This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seiden, M. V. Articles by Eder, J. P. Search for Related Content PubMed PubMed Citation Articles by Seiden, M. V. Articles by Eder, J. P., Jr.

A Phase I Clinical Trial of Sequentially Administered Doxorubicin and Topotecan in Refractory Solid Tumors¹

Dana-Farber Cancer Institute and Division of Adult Oncology, Departments of Medicine [D. K., A. S., J. P. E.] and Obstetrics and Gynecology, Brigham and Women’s Hospital [S-W. N., K-C. H.]; Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital [M. V. S., J. G. S., D. P. R., J. W. C., T. L.]; and Division of Hematology and Oncology, Department of Medicine Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Harvard Medical School [J. P. E.], Boston, Massachusetts 02115

Purpose: To determine whether agents that target topoisomerase I and II could be administered sequentially.

Design: A Phase I study was conducted to evaluate sequential treatment with bolus IV doxorubicin followed 48 h later by topotecan given as a 30-min i.v. infusion on 3 consecutive days, with additional cycles of therapy repeated every 3 weeks. Characteristics of the 22 patients entered into the study were: 13 male and 9 female; median age, 49.5 (range 33–66) years; Eastern Cooperative Oncology Group performance status, 0–1; and normal cardiac, hematological, hepatic, and renal function. All patients had received prior therapy (median 2 prior regimens).

Results: The maximum tolerated dose of the combination was 25 mg/m² doxorubicin and 5.25 mg/m² topotecan (1.75 mg/m²/day x 3). Neutropenia was the dose-limiting toxicity. Attempts to further escalate the dose using 5 µg/kg granulocyte colony-stimulating factor proved unsuccessful because of thrombocytopenia. Among the 17 patients who were evaluable for response, 6 had a partial response, and 4 showed evidence of disease stabilization. The partial responses occurred in patients with small cell lung cancer (3 of 7), non-small cell lung cancer (1 of 6), esophageal adenocarcinoma (1 of 2), and ovarian carcinoma (1 of 1), and it lasted for 3–6 months. Administration of doxorubicin 2 days before topotecan did not alter topotecan pharmacokinetics. Changes in topoisomerase mRNA levels were observed during chemotherapy.

Conclusions: The sequential combination of doxorubicin followed by topotecan is highly active in several chemotherapy refractory long, ovary, and esophageal cancers. Despite significant neutropenia, toxicity is manageable and well tolerated. Phase II trials to further evaluate the efficacy of this promising combination regimen against non-Hodgkin’s lymphoma and lung cancer have been initiated.

This article has been cited by other articles:

				D. Mirchandani, H. Hochster, A. Hamilton, L. Liebes, H. Yee, J. P. Curtin, S. Lee, J. Sorich, C. Dellenbaugh, and F. M. Muggia Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer Clin. Cancer Res., August 15, 2005; 11(16): 5912 - 5919. [Abstract] [Full Text] [PDF]

				J. Aisner, R. Musanti, S. Beers, S. Smith, S. Locsin, and E. H. Rubin Sequencing Topotecan and Etoposide Plus Cisplatin to Overcome Topoisomerase I and II Resistance: A Pharmacodynamically Based Phase I Trial Clin. Cancer Res., July 1, 2003; 9(7): 2504 - 2509. [Abstract] [Full Text] [PDF]

				E. J. Licitra, V. Vyas, K. Nelson, R. Musanti, S. Beers, C. Thomas, E. Poplin, S. Smith, Y. Lin, Larry. J. Schaaf, et al. Phase I Evaluation of Sequential Topoisomerase Targeting with Irinotecan/Cisplatin Followed by Etoposide in Patients with Advanced Malignancy Clin. Cancer Res., May 1, 2003; 9(5): 1673 - 1679. [Abstract] [Full Text] [PDF]

				M. Hockel and P. Vaupel Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects J Natl Cancer Inst, February 21, 2001; 93(4): 266 - 276. [Abstract] [Full Text] [PDF]