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
Ardizzoni, A.; Manegold, C.; Debruyne, C.et al.
2003 • In Clinical Cancer Research, 9 (1), p. 143-150
[en] Purpose: The purpose of this study was to assess the activity and toxicity of a combined regimen of topotecan and cisplatin in "sensitive" (s) and "refractory" (r) small-cell lung cancer (SCLC) patients treated previously. Experimental Design: Patients with measurable SCLC and progressive disease after one first-line regimen were eligible for the study. Patients were enrolled in two separate groups: r group (patients who failed first-line treatment <3 months from treatment discontinuation) and s group (patients who responded to first-line treatment and progressed 2:3 months after treatment discontinuation). Cisplatin was given i.v. at the dose of 60 mg/m(2) on day 1, and topotecan was administered as a daily i.v. infusion at the dose of 0.75 mg/m(2) from day 1 to 5, every 3 weeks. Results: A total of 110 eligible (68 s and 42 r) patients were enrolled from 24 institutions. The main patient characteristics were as follows: median age 60 (s) and 55 (r) years, median performance status 1 for both (s) and (r). Seventy-four percent (s) and 67% (r) had extensive stage disease, including 22% and 36%, respectively, with brain metastases. A total of 398 chemotherapy courses were administered [median 4 (s) and 3 (r) per patient]. The most frequent and serious toxicity was myelosuppression. Grade IV neutropenia occurred in 62% (s) and 49% (r) of patients, with a 19% (s) and 15% (r) incidence of febrile neutropenia, and grade IV thrombocytopenia in 54% (s) and 44% (r). Most of these toxicities occurred during the first chemotherapy course and led to topotecan dose reduction and/or delay in the following courses. Grade III-IV nonhematological toxicity was uncommon. Five deaths possibly related to toxicity occurred among s patients only. Objective responses have been documented in 20 s patients, 19 partial responses and 1 complete response, (29.4% response rate; 95% confidence interval, 19-42), whereas, among r patients, 10 partial responses have been observed (23.8% response rate; 95% confidence interval, 12-39). Median survival for s and r was 6.4 and 6.1 months, respectively. Conclusions: The combination of cisplatin and topotecan, at this dose and schedule, shows activity and promising results in patients with refractory SCLC, with reversible myelosuppression being the main side effect. Additional development of this regimen, using better-tolerated schedules, is warranted in patients with refractory SCLC.
Disciplines :
Oncology
Author, co-author :
Ardizzoni, A.
Manegold, C.
Debruyne, C.
Gaafar, R.
Buchholz, E.
Smit, E. F.
Lianes, P.
ten Velde, G.
Bosquee, Léon ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
Legrand, Catherine; Centre Hospitalier Universitaire de Liège - CHU > Chimie médicale
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
Publication date :
January 2003
Journal title :
Clinical Cancer Research
ISSN :
1078-0432
eISSN :
1557-3265
Publisher :
American Association for Cancer Research, Inc. (AACR)
Simon, G., Ginsberg, R. J., and Ruckdeschel, J. C. Small cell lung cancer. Chest Surg. Clin. N. Am., 11: 165-188, 2001.
Grant, S. C., Gralla, R. J., Kriss, M. G., Orazem, J., and Kitsis, E. A. Single agent chemotherapy trials in small cell lung cancer, 1970-1990: the case for studies in previously treated patients. J. Clin. Oncol., 10: 484-498, 1992.
Postmus, P. E., and Smit, E. F. Treatment of relapsed small cell lung cancer. Semin. Oncol., 28: 48-52, 2001.
Figoli, F., Veronesi, A., Ardizzoni, A., Canobbio, L., Bruschi, G., Mazza, F., Zagonel, V., Lo Re, G., Rosso, R., and Monfardini, S. Cisplatin and etoposide as second line chemotherapy in patients with small cell lung cancer. Cancer Investig., 6: 1-5, 1988.
Albain, K. S., Crowley, J. J., Hutchins, L., Gandara, D., O'Bryan, R. M., Von Hoff, D. D., Griffin, B., and Livingston, R. B. Predictors of survival following relapse or progression of small cell lung cancer. Cancer (Phila.), 72: 1184-1191, 1993.
Roth, B. J., Johnson, D. H., Einhorn, L. H., Schacter, L. P., Cherng, N. C., Cohen, H. J., Crawford, J., Randolph, J. A., Goodlow, J. L., Broun, G. O., et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide versus alteration of these regimens in small cell lung cancer: Phase III trial of Southeastern Cancer Study Group. J. Clin. Oncol., 10: 282-291, 1992.
Fukuoka, M., Furuse, K., Saijo, N., Nishiwaki, Y., Ikegami, H., Tamura, T., Shimoyama, M., and Suemasu, K. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alteration of these regimens in small cell lung cancer. J. Natl. Cancer Inst. (Bethesda), 83: 855-861, 1991.
Giaccone, G., Donadio, M., Bonardi, G., Testore, F., and Calciati, A. Teniposide in the treatment of small cell lung cancer: the influence of prior chemotherapy. J. Clin. Oncol., 6: 1264-1270, 1988.
Postmus, P. E., Smit, E. F., Kirkpatrick, A., and Splinter, T. A. Testing the possible non-cross resistance of two equipotent combination chemotherapy regimens against small cell lung cancer: a Phase II study of the EORTC Lung Cancer Cooperative Group. Eur. J. Cancer Clin. Oncol., 29A: 204-207, 1993.
Postmus, P. E., Berendsen, H. H., Van Zandwijk, N., Splinter, T. A., Burghouts, J. T., and Bakker, W. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur. J. Cancer Clin. Oncol., 23: 1409-1411, 1987.
Ardizzoni, A., Hansen, H., Dombernowsky, P., Gamucci, T., Kaplan, S., Postmus, P., Giaccone, G., Schaefer, B., Wanders, J., and Verweij, J. Topotecan, a new active drug in the second-line treatment of small cell lung cancer (SCLC): a Phase II study in patients with refracory and sensitive disease. J. Clin. Oncol., 15: 2090-2096, 1997.
Perez-Soler, R., Glisson, B. S., Lee, J. S., Fossella, F. V., Murphy, W. K., Shin, D. M., and Hong, W. K. 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.
Eckardt, J. R., Palmer, M. C., Fanucci, M. P., Gralla, R., Martins, H., Poulin, R., and Fields, S. Z. Single agent oral topotecan as first-line treatment for patients with extensive disease small cell lung cancer ineligible for standard therapy: a Phase II study (Abstract). Lung Cancer, 29: 10, 2000.
Depierre, A., Von Pawel, J., Hans, K., Moro, D., Clark, P., Gatzemeier, U., Paillot, N., Scheithauer, W., Carmichael, J., and Santoro, A. Evaluation of topotecan (Hycamtin) in relapsed small cell lung cancer (SCLC): a multicenter Phase II study (Abstract). Lung Cancer, 18: 35, 1997.
Von Pawel, J., Schiller, J. H., Shepherd, F. A., Fields, S. Z., Kleisbauer, J. P., Chrysson, N. G., Stewart, D. J., Clark, P. I., Palmer, M. C., Depierre, A., Carmichael, J., Krebs, J. B., Ross, G., Lane, S. R., and Gralla, R. Topotecan versus cyclophosphamide, doxorubicin and vincristine for the treatment of recurrent small cell lung cancer. J. Clin. Oncol., 17: 658-667, 1999.
Miller, A. A., Hargis, J. B., Lilenbaum, R. C., Fields, S. Z., Rosner, G. L., and Schilsky, R. Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study. J. Clin. Oncol., 12: 2743-2750, 1994.
WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication No. 48. Geneva: WHO, 1979.
Simon, R. Optimal two-stage designs for Phase II clinical trials. Controlled Clin. Trials, 10: 1-10, 1989.
Kaplan, E. L., and Meier, P. Non-parametric estimation for incomplete observations. J. Am. Stat. Assoc., 53: 457-481, 1958.
Johnson, R. K., Mccabe, F. L., and Young, Y. Combination regimens with topotecan in animal tumor models. Ann. Oncol., 3 (Suppl. 1): 85, 1992.
Kauffman, S. H. Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. Cancer Res., 51: 1129-1136, 1991.
Miller, A. A., Lilenbaum, R. C., Lynch, T. J., Rosner, G. L., Ratain, M. G., Green, M. R., and Schilsky, R. L. Treatment-related fatal sepsis from topotecan/cisplatin and topotecan/paclitaxel. J. Clin. Oncol., 14: 1964-1965, 1996.
Rowinsky, E. K., Kaufmann, S. H., Baker, S. D., Grochow, L. B., Chen, T. L., Peereboom, D., Bowling, M. K., Sartorius, S. E., Ettinger, D. S., Forastiere, A. A., and Donehower, R. C. Sequence of topotecan and cisplatin: Phase I, pharmacologic, and in vitro studies to examine sequence dependence. J. Clin. Oncol., 14: 3074-3084, 1996.
Sorensen, M., Jensen, P. B., Herrstedt, J., Hirsch, F. R., and Hansen, H. H. A dose escalating study of topotecan preceding cisplatin in previously untreated patients with small cell lung cancer. Ann. Oncol., 11: 829-835, 2001.
Von Pawel, J., Gatzemeier, U., Pujol, J. L., Moreau, L., Bildat, S., Ranson, M., Richardson, G., Steppert, C., Riviere, A., Camlett, I., Lane, S., and Ross, G. Phase II comparator study of oral versus intravenous topotecan in patients with small cell lung cancer. J. Clin. Oncol., 19: 1743-1749, 2001. mc
Palshof, T., Riviere, A., Moreau, L., Breton, J. L., Hearn, S., Fields, S. Z., and Ross, G. Phase II study of oral topotecan with cisplatin in advanced, non-resectable NSCLC: a promising combination (Abstract). Lung Cancer, 29: 36, 2000.
Smit, E. F., Fokkema, E., Biesma, B., Groen, H. J., Snoek, W., and Postmus, P. E. A Phase II study of paclitaxel in heavily pretreated patients with small cell lung cancer. Br. J. Cancer, 77: 347-351, 1998.
Groen, H. J., Fokkema, E., Biesma, B., Kwa, B., van Putten, J. W., Postmus, P. E., and Smit, E. F. Paclitaxel and carboplatin in the treatment of small cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule. J. Clin. Oncol., 17: 927-932, 1999.
Kakolyris, S., Mavroudis, D., Tsavaris, N., Souglakos, J., Tsiafaki, P., Kalbakis, K., Agelaki, S., Androulakis, N., and Georgoulias, V. Paclitaxel in combination with carboplatin as salvage treatment in refractory small cell lung cancer (SCLC): a multicenter Phase II study. Ann. Oncol., 12: 193-197, 2001.
Masuda, N., Fukuoka, M., Kusunoki, Y., Matsui, K., Takifuji, N., Kudoh, S., Negoro, S., Nishioka, M., Nakagawa, K., and Takada, M. 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.
Noda, K., Nishiwaki, Y., Kawahara, M., Negoro, S., Sugiura, T., Yokoyama, A., Fukuoka, M., Mori, K., Watanabe, K., Tamura, T., Yamamoto, S., and Saijo, N. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. N. Engl. J. Med., 346: 85-91, 2002.