for steps 1 and 2. Univariate analysis. The distributions for survival time and PFS were estimated with the Kaplan-Meier method15 and compared with the log-rank test.16 Statistical significance was set at a two-sided level of .05, and all log-rank test P values reported are two-sided.
Multivariate Analysis QOL. In order to evaluate the short-term and long-term effects of treatment on QOL, changes in the FACT-L, TOI, and all subscales from baseline were also calculated for each patient. The Wilcoxon rank sum test14 was used to test whether there were significant differences in the changes in QOL from baseline between the two arms of the study. This is a preliminary exploratory analysis of the QOL scores at individual assessment time points using all available data (among patients who were eligible and randomized to step 2). A more extended analysis will follow in a separate article, which will include joint models for survival and QOL to account for nonrandom missingness.
Four hundred twenty-one patients were entered onto the trial between March 1995 and January 1999. Nineteen patients were considered ineligible on step 1 because of wrong histologic diagnosis (four), limited disease (one), baseline measurements or scans not done (eight), second primary cancer (one), progression requiring radiation therapy or development of medical problems before chemotherapy was initiated (three), uncontrolled infection (one), and duplicate registration (one). Two hundred forty-two patients were randomized to step 2 (120 on the observation arm and 122 on the topotecan arm); of these, 19 patients were ineligible because of progression on step 1 (nine), insufficient response data (one), and ineligibility on step 1 (nine). There were 223 eligible patients on step 2 (111 on the observation arm and 112 on the topotecan arm). The target accrual of 284 patients for randomization was not met because of additional attrition, primarily due to death (6.7%) and unassessable response (4.3%). The observed dropout from step 1 due to progression was 25.4%, as anticipated by the design. Although the target accrual for the randomization was not met, the data from the 223 eligible patients were still sufficient to guarantee greater than 80% power to detect the survival differences specified in the design. As a result, the ECOG Data Monitoring Committee decided in November 1998 to allow the trial to close on schedule. Baseline characteristics of all eligible patients, as well as those randomized on step 2, are listed in Table 1. The two groups were well balanced for the usual prognostic factors. The median age of the 402 eligible patients was 63 years.
Step 1: Cisplatin/Etoposide Of all 420 patients (one duplicate registration out of 421), 385 patients (92%) have died. The overall median survival time was 9.5 months with a 95% confidence interval (CI) of 8.9 to 10.2 months.
Of the 402 eligible patients, the overall objective response rate to induction PE was 35% (CR, 3%; PR, 32%) ( Table 2). With a median follow-up of 21 months (range, 0 to 47 months), 373 patients (93%) have died. The median survival and median PFS times for all 402 eligible patients was 9.6 months and 8.0 months, respectively ( Fig 2). The 1-year survival rate was 35% (Table 2). For patients with a performance status of 1 or higher (relative risk for performance status
Step 2: Observation v Topotecan A total of 242 patients were randomized to step 2. Of these, 217 (90%) have died with an overall median survival time from the time of randomization to step 2 of 8.9 months. The median survival times of the 120 patients randomized to the observation arm and of the 122 patients randomized to the topotecan arm were 8.9 months (95% CI, 7.5 to 9.9 months) and 9.3 months (95% CI, 8.5 to 10.0 months), respectively. The difference in survival distributions was not statistically significant (log-rank P = .53; relative risk for observation v topotecan, 1.09; 95% CI, 0.83 to 1.42). The overall response rate to topotecan was 7% (CR, 2%; PR, 5%). On the observation arm, 14% had stable disease after induction chemotherapy with PE, whereas on the topotecan arm, 34% had stable disease after induction chemotherapy with PE. The difference in the rate of stable disease in the two arms is statistically significant (Fisher’s exact test P < .001). Two hundred twenty-three eligible patients were randomized to step 2 (observation, n = 111; topotecan, n = 112). Reasons for not being randomized to step 2 were ineligibility on step 1 (4.5%: 19 patients); ineligibility on step 2 (2%: 10 patients), progression on step 1 (26%: 111 patients), death during step 1 (7%: 28 patients), unassessable disease after step 1 (4.5%: 19 patients), step 1 treatment discontinued due to patient withdrawal, complications, and so on (1%: five patients), declined to be randomized (1%: four patients), and unknown (0.5%: two patients). Of the 111 eligible patients on the observation arm, 102 (92%) have died; of the 112 eligible patients on the topotecan arm, 100 (89%) have died. The median follow-up time was 18.4 months (range, 6 to 44 months). The overall survival time from date of randomization for eligible patients on step 2 was not significantly different between the observation and topotecan arms (median survival, 8.9 months v 9.3 months; log-rank P = .43) (Table 2 and Fig 3A). The 1-year survival rates for the observation and topotecan arms were 28% and 25%, respectively (Table 2). However, PFS from date of randomization on step 2 was significantly better with topotecan compared with observation (3.7 months v 2.3 months; relative risk for observation v topotecan, 1.90; log-rank P < .001) (Table 2 and Fig 3B).
In a multivariate analysis of survival and PFS, treatment arm was not selected as a significant predictor. Age group (relative risk for age > 65 years v age 65 years, 1.75; 95% CI, 1.25 to 2.45), sex (relative risk for males v females, 1.55; 95% CI, 1.11 to 2.16), and alkaline phosphate (relative risk for 115 mg/mL v < 115 mg/mL, 1.97; 95% CI, 1.44 to 2.70) were selected as significant predictors of survival by a stepwise Cox model.
Sites of Recurrence
Toxicities Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2 ( Table 4). Grade 4/5 infection was observed in 5% of PE patients and 2% of topotecan patients. Grade 3/4 anemia developed in 21% of patients receiving topotecan.
Toxicity was lethal for 17 patients on step 1, with nine deaths from infection (2%), three from cardiac causes, two due to hemorrhage, one each due to hepatic and CNS toxicity, and two due to multiple toxicities. One patient on the topotecan arm experienced a grade 5 cardiac toxicity.
QOL There were no significant differences over 4 months in the TOI and the total FACT-L scores between the arms (P = .965 for TOI scores; P = .708 for the total FACT-L scores) ( Table 5). Short-term QOL responses (difference in TOI scores at baseline and 6 weeks) are listed in Table 6. A more detailed analysis with joint models for survival and QOL scores, which accounts for the nonrandomness in the missing data, will be reported in a separate article.
In this study, the sequential addition of topotecan to first-line standard chemotherapy in previously untreated patients with extensive SCLC did not have a measurable impact on survival. Although PFS was significantly improved, the absence of benefit in patient-related QOL makes it difficult to consider these modest improvements as clinically meaningful. Despite previously documented activity of topotecan as first- and second-line therapy for SCLC, we did not see any improvement in survival in this trial, in which previously untreated patients with extensive SCLC received four cycles of PE followed by either observation or topotecan. Given the known second-line activity of topotecan in this disease, it is possible that patients randomized to the observation arm "crossed over" to receive topotecan or other drug(s) off study on progression. Postprogression clinical management was not controlled. This could have resulted in a prolonged time to progression on the study arm with no overall improvement in survival, as was observed here. However, it is also possible that patients randomized to the topotecan arm received other therapies on progression. Thus, without a randomized trial incorporating second-line therapy after failure of first-line therapy, it is impossible to determine the impact of second-line therapy based on our results. Another possible cause of the "negative" results could be associated with the schedule of administration, in which PE and topotecan were administered sequentially. The efficacy and toxicity of topoisomerase inhibitors seem to be schedule-dependent when they are administered with other cytotoxic drugs.6-9 In our study, topotecan was given after four cycles of an etoposide-based regimen in order to capitalize on any upregulation of topoisomerase I after a topoisomerase II inhibitor. However, other preclinical studies have suggested that maximum synergy between topotecan and etoposide occurs when etoposide is given after the topotecan, and not the reverse sequence.10 "Consolidation" or "maintenance" therapy for SCLC has been a subject of extensive interest. The Southeastern Cancer Study Group conducted a randomized study comparing six cycles of CAV with six cycles of CAV followed by two cycles of PE.17 Although this was a positive study, with a 68-week median survival time in the CAV-alone arm compared with a 98-week median survival time in the CAV/PE arm, most studies have failed to detect a benefit for prolonged, maintenance chemotherapy.18-20 A recent review of the literature identified 13 randomized trials evaluating maintenance chemotherapy after induction therapy. One study showed a significantly shorter survival time with maintenance, and 11 studies failed to identify a difference between arms. Only one showed a statistically significant advantage in favor of maintenance.21 These results suggest that prolonged treatment with even active drugs in this disease is not beneficial. It is possible that topotecan would have been more efficacious had it been administered with the first cycle of therapy. A recent phase III Japanese trial reported enhanced survival when another topoisomerase inhibitor, irinotecan, was combined with cisplatin as "upfront" first-line therapy. The median survival time and 1-year survival rate on the irinotecan/etoposide arm was 420 days and 60%, respectively, compared with 300 days and 40% for patients randomized to receive cisplatin and etoposide.22 A randomized study in limited-stage disease observed a survival benefit when 20% higher doses of standard cisplatin and cyclophosphamide were administered in the first cycle of treatment (43% v 26% 2-year survival in the higher and lower chemotherapy groups, respectively).14 Although other studies were unable to confirm the findings regarding dose-intensity of the first two cycles, taken together, these data suggest that the benefit of chemotherapy for SCLC patients may have its greatest impact in the first several cycles of chemotherapy, and prolonged administration of chemotherapy beyond four cycles, regardless of the drugs used, is of less importance.23,24 Topotecan has been shown to cross the blood-brain barrier and thus has been postulated to have a possible role in CNS metastases.25 In a primate study, the mean CSF-to-plasma ratio of topotecan exceeded 30%.26 Topotecan also had preclinical activity against a panel of xenografts derived from childhood and adult brain tumors growing subcutaneously and intracranially in athymic nude mice.27 A phase II study of topotecan in SCLC included seven patients who had CNS metastases. Four of these seven patients had a response to IV topotecan, even though their non-CNS lesions did not respond.28 A retrospective review of 24 patients with both NSCLC and SCLC brain metastases identified 12 who had a response in the CNS, including four patients with SCLC who had a complete CNS response.29 The extracerebral response rate in this group of patients was 25%, less than the brain response. Despite these data, topotecan has not been clinically effective when tested prospectively in patients with pediatric or adult brain tumors.30,31 In this study, we also failed to observe an impact of topotecan on the prevention of CNS metastases. Topotecan has been reported to palliate symptoms in the second-line setting for SCLC. In the randomized second-line therapy trial comparing topotecan to CAV, more patients receiving topotecan had an improvement in anorexia, fatigue, and daily activity level than did patients receiving CAV.5 More patients on the topotecan arm also had a statistically significant improvement in two lung cancer symptoms (shortness of breath and hoarseness) compared with patients on the CAV arm. However, in this first-line study in which topotecan was compared with observation (rather than combination chemotherapy), we failed to show an improvement in QOL as assessed by the FACT-L. Thus, any benefit to tumor-related symptoms afforded by the response to topotecan seems to be offset by toxicity or perhaps is merely overwhelmed by the larger nonresponding and progressive groups of patients. In addition, patient dropouts and loss of data points are problematic. In this study, compliance with the QOL questionnaire was higher on the topotecan arm (83% v 68% on the observation arm at 7 weeks). If patients on the observation arm were dropping out more quickly because of progressive disease, this has the potential of biasing the study against the experimental arm. The overall response rate of 35% observed in this trial with PE is lower than has been previously reported, although the median survival time of 9.6 months was virtually identical. One possible reason for the low response rate in the face of unchanged survival may be the changes in pattern of care practiced by medical oncologists over time. A significant number of patients (21%) on this trial were unassessable for response. Of those unassessable for response, 40% were considered unassessable because they did not have a response confirmed in all their sites of disease, as required by the standard ECOG response criteria. This was particularly true of bony metastases, where patients would often have a confirmatory chest or abdominal computed tomography scan but no repeat bone scan. As per standard ECOG criteria, all sites of disease needed to be confirmed at least 4 weeks later for the patient to be considered a responder. We reanalyzed our data to include patients whose response was confirmed in all sites except bone and found no qualitative change in our results (40% response rate). That response rate does not predict for survival suggests how arbitrarily this criterion has been defined. Utilization of the new Response Evaluation Criteria in Solid Tumors should allow physicians to more easily incorporate tumor measurements into their everyday practice. In conclusion, although there was a modest improvement in time to progression, four cycles of topotecan after four cycles of PE did not result in a significant survival or QOL benefit compared with PE alone. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC.
Supported in part by Public Health Service grants no. CA21076, CA23318, CA49957, CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health and Department of Health and Human Services, Bethesda, MD. J.H.S. is also supported in part by the William S. Middleton Veteran’s Administration Hospital.
The contents of this article are solely the responsibility of the authors and do not represent the official views of the National Cancer Institute.
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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
