Long-term results from a phase II study of paclitaxel combined with doxorubicin in recurrent platinum refractory ovanan cancer

Background: There is still a need for newer non-cross-resistant agents and combinations to be tried in cases of failure after first line platinum-based therapy. Several agents have demonstrated activity after failure of platinum-containing regimens. Response rate in true platinum refractory disease up to 20% but with poor long-term survival, has been reported by single drug paclitaxel. In an effort to improve response rate and survival duration obtainable with single drug paclitaxel, we have combined paclitaxel with doxorubicin for the treatment of patients refractory to cisplatin-cyclophosphamide.

Patients and methods: Between October 1994 and November 1996, 23 patients whereof 21 refractory to cisplatin-cyclophosphamide were enrolled for toxicity and survival analysis after receiving the combination doxorubicin 50 mg/m2 and paclitaxel 135 mg/m2 every third week for four courses. Responding patients continued on single drug paclitaxel 175 mg/m2 every third week until unacceptable toxicity or tumor progression occurred.

Results: The objective response rate (CR + PR) was 33%, 95% CI (14.6-57). The median duration of response was 8.5 months (range 4.0-62.5+) and the median overall survival was 15.5 months (range 4.0-63.5+). No serious toxicity was registered.

Conclusion: Doxorubicin combined with paclitaxel could safely be administered using this schedule. This study shows that some patients obtaining CR can be rendered disease-free for a substantial period of time, sometimes five years or more. A median overall survival of 15.5 months with a 5-year survival probability of 15% is impressive. However, although responses can be induced in a significant number of patients, the survival figures remain poor.

Cisplatin refractory ovarian cancer; Paclitaxel; Doxorubicin; Second-line treatment

[1] McGuire W. P., Hoskins W. J., Brady M. F., Kucera P. R., Partridge E. E., Look K. Y., D. L., Davidson M.: "Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer". N. Engl. J. Med., 1996, 334 (1), 1.

[2] Piccart M. J., Bertelsen K., James K., Cassidy J., Mangioni C., Simonsen E. et al.: "Randomized intergroup trial of cisplatinpaclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results". J. Natl. Cancer Inst., 2000, 92 (9), 699.

[3] Trope C., Kristensen G.: "Current status of chemotherapy in gynecologic cancer". Semin. Oncol., 1997, 24 (5 Suppl. 15), Sl5.

[4] McGuire W. P., Rowinsky E. K., Rosenshein N. B., Grumbine F. C., Ettinger D. S., Armstrong D. K., Donehower R. C.: "Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms". Ann. Intern. Med., 1989, 111 (4), 273.

[5] A'Hern R. P., Gore M. E.: "Impact of doxorubicin on survival in advanced ovarian cancer". J. Clin. Oncol., 1995, 13 (3), 726.

[6] Verrnorken J. B., Harper P. G., Buyse M.: "The role of anthracyclines in epithelial ovarian cancer". Ann. Oncol., 1999, 10 (Suppl]), 43.

[7] Ovarian Cancer Meta-Analysis Project: "Cyclophosphamide, doxorubicin, and cisplatin chemotherapy for ovarian carcinoma: A metanalysis". J. Clin. Oneal., 1991, 9, 1668.

[8] Stuart G., Bertelsen K., Mangioni C. et al.: "Updated analysis shows a highly significant improved overall survival for cisplatinpaclitaxel as first-line treatment of advanced ovarian cancer Mature results of the EORTC-GCCG, NOCOVA, NCIC CTG and Scottish Intergroup Trial". Proc. Am. Soc. Clin. Oneal., l 998, 17, 361.

[9] Fanning J., Benner T. Z., Hilgers R. D.: "Meta-analysis of cisplatin doxorubicin, and cyclophosphamide vs. cisplatin and cyclophosphamide chemotherapy of ovarian carcinoma". Obstet. Gynecol., 1992, 80, 954.

[10] Trope C.,A ndersson H., Bjorkholm E., Frankendal B., Himmelman A., Hogberg T. et al.: "Doxorubicin-melphalan with and without cisplatin in advanced ovarian cancer-ten-year survival results from a prospective randomized study by the Swedish Cooperative Ovarian Cancer Study Group". Acta Oncol., 1996, 35 Suppl. 8, 109.

[11] Trope C., Hogberg T., Kaern J., Bertelsen K., Bjorkholm E., Boman K. et al.: "Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience" Ann. Oneal., 1998, 9 (12), 1301.

[12] Goldberg J. M., Piver M. S., Hempling R. E., Recio F. 0.: "Pachtaxel and cisplatin combination chemotherapy in recurrent epithelial ovarian cancer". Gynecol. Oncol., 1996, 63 (3), 312.

[13] Vermorken J. 8., KobierskaA., van-der-Burg M. E., Chevallier B., Zanaboni F., ten-Bokkel-Huinink W.W. et al.: "High-dose epirubicin in platinum-pretreated patients with ovarian carcinoma: the EORTC-GCCG experience". Eur. J. Gynaecol. Oncol., 1995, 16(6), 433.

[14] Havsteen H., Bertelsen K., Gadeberg C. C. et al.: "A phase II study with epirubicin as second-line treatment of patients with advanced epithelial ovarian cancer". Gynecol. Oneal., 1996, 63, 210.

[15] Vermorken J. B., KobierskaA., Chevallier B., Zanaboni F., Pawmski A., Bolis G. for the EORTC Gynecological Cancer Cooperative group: "A phase II study of high-dose epirubicin in ovarian cancer patients previously treated with cisplatin". Ann. Oncol., 2000, 11, 1035.

[16] du Bois, Luck H.J., Bauknecht T., Meier W., Richter B., Kuhn W et al.: "First-line chemotherapy with epirubicin, paclitaxel, and carboplatin for advanced ovarian cancer: a phase I/II study of the Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group". J. Clin. Oneal., 1999, 77 (1), 46.

[17] World Health Organization. Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication No 48. Geneav, WHO 1979.

[18] Markman M., Hoskins W.: "Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population [editorial; comment]". J. Clin. Oncol., 1992, 10(4), 513.

[19] Thigpen J. T., Vance R. B., Khansur T.: "Second-line chemotherapy for recurrent carcinoma of the ovary". Cancer, 1993, 71 (4 Suppl.), 1559.

[20] Bookman M. A., Malmstrom H., Bolis G., Gordon A., Lissoni A., Krebs J. B.，FieIds S. Z.: "Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel". J. Clin. Oneal., 1998, 16 (10), 3345.

[21] Rose P. G., Blessing J. A., Soper J. T., Barter J. F.: "Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus a gynecologic oncology group study". Gynecol. Oncol., 1998, 70(2), 267.

[22] Shapiro J. D., Millward M. J., Rischin D., Michael M., Walcher V., Francis P. A., Toner G. C.: "Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel". Gynecol. Oneal., 1996, 63 (1), 89.

[23] Gordon A. N., Granai C. 0., Rose P. G., Hainsworth J., Lopez A., Weissman C. et al.: "Phase II Study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer". J. Clin. Oneal., 2000, 18, 3093.

[24] Johnston C. M., Pearl M. L., Reynolds R. K., Roberts J. A., Morley G. W.:'Treatment of refractory ovarian carcinoma with paclitaxel and cisplatin after treatment failure with single-agent paclitaxel". Eur. J. Gynaecol. Oncol., 1995, 16, 439.

[25] Eisenhauer E. A., ten-Bokkel-Huinink W. W., Swenerton K. D., Gianni L., Myles J., van-der-Burg M. E. et al.: "European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion". J. Clin. Oneal., 1994, 12 (12), 2654.

[26] ten-Bokkel H. W., Gore M., Carmichael J., Gordon A., Malfetano J., Hudson I. et al.: "Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer [see comments]". J. Clin. Oncol., 1997, 15 (6), 2183.

[27] Conte P. F., Gennari A.: "Anthracyclines-paclitaxel combinations in the treatment of breast cancer". Ann. Oneal., 1997, 8 (10), 939.

[28] Gehl J., Boesgaard M., Paaske T., Vittrup J. B., Dombernowsky P: "Combined doxorubicin and paclitaxel in advanced breast cancer: effective and cardiotoxic". Ann. Oneal., 1996, 7 (7), 687.

[29] Gianni L., Munzone E., Capri G. et al.: "Paclitaxel by 3-hour infosion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study". J. Clin. Oncol., 1995, 13, 2688.

[30] Kurtz J. E., Deplanque G., Duclos B., Eichler F., Giron C., Limacher J. M. et al.: "Paclitaxel-anthracycline combination chemotherapy in relapsing advanced ovarian cancer after platinum-based chemotherapy: a pilot study". Gynecol. Oneal., 1998, 70 (3), 414.

[31] Colombo N., Marzola M., Parma G. et al.: "Paclitaxel vs CAP (cyclophosphamide, adriamycin, cisplatin) in recurrent platinum sensitive ovarian cancer: A randomized phase II study (Abstract)". Proc. Am. Soc. Clin. Oncol., 1996, 15, 751a.