A phase I dose-escalation study was undertaken to determine the maximum tolerated dose of the intravenous combination of topotecan and etoposide in previously untreated patients with small-cell lung cancer. Nineteen patients were treated with 30-min infusions of topotecan (0.5 mg/m2/day for cohort 1; 0.75 mg/m2/day for cohort 2) followed by 1-hour infusions of a fixed daily dose of etoposide (60 mg/m2/day) for 5 consecutive days every 3 weeks. Patient cohort 1 (n = 7) received a total of 41 courses of chemotherapy. Grade 4 neutropenia occurred after 17% of the courses of therapy, and there was 1 episode of dose-limiting toxicity in this patient cohort. In patient cohort 2 (n = 12), a total of 64 courses of chemotherapy were administered. Grade 3 or 4 neutropenia occurred following 41 and 37% of the courses of therapy, respectively. Grade 3 thrombocytopenia occurred following 19% of the courses of therapy, and there were 3 episodes of dose-limiting toxicity in this patient cohort. There were no toxic deaths, and all nonhematologic toxicity (except hair loss) was ≤ grade 2. No further dose escalation was performed because of the degree of myelosuppression seen in patient cohort 2. All 19 patients were evaluable for response. Eighteen (95%) patients responded (14 partial responses and 4 complete responses) and the median survival was 10 months. This 5-day schedule of intravenous topotecan and etoposide administered sequentially on the same day is well tolerated, and the preliminary response rates were high in patients with previously untreated small-cell lung cancer.

Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, Crawford J, Randolph JA, Goodlow JL, Broun GO: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282–291.
Furuse K, Fukuoka M, Nishiwaki Y, Kurita Y, Watanabe K, Noda K, Ariyoshi Y, Tamura T, Saijo N: Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol 1998;16:2126–2132.
Sculier JP, Klastersky J, Libert P, Ravez P, Thiriaux J, Lecomte J, Bureau G, Vandermoten G, Dabouis G, Michel J: A randomized study comparing etoposide and vindesine with or without cisplatin as induction therapy for small cell lung cancer. EORTC Lung Cancer Working Party. Ann Oncol 1990;1:128–133.
Ali MA, Kraut MJ, Valdivieso M, Herskovic AM, Du W, Kalemkerian GP: Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer. Lung Cancer 1998;22:39–44.
Johnson BE, Bridges JD, Sobczeck M, Gray J, Linnoila RI, Gazdar AF, Hankins L, Steinberg SM, Edison M, Frame JN, Pass H, Nesbitt J, Holden D, Mulshine JL, Glatstein E, Ihde DC: Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 1996;14:806–813.
Kelly K: Treatment of extensive stage small cell lung cancer. Cancer Treat Res 2001;105:253–276.
Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G, Caranfa MJ, McCabe FL, Faucette LF, Johnson RK, Hertzberg RP: Synthesis of water-soluble (aminoalkyl) camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem 1991;34:98–107.
Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, Hurowitz LA, McGuire WP, Sartorius SE, Lubejko BG, Kaufmann SH: Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992;10:647–656.
Verweij J, Lund B, Beijnen J, Planting A, de Boer-Dennert M, Koier I, Rosing H, Hansen H: Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor. Ann Oncol 1993;4:673–678.
Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, Giaccone G, Schaefer B, Wanders J, Verweij J: 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. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997;15:2090–2096.
Depierre A, von Pawel J, Hans K, Moro D, Clark P, Gatzemeier U, Paillot N, Scheithauer W, Carmichael J, Santoro A, Ross G, Marangolo M: Evaluation of topotecan (Hycamtin™) in relapsed small cell lung cancer (SCLC). A multicenter phase II study [abstract]. Lung Cancer 1997;18(suppl 1):35 (abstract 126).
Eckardt J, Gralla R, Palmer MC, Gandara D, Laplante J, Sandler A, Fields SZ, Fitts D, Broom C: Topotecan (T) as second-line therapy in patients (Pts) with small cell lung cancer (SCLC): a phase II study [abstract]. Ann Oncol 1996;7(suppl 5):107 (abstract 513P).
Schiller JH, Kim K, Hutson P, DeVore R, Glick J, Stewart J, Johnson D: Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial. J Clin Oncol 1996;14:2345–2352.
Brahmer JR, Ettinger DS: The role of topotecan in the treatment of small cell lung cancer. Oncologist 1998;3:11–14.
Jett JR, Day R, Levitt M, Woolley G, Jacobs S: Topotecan and paclitaxel in extensive stage small cell lung cancer (ED-SCLC) patients without prior therapy [abstract]. Lung Cancer 1997;18:13 (abstract 38).
von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, Stewart DJ, Clark PI, Palmer MC, Depierre A, Carmichael J, Krebs JB, Ross G, Lane SR, Gralla R: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658–667.
Giovanella BC, Stehlin JS, Wall ME, Wani MC, Nicholas AW, Liu LF, Silber R, Potmesil M: DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 1989;246:1046–1048.
Whitacre CM, Zborowska E, Gordon NH, Mackay W, Berger NA: Topotecan increases topoisomerase IIα levels and sensitivity to treatment with etoposide in schedule-dependent process. Cancer Res 1997;57:1425–1428.
Anzai H, Frost P, Abbruzzese JL: Synergistic cytotoxicity with combined inhibition of topoisomerase (Topo) I and II [abstract]. Proc Am Assoc Cancer Res 1992;33:431 (abstract 2573).
McCabe FL, Funk LR, Yu Y: Combination chemotherapy utilising SK&F 104864 in female mice bearing L1210 lymphocytic leukemia, lewis lung cancer, mammary adenocarcinoma 16/C or B16 melanoma. SmithKline Beecham on file, report number PP-0013/SK&F 104864/1: King Prussia, PA, SmithKine Beecham Pharmaceuticals, 1992.
Bertrand R, O’Connor PM, Kerrigan D, Pommier Y: Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells. Eur J Cancer 1992;28A:743–748.
Kim R, Hirabayashi N, Nishiyama M, Jinushi K, Toge T, Okada K: Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice. Int J Cancer 1992;50:760–766.
Bonner JA, Kozelsky TF: The significance of the sequence of administration of topotecan and etoposide. Cancer Chemother Pharmacol 1996;39:109–112.
Saltz L, Sirott M, Young C, Tong W, Niedzwiecki D, Tzy-Jyun Y, Tao Y, Trochanowski B, Wright P, Barbosa K, Toomasi F, Kelsen D: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Cancer Inst 1993;85:1499–1507.
National Cancer Institute: Guidelines for reporting adverse reactions. Bethesda, MD, National Cancer Institute, 1988.
World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979.
Mok T, Chan A, Leung T, Leung S, Ho W, Wong H, Yeo W, Yang W, Yim A, Johnson P: Sequential administration of topotecan and oral etoposide in treatment of small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 2000;19:515a (abstract 2018).
Gervais R, Quoix E, Mattson K, Schramel FM, Rivière A, Fields S, Wheatley A, Ross G: Randomised phase II study of topotecan/cisplatin versus topotecan/etoposide in patients with untreated, extensive disease, small cell lung cancer (SCLC) [abstract]. Lung Cancer 2000;29(suppl):50 (abstract 1630).
Eckardt JR, Palmer MC, Fanucchi MP, Gralla R, Martins H, Poulin R, Fields SZ: Single agent oral topotecan (OT) as first-line treatment for patients (pts) with extensive disease (ED) small cell lung cancer (SCLC) ineligible for standard therapy: A phase II study [abstract]. Lung Cancer 2000;29(suppl 1):10 (abstract 25).
Burris HA III: The evolving role of oral topotecan. Semin Hematol 1999;36:26–32.
Ormrod D, Spencer CM: Topotecan: A review of its efficacy in small cell lung cancer. Drugs 1999;58:533–551.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.