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Originally published as JCO Early Release 10.1200/JCO.2008.18.1974 on October 14 2008 © 2008 American Society of Clinical Oncology. Randomized Phase II Trial Comparing Amrubicin With Topotecan in Patients With Previously Treated Small-Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 0402
From the Department of Respiratory Medicine, Sendai Kousei Hospital, Sendai; First Department of Medicine, Hokkaido University School of Medicine; Department of Respiratory Medicine, Sapporo City General Hospital, Sapporo; Division of Respirology and Chest Surgery, Miyagi Cancer Center, Natori; Department of Respiratory Medicine, Isawa Hospital, Oshu; Department of Cardiology, Respiratory Medicine, and Nephrology, and Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Hirosaki; Department of Internal Medicine, Senseki Hospital, Higashi-Matsushima; Department of Respiratory Medicine, Okitama Public General Hospital, Higashi-Okitama; Department of Respiratory Medicine, Iwamizawa Rousai Hospital, Iwamizawa; Department of Respiratory Medicine, Saka Hospital, Shiogama; and the Department of Respiratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan Corresponding author: Akira Inoue, MD, Department of Respiratory Medicine, Tohoku University Hospital, 1-1, Seiryomachi, Aoba-ku, Sendai, 980-8574, Japan; e-mail: akinoue{at}idac.tohoku.ac.jp
Purpose Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation. Patients and Methods Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m2 on days 1 through 3) or topotecan (1.0 mg/m2 on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. Results From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival. Conclusion Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.
Lung cancer is the leading cause of cancer death, and approximately 12% to 15% of patients with lung cancer are classified as having small-cell lung cancer (SCLC).1 Despite high response rates to first-line chemotherapy, most SCLC patients experience relapse within 2 years and die from systemic metastasis. Median survival time (MST) of patients with extensive-stage SCLC is generally less than 10 months.2 Topotecan is a semi-synthetic, water-soluble analog of camptothecin, with specific targeting to DNA topoisomerase-I. Topotecan showed an objective response rate of 39% in previously untreated patients with SCLC in an Eastern Cooperative Oncology Group (ECOG) phase II trial.3 Moreover, several phase II studies with intravenous administration of single-agent topotecan for 5 consecutive days have shown response rates of 14% to 38% among patients with SCLC with chemotherapy-sensitive relapse and response rates of 2% to 6% among patients with chemotherapy-refractory relapse4-6 A randomized study of a three-drug combination of cyclophosphamide, doxorubicin, and vincristine versus topotecan in patients with chemotherapy-sensitive relapsed SCLC showed equivalent response rate and survival for single-agent topotecan, with superior quality-of-life scores and symptom control for patients treated with topotecan.7 Nonetheless, response rates were modest for both arms at 24% and 18% for topotecan and the combination of cyclophosphamide, doxorubicin, and vincristine, respectively. Survival after relapse was also not satisfactory, with MST less than 6 months in each arm of this trial. Thus new therapeutic options are urgently required for patients with relapsed SCLC. Several studies have suggested the efficacy of combination regimens for relapsed SCLC.8 Kubota et al9 reported that a dose-intensive weekly chemotherapy regimen with cisplatin, vincristine, doxorubicin, and etoposide achieved a high response rate (88.2%) in patients with relapsed SCLC. Ardizzoni et al10 also reported a phase II study of combination with cisplatin and topotecan, which showed response rates of 29.4% in chemotherapy-sensitive relapse and 23.8% in chemotherapy-refractory relapse. However, MSTs of these studies (6.1 and 8.1 months) are disappointing in terms of the risk-benefit balance. Thus the superiority of single-agent or combination regimen still remains unclear, needing confirmatory large-scale phase III study in the future. Amrubicin, a fully synthetic 9-aminoanthracycline, is converted in the body to amrubicinol by reduction of the 13-position ketone, which has a higher antitumor activity than the parent molecule. Although classified as anthracycline agents, amrubicin and amrubicinol exert cytotoxic effects as DNA topoisomerase II inhibitors, not mainly as DNA intercalators. A Japanese phase II study with intravenous administration of single-agent amrubicin at 45 mg/m2 for 3 consecutive days in previously untreated extensive-stage SCLC showed high overall response rate (75.8%) and long MST (11.7 months), warranting investigation of its efficacy in patients with relapsed SCLC.11 Because there has been no comparative study of amrubicin with another single agent for relapsed SCLC, we conducted this randomized phase II study to select the superior single agent for a future large-scale trial.
Eligibility Criteria Patients older than 20 years with histologically or cytologically proven SCLC who had been previously treated with platinum-based chemotherapy were eligible. Patients were also required to have ECOG performance status (PS) of at least 2, adequate bone marrow function (absolute neutrophil count  1,500/mL, platelet count 100,000/mL, and hemoglobin 9.0 g/dL), hepatic function (AST and ALT  100 IU/L, total bilirubin level 2.0 mg/dL), renal function (serum creatinine level 1.5 mg/dL), arterial oxygen pressure 60 mmHg, adequate cardiac function (ECG findings within normal range and left ventricular ejection fraction 60%), and written informed consent. Patients with symptomatic brain metastasis, massive effusion requiring drainage, or severe comorbidities such as uncontrolled diabetes, heart disease, infectious disease, or pulmonary fibrosis were ineligible. The study protocol was reviewed and approved by the ethics committee or institutional review board of each institution.
Treatment Schedule
Amrubicin was dissolved in 20 mL of normal saline and administered intravenously as a 5-minute infusion at a dose of 40 mg/m2 on days 1 to 3 every 3 weeks. Topotecan was dissolved in 100 mL of normal saline and administered intravenously as a 30-minute drip infusion at a dose of 1.0 mg/m2, the approved dosage of topotecan in Japan as determined by the Japanese Ministry of Labor, Health, and Welfare from the results of previous phase I and phase II study in Japanese chemotherapy-naïve patients,12 on days 1 to 5 every 3 weeks. Each treatment was repeated for at least three cycles unless there was obvious disease progression, patient refusal, or intolerable toxicity. Patients were required to have absolute neutrophil count Granulocyte colony-stimulating factor was permitted as a therapeutic intervention for neutropenia but not for use as a prophylactic.
Subsequent dosages were modified based on hematologic and nonhematologic toxicities. If grade 4 neutropenia for Subsequent (third-line or later) chemotherapy after disease progression in this study was not limited. Cross-over administration (eg, third-line amrubicin to patients in the topotecan arm) was permitted. Regimens used for subsequent chemotherapy and their responses in each patient were also reported by the attending physician.
Patient Assessment
Statistical Analysis
Patient Characteristics From February 2004 to July 2007, 60 patients were enrolled from 12 institutions. One patient in the amrubicin arm did not receive any protocol treatment as a result of rapid disease progression, and 59 patients (36 patients in chemotherapy-sensitive relapse and 23 patients in chemotherapy-refractory relapse) were assessable for the efficacy and the safety. No significant differences in demographic characteristics were found between the two treatment arms. Patients in the topotecan arm were slightly younger than those in the amrubicin arm (P = .195; Table 1). The median number of treatment cycles was three in the amrubicin arm (range, one to seven cycles) and two (range, one to four cycles) in the topotecan arm. The most common reason for treatment cessation was disease progression in both arms.
After the protocol treatment, 59% of patients (35 of 59 patients) received subsequent chemotherapy (14 patients in the amrubicin arm and 21 patients in the topotecan arm). The cross-over administration was performed in 41% of patients (five patients in the amrubicin arm and 19 patients in the topotecan arm), and four (21%) of 19 patients treated with amrubicin after topotecan achieved partial response; no partial response was observed among five patients treated with topotecan after amrubicin. Other regimens used in subsequent chemotherapy in each arm were as follows: in the amrubicin arm, carboplatin plus etoposide (n = 6), irinotecan alone (n = 5), carboplatin plus irinotecan (n = 2), and etoposide alone (n = 1); and in the topotecan arm, irinotecan alone (n = 4), carboplatin plus irinotecan (n = 4), carboplatin plus etoposide (n = 1), cisplatin plus irinotecan (n = 1), and docetaxel alone (n = 1).
Safety
Response ORR and disease control rate (DCR) were 38% (95% CI, 21% to 58%) and 79% (95% CI, 60% to 92%) for the amrubicin arm, respectively, and 13% (95% CI, 1% to 25%) and 47% (95% CI, 28% to 66%) for the topotecan arm, respectively (Table 3). These differences in ORR and DCR between the two arms were statistically significant. In patients with chemotherapy-sensitive relapse, ORR and DCR were 53% and 88%, respectively, for the amrubicin arm and 21% and 63%, respectively, for the topotecan arm. In patients with chemotherapy-refractory relapse, ORR and DCR were, respectively, 17% and 67% for the amrubicin arm and 0% and 18% for the topotecan arm (Table 4). Other subgroup analysis also revealed that better ORRs and DCRs were observed in the amrubicin arm regardless of age, sex, or prior chemotherapy regimen (data not shown). It is noteworthy that the response rate in the amrubicin arm (36%) did not decrease in patients previously treated with etoposide (a DNA topoisomerase II inhibitor)-containing chemotherapy and that no partial response was observed in patients previously treated with prior irinotecan (a DNA topoisomerase I inhibitor)-containing chemotherapy in the topotecan arm.
Survival Analysis The median PFS on the amrubicin arm was 3.5 months (chemotherapy-sensitive relapse, 3.9 months; chemotherapy-refractory relapse, 2.6 months) and on the topotecan arm was 2.2 months (chemotherapy-sensitive relapse, 3.0 months; chemotherapy-refractory relapse, 1.5 months; Fig 1A). The MST was 8.1 months for the amrubicin arm (sensitive relapse, 9.9 months; refractory relapse, 5.3 months) and 8.4 months for the topotecan arm (chemotherapy-sensitive relapse, 11.7 months; chemotherapy-refractory relapse, 5.4 months; Fig 1B).
Because many patients in this study received subsequent chemotherapy, we examined the overall survival of each patient group treated with amrubicin, topotecan, or regimens except amrubicin and topotecan, such as carboplatin plus etoposide or irinotecan alone in any line (not only second line but also third line or later) after the enrollment of this study (Figs 2A, B, and C). The significant difference in overall survival was observed between patients treated with amrubicin and those without (P < .0001; Fig 2A). We also performed multivariate analysis to evaluate the influence of each regimen on overall survival using variables including age, sex, initial clinical stage, PS, type of relapse, and the use of amrubicin, topotecan, or regimens except amrubicin and topotecan, which revealed that amrubicin has stronger influence than topotecan on the overall survival of patients with relapsed SCLC (Appendix Table A1, online only).
Treatment options for patients with relapsed SCLC remain limited. Several single agents are known to be active for relapsed SCLC.13-22 However, most studies of those agents have shown response rates of less than 30%. For patients with SCLC with chemotherapy-refractory relapse, few single agents achieved a response rate greater than 10%. In addition, few single agents besides topotecan had been evaluated in randomized studies, so the superior agent among them remained unclear. Recently, two phase II studies of amrubicin for relapsed SCLC were reported by Onoda et al23 and Kato et al.24 The response rate of 50% (same in both studies) in chemotherapy-sensitive relapse and 52% and 60% in chemotherapy-refractory relapse reported in their studies are quite promising compared with previous agents. However, such apparently high activity may have been the result of some selection bias, and therefore a comparison between their results and historical data of other single agents is not appropriate. Thus a prospective comparative study was clearly required. In the current randomized study, amrubicin achieved higher efficacy than topotecan. Regarding the primary end point, the ORR of the amrubicin arm was significantly better than that of the topotecan arm. Although the sample size in this study was small, the efficacy data of the topotecan arm are similar to those reported in previous studies (3.8% to 21.9% of response rate in patients with chemotherapy-sensitive relapse).7,25,26 The dosage of topotecan in this study (1.0 mg/m2) was lower than that used in trials in Western countries (1.5 mg/m2); however, this was the approved dosage of topotecan in Japan as determined by the Japanese Ministry of Labor, Health, and Welfare from the results of a previous phase II study in Japanese chemotherapy-naïve patients.12 The previous Japanese phase II study of topotecan at a dose of 1.0 mg/m2 for relapsed SCLC also produced similar efficacy (response rate of 26% and MST of 8.6 months).27 Thus the patients in the topotecan arm were considered to have been treated with the appropriate dosage. Regarding the response rates of amrubicin, the results of this study were lower than those reported in the studies of Onoda et al23 and Kato et al.24 These differences may due to differences of patient characteristics or other biases. However, the response rate of 53% (nine of 17 patients) and PFS of 3.9 months in patients with chemotherapy-sensitive relapse are still attractive. Regarding the efficacy for patients with chemotherapy-refractory relapse SCLC, the results of our study (response rate of 17% [two of 12 patients], disease control rate of 68%) are also encouraging, as there has been no single agent that consistently achieved more than a 10% response rate in chemotherapy-refractory relapsed SCLC, warranting a trial of amrubicin in this population. Although the ORR in amrubicin in chemotherapy-refractory relapse was quite low compared with those reported in the studies by Onoda et al23,24 the sample size of patients with chemotherapy-refractory relapse in their studies (n = 16 and n = 10, respectively) as well as in our study (n = 12) were too small to draw any valid conclusion. In a recent larger-scaled phase II study of amrubicin (n = 69), ORR of 17.4% was achieved in patients with chemotherapy-refractory relapsed SCLC,28 which is similar to the result in our study. It is interesting that the overall survival curve of the topotecan arm can be superimposed on that of the amrubicin arm, despite the lower response and shorter PFS of topotecan than amrubicin. On further analysis, we found that most long survivors in the topotecan arm received amrubicin for third-line or later chemotherapy. Subsequent multivariate analysis revealed that amrubicin had the strongest effect to prolong overall survival of patients with relapsed SCLC, although topotecan and other regimens (irinotecan or platinum doublet) also prolonged their survival, which suggests that amrubicin may be superior in the treatment of relapsed SCLC. Regarding toxicity, amrubicin seems to be more toxic than topotecan, although most cases of toxicity were manageable, which may in part be related to a lower dose of topotecan in this study, because patients treated with topotecan at a dose of 1.5 mg/m2 experienced grade 4 neutropenia or febrile neutropenia more frequently in previous studies.7,25,26 One treatment death owing to sepsis after severe myelosuppression occurred in the forth cycle of amrubicin treatment in a 75-year-old female patient. Patients with poor PS or older patients should be treated with amrubicin with caution. In conclusion, amrubicin may be superior to topotecan, with acceptable toxicity for patients with relapsed SCLC. Further evaluation of amrubicin in large-scale studies as a single agent or in combination is warranted in this population.
The author(s) indicated no potential conflicts of interest.
Conception and design: Akira Inoue Financial support: Yasuo Saijo, Toshihiro Nukiwa Administrative support: Shunichi Sugawara, Koichi Yamazaki, Makoto Maemondo, Toshiro Suzuki, Shingo Takanashi, Chieko Inoue, Minoru Inage, Hiroshi Yokouchi, Hiroshi Watanabe, Toumei Tsukamoto, Osamu Ishimoto, Fumihiro Hommura Provision of study materials or patients: Shunichi Sugawara, Koichi Yamazaki, Makoto Maemondo, Toshiro Suzuki, Kazunori Gomi, Shingo Takanashi, Chieko Inoue, Minoru Inage, Hiroshi Yokouchi, Hiroshi Watanabe, Toumei Tsukamoto, Osamu Ishimoto, Fumihiro Hommura Collection and assembly of data: Akira Inoue Data analysis and interpretation: Akira Inoue Manuscript writing: Akira Inoue Final approval of manuscript: Toshihiro Nukiwa
published online ahead of print at www.jco.org on October 13, 2008. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Govindan R, Page N, Morgensztern D, et al: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24:4539-4544, 2006 2. Murren J, Glasten E, Pass H, et al: Small cell lung cancer, in Devita VT, Rosenberg SA, Hellman S (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott-Raven, 2001, pp 983-1018 3. Schiller J, Kim K, Hutson P, et al: Phase II study of topotecan in patients with extensive stage small cell carcinoma of the lung: Cooperative Group Trial. J Clin Oncol 14:2345-2352, 1996[Abstract] 4. Ardizzoni A, Hansen H, Dombernowsky P, et al: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. J Clin Oncol 15:2090-2096, 1997 5. Depierre A, von Pawel J, Hans K, et al: Evaluation of topotecan (Hycamtin) in relapsed small-cell lung cancer (SCLC): A multicenter phase II study. Lung Cancer 18:35, 1997 (suppl 1)[Medline] 6. Eckardt J, Gralla R, Palmer MC, et al: Topotecan (T) as second-line therapy in patients (pts) with small cell lung cancer (SCLC): A phase II study. Ann Oncol 7:107, 1996 (suppl 5) 7. von Pawel J, Schiller JH, Shepherd FA, et al: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658-667, 1999 8. Tiseo M, Ardizzoni A: Current status of second-line treatment and novel therapies for small cell lung cancer. J Thorac Oncol 2:764-772, 2007 9. Kubota K, Nishiwaki Y, Kakinuma R, et al: Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer. J Clin Oncol 15:292-296, 1997 10. Ardizzoni A, Manegold C, Debruyne C, et al: European Organization for Research and Treatment of Cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as second-line treatment of refractory and sensitive small cell lung cancer. Clin Cancer Res 9:143-150, 2003 11. Yana T, Negoro S, Takada M, et al: Phase II study of amrubicin in previously untreated patients with extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) study. Invest New Drugs 25:253-258, 2007[Medline] 12. Kobayashi K, Hino M, Fukuoka M, et al: Phase I studies of nogitecan hydrochloride for Japanese. Int J Clin Oncol 7:177-186, 2002[CrossRef][Medline] 13. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10:1225-1229, 1992 14. Perez-Soler R, Glisson BS, Lee JS, et al: Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14:2785-2790, 1996 15. Smyth JF, Smith IE, Sessa C, et al: Activity of docetaxel (Taxotere) in small cell lung cancer: The Early Clinical Trials Group of the EORTC. Eur J Cancer 30A:1058-1060, 1994 16. van der Lee I, Smit EF, van Putten JW, et al: Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol 12:557-561, 2001 17. Masters GA, Declerck L, Blanke C, et al: Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 21:1550-1555, 2003 18. Hoang T, Kim K, Jaslowski A: Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer. Lung Cancer 42:97-102, 2003[CrossRef][Medline] 19. Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al: Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients: EORTC Lung Cancer Cooperative Group. Eur J Cancer 29A:1720-1722, 1993[CrossRef] 20. Furuse K, Kubota K, Kawahara M, et al: Phase II study of vinorelbine in heavily previously treated small cell lung cancer: Japan Lung Cancer Vinorelbine Study Group. Oncology 53:169-172, 1996[CrossRef][Medline] 21. Smit EF, Fokkema E, Biesma B, et al: A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 77:347-351, 1998[Medline] 22. Hanna NH, Ansari R, Bhatia S, et al: Pemetrexed in patients with relapsed small cell lung cancer: A phase II study from the Hoosier Oncology Group. J Clin Oncol 24:379s, 2006 (suppl; abstr 7063)[CrossRef] 23. Onoda S, Masuda N, Seto T, et al: Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 24:5448-5453, 2006 24. Kato T, Nokihara H, Ohe Y, et al: Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC). J Clin Oncol 24:379s, 2006 (suppl; abstr 7061)[CrossRef] 25. Eckardt JR, von Pawel J, Pujol JL, et al: Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 25:2086-2092, 2007 26. Jotte R, Conkling PR, Reynolds C, et al: A randomized phase II trial of amrubicin (AMR) vs topotecan as second-line treatment in extensive-disease small-cell lung cancer (SCLC) sensitive to platinum-based first-line chemotherapy. J Clin Oncol 26:433s, 2008 (suppl; abstr 8040) 27. Takeda K, Negoro S, Sawa T, et al: A phase II study of topotecan in patients with relapsed small-cell lung cancer. Clin Lung Cancer 4:224-228, 2003[Medline] 28. Ettinger DS, Jotte R, Gupta V, et al: A phase 2 trial of single-agent amrubicin in patients with extensive-disease small cell lung cancer (ED-SCLC) that is refractory or progressive within 90 days of completion of first-line platinum-based chemotherapy. J Clin Oncol 26:xxx, 2008 (suppl; abstr 8041) Submitted May 22, 2008; accepted July 7, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05 and β = .10, the estimated accrual was 27 patients in each arm. Fisher's exact test was used to estimate the correlation among different variables between arms. Survival estimation was performed using the Kaplan-Meier method and log-rank test. Stepwise multivariate analysis was used to assess the prognostic significance of several variables. 
