GYNECOLOGIC ONCOLOGY
39, 146-149 (19%)
Crossover Study with Cisplatin or Carboplatin in Advanced Ovarian Cancer L. REPETTO,*J S. CHIARA,* S. MAMMOLITI,* T. GUIDO,” M. BRUZZONE ,* V. SECONDO,t G. DONADIO,$ F. ODICINO,~ N. RAGNI,§ P. F. CONTE,* AND R. ROSSO* *htituto
Nazionale
per la Ricerca sul Cancro,
Genoa;
TOspedale
Ginecologica,
Galhera,
Universitd
Genoa;
.$Gspeda[e
S. Giovanni,
Torino;
and BClinica
Ostetrica
e
di Genova, Genoa, Italy
Received March 15, 1990
Fifty-seven patients who had progressed during or relapsed after randomized first-line combination chemotherapy containing cisplatin or carboplati were entered into a crossover study in which the analog not previously assigned was administered alone as salvage treatment. Carboplatin and cisplatin were administered at doses of 400 and 100 mg/m’, respectively, every 28 days. Among the 24 patients enrolled in the cisplatin arm, 6 (25%) objective responses(OR@ (3 complete, 3 partial) were observed, whereas 3 partial responseswere obtained in the 33 carboplatintreated patient (9%). Analysis of results, according to response to first-line chemotherapy, demonstrated that the patients who progressed were sensitive only to cisplatin second-line treatment (OR: 3/12), with no responders among carboplatin-treated patients (OR: O/11). All patients were treated on an outpatient basis and therapy-related toxic effects were mild, consisting chiefly of myelosuppression, and more frequent in the carboplatiq group. In our opinion, carboplatin 400 mg/m* per cycle is scarcely effective in patients with refractory or relapsed ovarian cancer pretreated with cisplatin regimens, whereas cisplatin 100 mg/m* per cycle appears to be an effective salvage therapy even in patients not responding to carboplatin. The dose of carboplatin should be further escalated especially in refractory patients. Q 1990 Acad& Press, Inc.
icities [l]. Moreover the lack of effective salvage treatment for refractory or relapsed patients requires the utilization of pon-cross-resistant drugs whose toxicity is not cumulative with primary treatment [2]. Among second-generation cisplatin analogs, carboplatin appears the most effective. Phase I studies have shown that carboplatin causes myelotoxicity, particularly thrombocytopenia, but not nephrotoxicity. In phase II trials responses were seen in ovarian cancer patients both previously treated and previously untreated with cisplatin [3-51. However, the optimal dose, dose intensity, and in particular the equivalent dose of cisplatin and carboplatin have not been found, and the platinum analog of choice for first-line treatment remains undetermined. In an attempt to retain the therapeutic benefit of platinum derivatives without additional toxicity, we have performed a crossover study in which ovarian cancer patients failing front-line combination chemotherapy including cisplatin or carboplatin were switched to the platinum analogs as salvage treatment. PATIENTS AND METHODS
INTRODUCTION
Between March 1985 and October 1987, 164 patients with advanced ovarian cancer entered a randomized study comparing cisplatin 50 mg/m*, Adriamycin 45 mg/m*, and cyclophosphamide 600 mg/m* (PAC) versus inconsequential toxicity of cisplatin have stimulated the carboplatin 200 mg/m*, Adriamycin 45 mg/ms;2, and search for platinum analogs either more active or less cyclophosphamide 600 mg/m* (CAC), on Day 1 and toxic than cisplatin. In particular, emesis and neurologevery 28 days thereafter. Details of this trial have been ical side effects are the most important dose-limiting toxpublished elsewhere [6]. Patients who were no longer responding to front-line ’ To whom requests for reprints should be addressed at Istituto therapy or who had relapsed after an initial objective Nazionale Ricerca Cancro, Viale Benedetto XV, 10, 16132-Genoa, Italy. response were entered into a crossover study in which
The major role of cisplatin in the treatment of patients with advanced ovarian cancer has been established. The effective antitumor activity and the manageable but not
146 0090-8258/90 $1.50
Copyright 8 1990by AcademicPress,Inc. All rights of reproductionin any form reserved.
CISPLATIN
VERSUS CARBOPLATIN
AS SECOND LINE IN OVARIAN
TABLE 1 Characteristicsof the PatientsEntering the CrossoverStudy of Cisplatin versusCarboplatin Second-line treatment Carboplatin
Cisplatin
33 54 (43-68)
24 56 (36-70)
16 15 2
13 9 2
2 31 6 (4-12)
24 7 (2-12)
6 13 8 3 3
1 11 11 1 -
15 17 1
11 12 1
Number of patients Median age (range) ECOC PS 0 1 2 First-line chemotherapy PC PAC CAC Median numberof courses (range) Response to first-line chemotherapy Complete response Partial response Stable disease Progressive disease Not evaluable Residual disease at crossover >5 cm 2-5 cm 800 mg/m*) can be safely repeated either alone or combined with an alkylating agent in previously treated ovarian cancer patients. It appears that even higher doses should be tested in patients whose disease is refractory to cisplatin. ACKNOWLEDGMENT This work was supported in part by Bristol-Myers Squibb Company, Wallingford, Connecticut.
REFERENCES 1. Williams, C. J., and Whitehouse, J. M. A. cis-Platinum: A new anticancer agent, &it. Med. J. 1, 1689-1691 (1979). 2. Bruzzone, M., Chiara, S., Conte, P. F., Rosso, R., Giaccone, G., Camino, F., and Pescetto, G. Second line chemotherapy in ovarian carcinoma after failure of platinum based front line treatment, J. Clin. Exp. Cancer. Res. 5, 79-83 (1986).
CANCER
149
3. Canetta, R., Bragman, K., Smaldone, L., and Rozencweig, M. Carboplatin: Current status and future prospects, Cancer Treat. Rev. 15 (Suppl. B), 17-32 (1988). 4. Eisenhauer, E. A., Swenerton, K. D., Sturgeon, .I. F. G., Fine, S., and O’Reilly, S. E. Phase II study of carboplatin in patients with ovarian carcinoma: A National Cancer Institute of Canada Clinical Group Study, Cancer Treat. Rep. 70, 1195-1198 (1986). 5. Wiltshaw, E., Gore, M. Sheperd, J., Blake, B., Mott, A., and Fryatt, I. Carboplatin: The present position, in Mulfimodality treatment of ovarian cancer (P. F. Conte, R. Rosso, N. Ragni, and J. B. Vermoken, Eds.), Raven Press, New York, pp. 265-270 (1989). 6. Conte, P. F., Bruzzone, M., Camino, F., Chiara, S., Donadio, M., Facchini, V., Fioretti, P., Foglia, G., Gadducci, A., Gallo, L., G&cone, G., Guercio, E., Iskra, L., Jassen, N., Maresi, M. P., Parodi, G., Ragni, N., Rosso, R., Rubagotti, A., Rugiati, S., Storace, A., Venturini, S., and Pescetto, G. Carboplatin, doxorubicin and cyclophosphamide versus cisplatin, doxorubicin and cyclophosphamide: A randomized trial in stage III-IV epithelial ovarian carcinoma, J. C/in. Oncol. (1990) (in press). 7. Ozols, R. F., Ostchega, Y., Curt, G., and Young, R. High-dose carboplatin in refractory ovarian cancer patients, J. Clin. Oncol. 5, 197-201 (1987). 8. Behrens, B. C., Grotzinger, K. R., Hamilton, T. C., Whang-Peng, J., Batist, G., Louie, K. G., Knutsen, T., Tsuruo, T., McKay, W. M., Young, R. C., and Ozols, R. F. Cytotoxicity of 3 cisplatin analogues in a drug sensitive and a new cisplatin resistant human ovarian cancer ceh line, Proc. Amer. Assoc. Cancer Res. 26, 262 (1985) (Abstract). 9. Gore, M. E., Fryatt, I., Wilthshaw, E., Dawson, T., Robinson, B. A., and Calvert, A. H. Cisplatin/carboplatin cross-resistance in ovarian cancer, Brit. J. Cancer 60, 767-769 (1989). 10. Reed, E., Behrens, B. Yuspa, S. H., Poirier, M. C., Hamilton, T., and Ozols, R. F. Differences in cisplatin-DNA adduct formation in sensitive and resistant sublines of human ovarian cancer cells, Proc. Amer. Assoc. Cancer Res. 27, 285 (1986) (Abstract). 11. Rosemberg, B. Fundamental studies with cisplatin, Cancer 55, 2303-2316 (1985). 12. Plooy, A. C. M., Van Dijk, M., and Lohman, P. H. M. Induction and repair of DNA cross-links in Chinese hamster ovary cells treated with various platinum coordination compounds in relation to platinum binding to DNA, cytotoxicity, mutagenicitiy, and antitumor activity, Cancer Res. 44, 2043-2061 (1984). 13. Kelley, S. L., and Rozencweig, M. Resistance to platinum compounds: Mechanisms and beyond, Eur. .I. Clin. Oncol. 25, 11351140 (1989). 14. Kjorstad, K., Bertelsen, K., Slevin, M., Uytdenhoef, M., Franks, C. R., Canetta, R., Rozencweig, hf., and Members of BristolMyers Study Group. Phase II trial of carboplatin in ovarian cancer, Proc. Amer. Sot. Clin. Oncol. 5, 113 (1986). 15. Marsoni, S., Bolis, G., Epis, A., Pecorelli, S., Redaelli, L., Sessa, C., Vassena, L., Zanaboni, F., Franks, C. R., and Mangioni, C. A phase II trial of carboplatin (CBDCA; NSC 241248)in advanced ovarian cancer patients (OACP), in Fourteenth Znternational Cancer Congress, Vol. 14, p. 1004. 16. Sessa, C., Vermoken, J., and Renard, J. Phase II study of iproplatin in advanced ovarian carcinoma, J. Clin. Oncol. 6, 98-105 (1988).
39, 146-149 (19%)
Crossover Study with Cisplatin or Carboplatin in Advanced Ovarian Cancer L. REPETTO,*J S. CHIARA,* S. MAMMOLITI,* T. GUIDO,” M. BRUZZONE ,* V. SECONDO,t G. DONADIO,$ F. ODICINO,~ N. RAGNI,§ P. F. CONTE,* AND R. ROSSO* *htituto
Nazionale
per la Ricerca sul Cancro,
Genoa;
TOspedale
Ginecologica,
Galhera,
Universitd
Genoa;
.$Gspeda[e
S. Giovanni,
Torino;
and BClinica
Ostetrica
e
di Genova, Genoa, Italy
Received March 15, 1990
Fifty-seven patients who had progressed during or relapsed after randomized first-line combination chemotherapy containing cisplatin or carboplati were entered into a crossover study in which the analog not previously assigned was administered alone as salvage treatment. Carboplatin and cisplatin were administered at doses of 400 and 100 mg/m’, respectively, every 28 days. Among the 24 patients enrolled in the cisplatin arm, 6 (25%) objective responses(OR@ (3 complete, 3 partial) were observed, whereas 3 partial responseswere obtained in the 33 carboplatintreated patient (9%). Analysis of results, according to response to first-line chemotherapy, demonstrated that the patients who progressed were sensitive only to cisplatin second-line treatment (OR: 3/12), with no responders among carboplatin-treated patients (OR: O/11). All patients were treated on an outpatient basis and therapy-related toxic effects were mild, consisting chiefly of myelosuppression, and more frequent in the carboplatiq group. In our opinion, carboplatin 400 mg/m* per cycle is scarcely effective in patients with refractory or relapsed ovarian cancer pretreated with cisplatin regimens, whereas cisplatin 100 mg/m* per cycle appears to be an effective salvage therapy even in patients not responding to carboplatin. The dose of carboplatin should be further escalated especially in refractory patients. Q 1990 Acad& Press, Inc.
icities [l]. Moreover the lack of effective salvage treatment for refractory or relapsed patients requires the utilization of pon-cross-resistant drugs whose toxicity is not cumulative with primary treatment [2]. Among second-generation cisplatin analogs, carboplatin appears the most effective. Phase I studies have shown that carboplatin causes myelotoxicity, particularly thrombocytopenia, but not nephrotoxicity. In phase II trials responses were seen in ovarian cancer patients both previously treated and previously untreated with cisplatin [3-51. However, the optimal dose, dose intensity, and in particular the equivalent dose of cisplatin and carboplatin have not been found, and the platinum analog of choice for first-line treatment remains undetermined. In an attempt to retain the therapeutic benefit of platinum derivatives without additional toxicity, we have performed a crossover study in which ovarian cancer patients failing front-line combination chemotherapy including cisplatin or carboplatin were switched to the platinum analogs as salvage treatment. PATIENTS AND METHODS
INTRODUCTION
Between March 1985 and October 1987, 164 patients with advanced ovarian cancer entered a randomized study comparing cisplatin 50 mg/m*, Adriamycin 45 mg/m*, and cyclophosphamide 600 mg/m* (PAC) versus inconsequential toxicity of cisplatin have stimulated the carboplatin 200 mg/m*, Adriamycin 45 mg/ms;2, and search for platinum analogs either more active or less cyclophosphamide 600 mg/m* (CAC), on Day 1 and toxic than cisplatin. In particular, emesis and neurologevery 28 days thereafter. Details of this trial have been ical side effects are the most important dose-limiting toxpublished elsewhere [6]. Patients who were no longer responding to front-line ’ To whom requests for reprints should be addressed at Istituto therapy or who had relapsed after an initial objective Nazionale Ricerca Cancro, Viale Benedetto XV, 10, 16132-Genoa, Italy. response were entered into a crossover study in which
The major role of cisplatin in the treatment of patients with advanced ovarian cancer has been established. The effective antitumor activity and the manageable but not
146 0090-8258/90 $1.50
Copyright 8 1990by AcademicPress,Inc. All rights of reproductionin any form reserved.
CISPLATIN
VERSUS CARBOPLATIN
AS SECOND LINE IN OVARIAN
TABLE 1 Characteristicsof the PatientsEntering the CrossoverStudy of Cisplatin versusCarboplatin Second-line treatment Carboplatin
Cisplatin
33 54 (43-68)
24 56 (36-70)
16 15 2
13 9 2
2 31 6 (4-12)
24 7 (2-12)
6 13 8 3 3
1 11 11 1 -
15 17 1
11 12 1
Number of patients Median age (range) ECOC PS 0 1 2 First-line chemotherapy PC PAC CAC Median numberof courses (range) Response to first-line chemotherapy Complete response Partial response Stable disease Progressive disease Not evaluable Residual disease at crossover >5 cm 2-5 cm 800 mg/m*) can be safely repeated either alone or combined with an alkylating agent in previously treated ovarian cancer patients. It appears that even higher doses should be tested in patients whose disease is refractory to cisplatin. ACKNOWLEDGMENT This work was supported in part by Bristol-Myers Squibb Company, Wallingford, Connecticut.
REFERENCES 1. Williams, C. J., and Whitehouse, J. M. A. cis-Platinum: A new anticancer agent, &it. Med. J. 1, 1689-1691 (1979). 2. Bruzzone, M., Chiara, S., Conte, P. F., Rosso, R., Giaccone, G., Camino, F., and Pescetto, G. Second line chemotherapy in ovarian carcinoma after failure of platinum based front line treatment, J. Clin. Exp. Cancer. Res. 5, 79-83 (1986).
CANCER
149
3. Canetta, R., Bragman, K., Smaldone, L., and Rozencweig, M. Carboplatin: Current status and future prospects, Cancer Treat. Rev. 15 (Suppl. B), 17-32 (1988). 4. Eisenhauer, E. A., Swenerton, K. D., Sturgeon, .I. F. G., Fine, S., and O’Reilly, S. E. Phase II study of carboplatin in patients with ovarian carcinoma: A National Cancer Institute of Canada Clinical Group Study, Cancer Treat. Rep. 70, 1195-1198 (1986). 5. Wiltshaw, E., Gore, M. Sheperd, J., Blake, B., Mott, A., and Fryatt, I. Carboplatin: The present position, in Mulfimodality treatment of ovarian cancer (P. F. Conte, R. Rosso, N. Ragni, and J. B. Vermoken, Eds.), Raven Press, New York, pp. 265-270 (1989). 6. Conte, P. F., Bruzzone, M., Camino, F., Chiara, S., Donadio, M., Facchini, V., Fioretti, P., Foglia, G., Gadducci, A., Gallo, L., G&cone, G., Guercio, E., Iskra, L., Jassen, N., Maresi, M. P., Parodi, G., Ragni, N., Rosso, R., Rubagotti, A., Rugiati, S., Storace, A., Venturini, S., and Pescetto, G. Carboplatin, doxorubicin and cyclophosphamide versus cisplatin, doxorubicin and cyclophosphamide: A randomized trial in stage III-IV epithelial ovarian carcinoma, J. C/in. Oncol. (1990) (in press). 7. Ozols, R. F., Ostchega, Y., Curt, G., and Young, R. High-dose carboplatin in refractory ovarian cancer patients, J. Clin. Oncol. 5, 197-201 (1987). 8. Behrens, B. C., Grotzinger, K. R., Hamilton, T. C., Whang-Peng, J., Batist, G., Louie, K. G., Knutsen, T., Tsuruo, T., McKay, W. M., Young, R. C., and Ozols, R. F. Cytotoxicity of 3 cisplatin analogues in a drug sensitive and a new cisplatin resistant human ovarian cancer ceh line, Proc. Amer. Assoc. Cancer Res. 26, 262 (1985) (Abstract). 9. Gore, M. E., Fryatt, I., Wilthshaw, E., Dawson, T., Robinson, B. A., and Calvert, A. H. Cisplatin/carboplatin cross-resistance in ovarian cancer, Brit. J. Cancer 60, 767-769 (1989). 10. Reed, E., Behrens, B. Yuspa, S. H., Poirier, M. C., Hamilton, T., and Ozols, R. F. Differences in cisplatin-DNA adduct formation in sensitive and resistant sublines of human ovarian cancer cells, Proc. Amer. Assoc. Cancer Res. 27, 285 (1986) (Abstract). 11. Rosemberg, B. Fundamental studies with cisplatin, Cancer 55, 2303-2316 (1985). 12. Plooy, A. C. M., Van Dijk, M., and Lohman, P. H. M. Induction and repair of DNA cross-links in Chinese hamster ovary cells treated with various platinum coordination compounds in relation to platinum binding to DNA, cytotoxicity, mutagenicitiy, and antitumor activity, Cancer Res. 44, 2043-2061 (1984). 13. Kelley, S. L., and Rozencweig, M. Resistance to platinum compounds: Mechanisms and beyond, Eur. .I. Clin. Oncol. 25, 11351140 (1989). 14. Kjorstad, K., Bertelsen, K., Slevin, M., Uytdenhoef, M., Franks, C. R., Canetta, R., Rozencweig, hf., and Members of BristolMyers Study Group. Phase II trial of carboplatin in ovarian cancer, Proc. Amer. Sot. Clin. Oncol. 5, 113 (1986). 15. Marsoni, S., Bolis, G., Epis, A., Pecorelli, S., Redaelli, L., Sessa, C., Vassena, L., Zanaboni, F., Franks, C. R., and Mangioni, C. A phase II trial of carboplatin (CBDCA; NSC 241248)in advanced ovarian cancer patients (OACP), in Fourteenth Znternational Cancer Congress, Vol. 14, p. 1004. 16. Sessa, C., Vermoken, J., and Renard, J. Phase II study of iproplatin in advanced ovarian carcinoma, J. Clin. Oncol. 6, 98-105 (1988).
