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Originally published as JCO Early Release 10.1200/JCO.2005.03.6491 on May 8 2006 © 2006 American Society of Clinical Oncology. Phase III Study Comparing Oral Topotecan to Intravenous Docetaxel in Patients With Pretreated Advanced Non–Small-Cell Lung Cancer
From the Regional Lung Disease Centre, Oncology Department, Poznan; Centre of Oncology & Institute, Warsaw, Poland; Centre Francois Baclesse, Caen, France; Asklepios Klinik, Gauting bei Muenchen, Munich; Thoraxzentrum, Hamburg, Germany; University of Cape Town, Cape Town, South Africa; GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Harlow, United Kingdom; and Princess Margaret Hospital, Toronto, Ontario, Canada Address reprint requests to Rodryg Ramlau, MD, PhD, Lung Disease Centre, Oncology Department, ul.Szamarzewskiego 62, 60-569 Poznan, Poland; e-mail: rramlau{at}wcchpig.pl
PURPOSE: This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non–small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Patients with stage III or IV NSCLC, performance status RESULTS: A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of –3.6% (95% CI, –9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above –10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively). CONCLUSION: Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.
Treatment of non–small-cell lung cancer (NSCLC) for first relapse in patients with good performance status has been shown to prolong survival and improve quality of life. Single-agent docetaxel is an established therapy for second-line treatment of NSCLC, and has been proven superior to best supportive care, vinorelbine, or ifosfamide.1,2 Compared with best supportive care, docetaxel 75 mg/m2 led to longer overall survival (median, 7.5 v 4.6 months; log-rank P = .01) and improved 1-year survival (37% v 12%; P = .003).1 Erlotinib and pemetrexed are also emerging as standard second-line treatments of NSCLC based on results of phase III trials.3,4 Erlotinib produced a 2-month absolute improvement in survival compared with placebo (6.7 v 4.7 months; P < .001) and pemetrexed was associated with similar median survival compared with docetaxel (8.3 v 7.9 months). Topotecan is a topoisomerase-I inhibitor. In NSCLC clinical trials, single-agent intravenous (IV) topotecan 1.5 to 2.0 mg/m2 days 1 to 5 every 21 days as first-line therapy produced median survival times of 32 to 38 weeks.5-7 An oral form of topotecan has been developed. The maximum-tolerated dose of single-agent oral topotecan for 5 days every 3 weeks is 2.3 mg/m2/d.8 Dose-limiting toxicity is grade 4 neutropenia, consistent with IV topotecan. In a trial of single-agent oral topotecan in previously untreated stage III to IV NSCLC, median survival was 40 weeks, 1-year survival was 33%, and median time-to-progression (TTP) was 12 weeks.9 Improvements in one or more disease symptoms, including dyspnea, cough, and fatigue, occurred in 17% to 43% of patients. Oral topotecan may offer a treatment option for patients who prefer oral to IV therapy. This open-label, randomized, phase III study compared the efficacy and safety of oral topotecan versus the current standard, IV docetaxel, as second-line treatment of advanced NSCLC.
Patient Selection Patients were recruited from 30 countries outside of the United States. Patients were randomly assigned in a 1:1 ratio and stratified according to response to first-line chemotherapy (progression  90 v > 90 days), disease stage, sex, and performance status (PS).
Eligible patients had histologically or cytologically confirmed stage III or IV NSCLC with measurable or nonmeasurable disease, were not candidates for curative surgery or radiotherapy, and met the following inclusion criteria:
Prior radiotherapy was allowed if
Patients were excluded for symptomatic CNS metastases, concomitant or previous malignancies other than NSCLC within the last 5 years (except for adequately treated basal or squamous cell carcinoma of the skin, carcinoma-in-situ of the cervix, or localized low-grade prostate cancer), prior taxane treatment, pre-existing grade The protocol was approved by the institutional review board at each site. Each patient provided written informed consent.
Chemotherapy Regimens
Dose Delays and Modifications
The protocol specified dose reductions or escalations based on tolerability. For neutrophils less than 500/µL associated with fever or infection or lasting Incremental topotecan dose increases of 0.4 mg/m2 were allowed up to a maximum of 3.1 mg/m2/d if no toxicity more than grade 2 occurred during the previous course. No docetaxel dose escalations were permitted.
Assessments Before each course, the following assessments occurred: medical history, physical examination, LCSS (patient completed), toxicity (graded according to the National Cancer Institute Common Toxicity Criteria), PS, tumor status, neurologic status, and blood counts. During treatment, blood counts were obtained on day 8, 9, or 10 and on day 15. Blood chemistries were obtained on day 15 or earlier if indicated. Creatinine clearance was re-evaluated before the second course. Radiographic disease assessment was recommended after every second cycle. Tumor response/disease status was evaluated at the end of each course, by the same physician wherever possible. Responses were assessed using WHO criteria. The primary end point was 1-year survival. Secondary end points were overall survival (all-cause mortality), TTP, response rate, response duration, time to response, quality of life (QOL), and toxicities. Randomly assigned patients were observed until at least 1 year after randomization, and then until death. Patients were observed every 3 months after completing treatment.
Statistical Methods The intent-to-treat population comprised all randomly assigned patients and was assessed for survival and response. All patients who received at least one dose of study medication were assessed for drug exposure, toxicity, and QOL. For noninferiority testing of 1-year survival rates, the 95% CI of the difference in 1-year survival rates between topotecan and docetaxel were calculated using binomial methodology, and the lower limit of the CI was compared against the 10% margin of noninferiority. Overall survival and other event-related data were analyzed using the Kaplan-Meier method. Overall survival and TTP were compared using the log-rank test. Regression analyses were performed using a Cox proportional hazards model for both survival and TTP. Analyses of all other secondary end points were evaluated in an explorative or descriptive manner. No interim analyses were performed. The rate of change in LCSS scores (for symptom burden and total symptomatic distress, activity status, and global QOL) over time from baseline for each treatment group was estimated using a random coefficient regression model. It was required that more than 50% of the individual questions were answered for a score to be calculated. Any course with a missing score was deleted from the analysis. The LCSS symptom scores were reversed so that an adjustment score of zero indicated death. The actual visit dates were used in conjunction with the scores to create trapezoids. In a methodology described by Hollen et al,11 the total area under the curve (AUC) for each patient was calculated by summing over the area of the trapezoids, and the time-adjusted AUC was calculated by dividing the total AUC by the length of time the patient completed the LCSS. For patients who died between scheduled measurements, a score of zero was assigned to day of death and the time interval only included up to and including the date of death. Sensitivity analyses were performed to account for informatively missing data in case of death by imputing a score of zero to the LCSS scores and imputing date of death to the corresponding treatment cycle date.
Patients Between October 31, 2001, and April 30, 2003, 829 patients were randomly assigned: 414 to topotecan and 415 to docetaxel (Fig 1). The demographics and baseline characteristics were well matched between groups (Table 1). The major first-line regimens were well balanced between the topotecan and docetaxel arms: cisplatin (71% v 75%), gemcitabine (40% v 39%), vinorelbine (39% v 37%), and carboplatin (24% v 24%).
Delivered Chemotherapy The reasons for study withdrawal are summarized in Table 2. The numbers of courses administered were 1,412 in the topotecan arm (median, three; range, one to 17) and 1,579 in the docetaxel arm (median, four; range, 1 to 19). In the docetaxel arm, 363 (87%), 260 (63%), and 223 (54%) patients received courses 2, 3, and 4, respectively. In the topotecan arm, 342 (83%), 222 (54%), and 160 (39%) received courses 2, 3, and 4, respectively. Similar proportions of patients completed seven or more courses. A higher number of patients in the topotecan arm withdrew during course 1 due to adverse events, progressive disease, or reasons categorized as "other." Although the percentage of withdrawals from course 1 due to adverse events was higher in the topotecan group, the increase was not due to adverse events related to study medication. Compliance with topotecan was high; 370 (89%) patients took  90% of their prescribed capsules.
Dose reductions occurred in 82 topotecan courses (8%) versus 34 docetaxel courses (3%). Hematologic toxicity accounted for dose reductions in 59 (6%) and 24 (2%) courses in the topotecan and docetaxel arms, respectively. Dose delays occurred in 211 topotecan courses (21%) versus 136 docetaxel courses (12%). Hematologic toxicity accounted for delays in 108 (11%) and eight (1%) courses, respectively. Of the 1,412 courses of topotecan administered, 205 (15%) were dose escalated (62% administered at 2.7 mg/m2/d and 34% administered at 3.1 mg/m2/d). The overall median dose-intensity of that scheduled for topotecan and docetaxel was 87% and 91%, respectively. A slightly higher proportion of patients in the topotecan arm received any poststudy cancer therapy (59% v 55%) and poststudy chemotherapy (31% v 25%). In the topotecan arm, 61 patients (15%) received docetaxel poststudy, whereas in the docetaxel arm, three patients (1%) received topotecan poststudy. A similar proportion of patients in each arm received epidermal growth factor receptor (EGFR) inhibitors poststudy (40 patients in the topotecan arm and 47 patients in the docetaxel arm).
Efficacy
The Kaplan-Meier estimates of overall survival are shown in Figure 2. Although there was no statistically significant difference between the groups (log-rank P = .0568), the IV docetaxel treatment group had a higher survival rate than the oral topotecan treatment group across the entire treatment period. Events were censored for 19% of patients in the oral topotecan group and 25% of patients in the IV docetaxel group. With adjustment for stratification factors, the hazard ratio for topotecan versus docetaxel was 1.23 (95% CI, 1.06 to 1.44), demonstrating superiority of docetaxel.
Median TTP was longer in the docetaxel group (13 v 11 weeks; log-rank P = .02; Fig 3). With adjustment for stratification factors, the hazard ratio for topotecan versus IV docetaxel was 1.20 (95% CI, 1.04 to 1.39). Events were censored for 10% of patients in each group. Response rates were 5% in both arms (Table 3).
Toxicity Grade 3 or 4 leukopenia and neutropenia occurred more frequently in the docetaxel group (Table 4), which was associated with slightly higher rates of grade 2 infection and sepsis, but not febrile neutropenia (Table 5). The median duration of grade 4 neutropenia was 7 days in each arm. Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was administered to 22 (6%) patients in the topotecan arm and 30 (8%) patients in the docetaxel arm. Grade 3 thrombocytopenia occurred more frequently in the topotecan group, whereas grade 4 thrombocytopenia occurred in a similar proportion of patients in each group. The median duration of grade 4 thrombocytopenia was longer in the docetaxel arm (13 days; range, 1 to 58 days) versus 4 days (range, 1 to 15 days) in the topotecan arm. Grade 3 and 4 anemia occurred more frequently in the topotecan group. A higher percentage of patients in the topotecan group received RBC transfusions (28% v 10%) and platelet transfusions (8% v 0%).
Nonhematologic adverse events are listed in Table 6. Nausea, diarrhea, and vomiting occurred more frequently in the topotecan group, whereas alopecia, pyrexia, and cough occurred more frequently in the docetaxel group. The overall rate of neuropathy was three times less in the topotecan arm (8% v 26%). Deaths as a result of toxicity occurred in seven (2%) patients in the topotecan arm and nine (2%) patients in the docetaxel arm.
QOL Between 63% and 85% of patients completed the LCSS questionnaire at each course (Fig 4). The AUC analysis demonstrated a statistically significant improvement with docetaxel compared with topotecan (median AUC, 52.4 v 45.6; P < .0001). In the random coefficient regression analysis, rate-of-change estimates indicated that the QOL profile in the topotecan group worsened at a faster rate than in the docetaxel group (Fig 5). The 95% CI demonstrated statistical superiority of docetaxel for the items designated severity of symptoms of lung cancer and appetite. Sensitivity analyses revealed no statistically significant differences in LCSS symptoms between treatment arms.
This study demonstrates that oral topotecan is active and tolerable in patients with previously treated advanced NSCLC. In comparison with IV docetaxel, the 95% CI for the difference in 1-year survival rates (95% CI, –9.59 to 2.48), the primary end point, indicated that oral topotecan was not inferior to IV docetaxel based on the prespecified 10% noninferiority margin. The IV docetaxel treatment group had a higher survival rate than the oral topotecan treatment group across the entire treatment period (log-rank P = .057). It is unlikely that poststudy therapy confounded survival results. Prolonged survival with third-line therapy in NSCLC has only been demonstrated in one trial with the EGFR tyrosine kinase inhibitor erlotinib.3 In our study, the number of patients receiving poststudy erlotinib was low and similar between groups (four patients in the topotecan arm and two patients in the docetaxel arm). Likewise, the proportion of patients receiving any EGFR inhibitor poststudy was similar. Median TTP favored the docetaxel group, with an absolute difference of 1.8 weeks (log-rank P = .02). With respect to adverse events, the two treatments offered similar risk profiles, although each produced a different set of toxicities. Grade 3/4 neutropenia occurred more frequently with docetaxel, whereas grade 3/4 anemia and grade 3 thrombocytopenia were more frequent with topotecan. Nausea, diarrhea, and vomiting were more frequent in the topotecan group, whereas alopecia, neuropathy, and pyrexia were more frequent in the docetaxel group. Nausea and vomiting led to study discontinuation in 15 (4%) patients in the topotecan group compared with no patients in the docetaxel group, possibly due to the higher usage of antiemetics and corticosteroids in the docetaxel group. Ondansetron and dexamethasone were received by 35% and 70% of patients, respectively, in the docetaxel group compared with 22% and 16% of patients, respectively, in the topotecan group. Because topotecan is not known to cause neuropathy, the neuropathy reported by patients in this group (8% v 26% in the docetaxel group) is likely from first-line therapy or the malignant process itself. Patients in this study were taxane naïve. This difference is important because neuropathy can be debilitating in patients for whom symptom palliation is the primary therapeutic goal. Topotecan may be a good alternative for patients with pre-existing neuropathy who would not be candidates for neurotoxic agents. Overall, both treatments showed a progressive worsening of the QOL symptom scores. A statistically significant difference in favor of docetaxel was shown between the AUC and two of the symptoms measured (severity of symptoms and appetite). The 1-year survival rates in this trial (25% and 29%) were lower than that reported in the literature for docetaxel in the TAX 317 trial (37%).1 However, they are almost identical to the 1-year survival rate of 30% reported for the docetaxel 75 mg/m2 arm of the TAX 320 trial2 and the 29.7% rate in both arms of the JMEI trial that compared pemetrexed versus docetaxel.4 This trial, the largest conducted to date in this indication, supports the activity of topotecan in NSCLC. Oral topotecan may provide an option for patients who desire an oral treatment after relapse.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Supported by GlaxoSmithKline, Middlesex, United Kingdom. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000 2. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000 3. Shepherd FA, Pereira J, Ciuleanu TE, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 4. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versusdocetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004 5. Lynch TJ Jr, Kalish L, Strauss G, et al: Phase II study of topotecan in metastatic non-small-cell lung cancer. J Clin Oncol 12:347-352, 1994[Abstract] 6. Perez-Soler R, Fossella FV, Glisson BS, et al: Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy. J Clin Oncol 14:503-513, 1996 7. Weitz JJ, Marschke RF Jr, Sloan JA, et al: A randomized phase II trial of two schedules of topotecan for the treatment of advanced stage non-small cell lung cancer. Lung Cancer 28:157-162, 2000[CrossRef][Medline] 8. Gerrits CJ, Burris H, Schellens JH, et al: Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours. Eur J Cancer 34:1030-1035, 1998[CrossRef][Medline] 9. White SC, Cheeseman S, Thatcher N, et al: Phase II study of oral topotecan in advanced non small cell lung cancer. Clin Cancer Res 6:868-873, 2000 10. Hollen PJ, Gralla RJ, Kris MG. An overview of the Lung Cancer Symptom Scale, in Gralla RJ, Moinpour CM (eds): Assessing Quality of Life in Subjects with Lung Cancer: A Guide for the Clinician. Monograph, Quality of Life Symposium, 7th World Conference on Lung Cancer, June 26- July 1, 1994, Colorado Springs, CO. New York, NY, NCM, 1995, pp 57-63 11. Hollen PJ, Gralla RJ, Cox C, et al: A dilemma in analysis: Issues in the serial measurement of quality of life in subjects with advanced lung cancer. Lung Cancer 18:119-136, 1997[Medline] Submitted July 29, 2005; accepted February 7, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
