GYNECOLOGIC
ONCOLOGY
47, 353-357 (1992)
Phase 2 Trial of lntraperitoneal Carboplatin and Etoposide as Salvage Treatment of Advanced Epithelial Ovarian Cancer’ MAURIE Breast/Gynecology
MARKMAN,’ BONNIE REICHMAN, THOMAS HAKES, STEPHEN RUBIN, WALTER JONES, JOHN L. LEWIS, JR., RICHARD BARAKAT, JOHN CURTIN, LOIS ALMADRONES, AND WILLIAM HOSKINS Service,
Division
of Solid Memorial
Tumor Oncology, Sloan-Kettering
Department Cancer Center,
of Medicine, New York,
and the Gynecology New York 10021
Service,
Department
of Surgery,
Received March 24. 1992
bination chemotherapy program [l]. In a recent retrospective review of two cisplatin-based IP chemotherapy basedtherapy assalvagetreatment of ovarian cancer,46 patients [3], cisplatin/cytarabine with persistentor recurrent ovarian cancerfollowing initial sys- programs (cisplatin/etoposide [4]), 42% of 36 patients with small volume disease (largest temic chemotherapywere treated with a regimenof carboplatin tumor mass 18 years old, WBC a3500/mm3, platelets ~100,000/mm3, serum bilirubin ~1.5 mg%, serum creatinine ~1.8 mg%, and no prior chemotherapy within the previous 4 weeks. All patients were also required to sign an informed consent statement indicating that they were aware of the investigational nature of the treatment program. Peritoneal Cavity Access
All patients entered into this trial had a peritoneal cavity catheter surgically placed (Tenckhoff type), which was attached to a subcutaneous portal delivery device. Patients did not routinely undergo formal assessment of peritoneal fluid distribution before the initiation of the IP therapy. However, patients who experienced difficulty receiving the treatment volume (e.g., abdominal pain with fluid delivery, excessively slow flow) underwent a radionuclide distribution study. Treatment Plan
The starting dose level of carboplatin was 200 mg/m* and of etoposide 100 mg/m*. The drugs were mixed together in 2 liters 5% dextrose. Prior to administration, the solution was warmed to approximately body temperature. The treatment volume was delivered into the peritoneal cavity as rapidly as possible. The drugs and fluid were left in the cavity to be absorbed on their own into the systemic circulation. In an individual patient was uncomfortable due to abdominal distention with fluid, it was permitted that the abdomen be drained 24 hr after drug instillation. The drugs were to be administered monthly for a maximum of six courses. Antiemetics were administered to all patients. Patients treated on this protocol were hydrated with approximately 200 ml/hr for 3-5 hr beginning at the initiation of IP drug delivery. Both dose escalation as well as reduction were permitted in this trial. If following the first course of therapy the nadir WBC count was a2500/mm3 and platelet count ~90,000/mm3, the dose of carboplatin was to be increased to 300 mg/m* for course 2. If following the first course of therapy the nadir WBC count was l cm in diameter responded to the treatment program. Finally, of the 7 evaluable patients who had previously failed to respond to a systemic organoplatinum regimen, a single patient with microscopic disease responded to the IP program, achieving a surgically documented complete response.
ET AL.
ence of borderline renal function in augmenting carboplatin-induced marrow suppression in patients with ovarian cancer receiving salvage IP therapy has previously been noted [6]. Finally, 15 (33%) of our patients had previously been treated with systemic carboplatin before entering this phase 2 trial. Such patients are more likely to experience greater difficulty with a salvage carboplatin regimen compared to individuals initially treated with cisResponse Duration and Survival platin due to the known bone marrow suppressive effects Thirty-two (70%) of the 46 patients are currently alive, of the newer platinum drug [5]. including 11 (92%) of the 12 responding patients. The Thus, we are left with the following important question: median follow-up of the surviving patients is 21+ months If an ovarian cancer patient with small volume residual (range, 8+-32+ months). To date, only 1 of the 8 pa- disease following a response to a platinum-based systemic tients who achieved a surgically documented complete regimen is being considered for a salvage IP program, response has relapsed, 18 months following her reassess- which platinum drug should be employed, cisplatin or ment surgery. The median duration of complete response carboplatin? Individual patient characteristics are imporin the remaining 7 patients is 15 + months (range, 2+ - tant in this consideration. First, if the patient had pre23 + months). viously been treated with cisplatin and had experienced mild/moderate renal or neurological dysfunction, carboplatin would certainly be the preferred agent. ConDISCUSSION versely, if the patient had received an initial carboplatin In this trial we have confirmed the safety of a carbo- regimen and experienced major difficulties with marrow platin-based IP regimen and have demonstrated that pa- suppression, cisplatin would probably be the IP platinum tients with small volume residual ovarian cancer following drug of choice. systemic platinum-based chemotherapy may achieve obTwo additional points must be addressed in this disjective responses, including surgically documented com- cussion of salvage IP platinum treatment for individuals plete remissions with this second-line therapeutic strategy with advanced ovarian cancer. First, the follow-up of pa[6,7]. The overall response rate observed in this trial is tients treated with IP platinum-based therapy is limited similar to that previously, noted with salvage cisplatinand it is unknown if one of the two agents will be asbased regimens delivered by the IP route [1,2] and to sociated with a superior long-term disease-free survival single-agent IP carboplatin regimens [6,7]. This obser- advantage. In this regard it should be noted that one vation is not surprising as the two platinum drugs have group of investigators has reported the long-term survival demonstrated almost identical cytotoxic potential in ovar- of a subgroup of patients with small volume residual ovarian cancer (5,8-10) and have been shown to have similar ian cancer treated with salvage cisplatin-based IP therapy pharmacokinetic properties ‘when administered by the IP [161. Second, an experimental examination of the IP adminroute [ll-151. The dose-limiting toxicity of our regimen was bone istration of cisplatin and carboplatin has raised an immarrow suppression, particularly thrombocytopenia. portant question concerning the potential cytotoxic equivWhile we had hoped to escalate the dose of carboplatin alence of the two agents for IP delivery [17,18]. In this in this trial above our starting level of 200 mg/m2, this model system, while the AUC for peritoneal cavity exwas possible in less than one-half of the treated popuposure to carboplatin was three times higher than for lation. Even when the carboplatin concentration was in- cisplatin, the concentration of platinum within tumor cells was six to seven times higher following treatment with creased it was necessary in most patients to subsequently reduce the dose delivered secondary to unacceptable bone cisplatin, presumably secondary to decreased penetration marrow suppression. of carboplatin into cells [17]. The clinical significance of these experimental observations is uncertain, but longer This experience differs somewhat from that previously reported with single-agent IP carboplatin where it has follow-up of patients treated with both IP cisplatin and been suggested that doses of 300-400 mg/m’ can be ad- carboplatin-based regimens will be required before one ministered with acceptable marrow toxicity [6,7]. How- can conclude that the two programs are equivalent in ever, our patients were also receiving a single dose of therapeutic efficacy. etoposide with each IP treatment which may have resulted REFEIZJZNCES in synergistic cytotoxicity to the marrow. In addition, in this trial we permitted patients with serum creatinines up 1. Markman, M. Intraperitoneal chemotherapy, Semin. Oncol. 18, to 2.0 mg% to be treated with IP carboplatin. The influ248-254 (1991).
INTRAPERITONEAL
CARBOPLATIN
2. Markman, M., Reichman, B., Hakes, T., Jones, W., Lewis, J. L., Jr., Rubin, S., Almadrones, L., and Hoskins, W. Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: Influence of a prior response to systemic cisplatin, J. C/in. Oncol. 9, 1801-1805 (1991). 3. Reichman, B., Markman, M., Hakes, T., Hoskins, W., Rubin, S., Jones, W., Almadrones, L., Ochoa, M., Jr., Chapman, D., and Lewis, J. L., Jr. Intraperitoneal cisplatin and etoposide in the treatment of refractory/recurrent ovarian carcinoma, J. Clin. Oncol. 7, 1327-1332 (1989). 4. Markman, M., Hakes, T., Reichman, B., Hoskins, W., Rubin, S., Almadrones, L., Yordan, E. L., Jr., Eriksson, J., and Lewis, J. L., Jr. Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma, J. Clin. Oncol. 9,204210 (1991). 5. Alberts, D. S., and Mason-Liddil, N. Carboplatin in the treatment of ovarian cancer, Semin. Oncol. 16(2, suppl. S), 19-26 (1989). 6. Speyer, J. L., Beller, U., Colombo, N., Sorich, J., Wernz, J. C., Hockster, H., Green, M., Porges, R., Muggia, F. M., Canetta, R., and Beckman, E. M. Intraperitoneal carboplatin: Favorable results in women with minimal residual ovarian cancer after cisplatin therapy, J. Clin. Oncol. 8, 1335-1341 (1990). 7. Pfeiffer, P., Bennedaek, O., and Bertelsen, K. Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer, Gynecol. Oncol. 36, 306-311 (1990). 8. Alberts, D., Green, S., Hannigan, E., O’Toole, R., Mason-Liddll, N., Surwit, E., Stock-Novack, D., Goldberg, R., Malviya, V., and Nahhas, W. Improved efficacy of carboplatin/cyclophosphamide vs cisplatin/cyclophosphamide: Preliminary report of a phase III, randomized trial in stages III-IV suboptimal ovarian cancer, Proc. Am. Sot. Clin. Oncol. 8, 1.51 (1989). 9. Pater, J. Cyclophosphamide/cisplatin versus cyclophosphamide/ carboplatin in macroscopic residual ovarian cancer: Initial results of a National Cancer Institute of Canada Clinical Trials Group trial, Proc. Am. Sot. Clin. Oncol. 9, 155 (1990). 10. Advanced Ovarian Cancer Trialists Group. Chemotherapy in ad-
AND ETOPOSIDE
357
vanced ovarian cancer: An overview of randomized clinical trials, J. 303, 884-893 (1991). Casper, E. S., Kelsen, D. P., Alcock, N. W., and Lewis, J. L. Ip cisplatin in patients with malignant ascites: Pharmacokinetic evaluation and comparison with the iv route, Cancer Treat. Rep. 67, 325-328 (1983). Lopez, J. A., Krikorian, J. G., Reich, S. D., Smyth, R. D., Lee, F. H., and Issell, B. F. Clinical pharmacology of intraperitoneal cisplatin, Gynecol. Oncol. 20, l-9 (1985). Howell, S. B., Pfeifle, C. E., Wung, W. E., Olshen, R. A., Lucas, W. E., Yon, J. L., and Green, M. Intraperitoneal cisplatin with systemic thiosulfate protection, Ann. Intern. Med. 97, 845-851 (1982). DeGregorio, M., Lum, B. L., Holleran, W. M., Wilbur, B. J., and Sikic, B. I. Preliminary observations of intraperitoneal carboplatin pharmacokinetics during a phase 1 study of the Northern California Oncology Group, Cancer. Chemother. Pharmacol. 18, 235-238 (1986). Elferink, F., van der Vijgh, W. J. F., Klein, I., ten Bokkel Huinink, W. W., Dubbelman, R., and McVie, J. G. Pharmacokinetics of carboplatin after intraperitoneal administration, Cancer Chemother. Br. Med.
11.
12.
13.
14.
15.
Pharmacol.
21, 57-60(1988).
16. Howell, S. B., Zimm, S., Markman, M., Abramson, I. S., Cleary, S., Lucas, W. E., and Weiss, R. J. Long term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy, J. Clin. Oncol. 5,16071612 (1987). 17. Los, G., Mutsaers, P. H. A., van der Vijgh, W. J. F., Baldew, G. S., de Graaf, P. W., and McVie, J. G. Direct diffusion of cisdiamminedichloroplatinum(I1) in intraperitoneal rat tumors after intraperitoneal chemotherapy: A comparison with systemic chemotherapy, Cancer Res. 49, 3380-3384 (1989). 18. Los, G., Verdegaal, E. M. E., Mutsaers, P. H. A., and McVie, J. G. Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy, Cancer Chemother. Phnrmacol. 28, 159-165 (1991).
ONCOLOGY
47, 353-357 (1992)
Phase 2 Trial of lntraperitoneal Carboplatin and Etoposide as Salvage Treatment of Advanced Epithelial Ovarian Cancer’ MAURIE Breast/Gynecology
MARKMAN,’ BONNIE REICHMAN, THOMAS HAKES, STEPHEN RUBIN, WALTER JONES, JOHN L. LEWIS, JR., RICHARD BARAKAT, JOHN CURTIN, LOIS ALMADRONES, AND WILLIAM HOSKINS Service,
Division
of Solid Memorial
Tumor Oncology, Sloan-Kettering
Department Cancer Center,
of Medicine, New York,
and the Gynecology New York 10021
Service,
Department
of Surgery,
Received March 24. 1992
bination chemotherapy program [l]. In a recent retrospective review of two cisplatin-based IP chemotherapy basedtherapy assalvagetreatment of ovarian cancer,46 patients [3], cisplatin/cytarabine with persistentor recurrent ovarian cancerfollowing initial sys- programs (cisplatin/etoposide [4]), 42% of 36 patients with small volume disease (largest temic chemotherapywere treated with a regimenof carboplatin tumor mass 18 years old, WBC a3500/mm3, platelets ~100,000/mm3, serum bilirubin ~1.5 mg%, serum creatinine ~1.8 mg%, and no prior chemotherapy within the previous 4 weeks. All patients were also required to sign an informed consent statement indicating that they were aware of the investigational nature of the treatment program. Peritoneal Cavity Access
All patients entered into this trial had a peritoneal cavity catheter surgically placed (Tenckhoff type), which was attached to a subcutaneous portal delivery device. Patients did not routinely undergo formal assessment of peritoneal fluid distribution before the initiation of the IP therapy. However, patients who experienced difficulty receiving the treatment volume (e.g., abdominal pain with fluid delivery, excessively slow flow) underwent a radionuclide distribution study. Treatment Plan
The starting dose level of carboplatin was 200 mg/m* and of etoposide 100 mg/m*. The drugs were mixed together in 2 liters 5% dextrose. Prior to administration, the solution was warmed to approximately body temperature. The treatment volume was delivered into the peritoneal cavity as rapidly as possible. The drugs and fluid were left in the cavity to be absorbed on their own into the systemic circulation. In an individual patient was uncomfortable due to abdominal distention with fluid, it was permitted that the abdomen be drained 24 hr after drug instillation. The drugs were to be administered monthly for a maximum of six courses. Antiemetics were administered to all patients. Patients treated on this protocol were hydrated with approximately 200 ml/hr for 3-5 hr beginning at the initiation of IP drug delivery. Both dose escalation as well as reduction were permitted in this trial. If following the first course of therapy the nadir WBC count was a2500/mm3 and platelet count ~90,000/mm3, the dose of carboplatin was to be increased to 300 mg/m* for course 2. If following the first course of therapy the nadir WBC count was l cm in diameter responded to the treatment program. Finally, of the 7 evaluable patients who had previously failed to respond to a systemic organoplatinum regimen, a single patient with microscopic disease responded to the IP program, achieving a surgically documented complete response.
ET AL.
ence of borderline renal function in augmenting carboplatin-induced marrow suppression in patients with ovarian cancer receiving salvage IP therapy has previously been noted [6]. Finally, 15 (33%) of our patients had previously been treated with systemic carboplatin before entering this phase 2 trial. Such patients are more likely to experience greater difficulty with a salvage carboplatin regimen compared to individuals initially treated with cisResponse Duration and Survival platin due to the known bone marrow suppressive effects Thirty-two (70%) of the 46 patients are currently alive, of the newer platinum drug [5]. including 11 (92%) of the 12 responding patients. The Thus, we are left with the following important question: median follow-up of the surviving patients is 21+ months If an ovarian cancer patient with small volume residual (range, 8+-32+ months). To date, only 1 of the 8 pa- disease following a response to a platinum-based systemic tients who achieved a surgically documented complete regimen is being considered for a salvage IP program, response has relapsed, 18 months following her reassess- which platinum drug should be employed, cisplatin or ment surgery. The median duration of complete response carboplatin? Individual patient characteristics are imporin the remaining 7 patients is 15 + months (range, 2+ - tant in this consideration. First, if the patient had pre23 + months). viously been treated with cisplatin and had experienced mild/moderate renal or neurological dysfunction, carboplatin would certainly be the preferred agent. ConDISCUSSION versely, if the patient had received an initial carboplatin In this trial we have confirmed the safety of a carbo- regimen and experienced major difficulties with marrow platin-based IP regimen and have demonstrated that pa- suppression, cisplatin would probably be the IP platinum tients with small volume residual ovarian cancer following drug of choice. systemic platinum-based chemotherapy may achieve obTwo additional points must be addressed in this disjective responses, including surgically documented com- cussion of salvage IP platinum treatment for individuals plete remissions with this second-line therapeutic strategy with advanced ovarian cancer. First, the follow-up of pa[6,7]. The overall response rate observed in this trial is tients treated with IP platinum-based therapy is limited similar to that previously, noted with salvage cisplatinand it is unknown if one of the two agents will be asbased regimens delivered by the IP route [1,2] and to sociated with a superior long-term disease-free survival single-agent IP carboplatin regimens [6,7]. This obser- advantage. In this regard it should be noted that one vation is not surprising as the two platinum drugs have group of investigators has reported the long-term survival demonstrated almost identical cytotoxic potential in ovar- of a subgroup of patients with small volume residual ovarian cancer (5,8-10) and have been shown to have similar ian cancer treated with salvage cisplatin-based IP therapy pharmacokinetic properties ‘when administered by the IP [161. Second, an experimental examination of the IP adminroute [ll-151. The dose-limiting toxicity of our regimen was bone istration of cisplatin and carboplatin has raised an immarrow suppression, particularly thrombocytopenia. portant question concerning the potential cytotoxic equivWhile we had hoped to escalate the dose of carboplatin alence of the two agents for IP delivery [17,18]. In this in this trial above our starting level of 200 mg/m2, this model system, while the AUC for peritoneal cavity exwas possible in less than one-half of the treated popuposure to carboplatin was three times higher than for lation. Even when the carboplatin concentration was in- cisplatin, the concentration of platinum within tumor cells was six to seven times higher following treatment with creased it was necessary in most patients to subsequently reduce the dose delivered secondary to unacceptable bone cisplatin, presumably secondary to decreased penetration marrow suppression. of carboplatin into cells [17]. The clinical significance of these experimental observations is uncertain, but longer This experience differs somewhat from that previously reported with single-agent IP carboplatin where it has follow-up of patients treated with both IP cisplatin and been suggested that doses of 300-400 mg/m’ can be ad- carboplatin-based regimens will be required before one ministered with acceptable marrow toxicity [6,7]. How- can conclude that the two programs are equivalent in ever, our patients were also receiving a single dose of therapeutic efficacy. etoposide with each IP treatment which may have resulted REFEIZJZNCES in synergistic cytotoxicity to the marrow. In addition, in this trial we permitted patients with serum creatinines up 1. Markman, M. Intraperitoneal chemotherapy, Semin. Oncol. 18, to 2.0 mg% to be treated with IP carboplatin. The influ248-254 (1991).
INTRAPERITONEAL
CARBOPLATIN
2. Markman, M., Reichman, B., Hakes, T., Jones, W., Lewis, J. L., Jr., Rubin, S., Almadrones, L., and Hoskins, W. Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: Influence of a prior response to systemic cisplatin, J. C/in. Oncol. 9, 1801-1805 (1991). 3. Reichman, B., Markman, M., Hakes, T., Hoskins, W., Rubin, S., Jones, W., Almadrones, L., Ochoa, M., Jr., Chapman, D., and Lewis, J. L., Jr. Intraperitoneal cisplatin and etoposide in the treatment of refractory/recurrent ovarian carcinoma, J. Clin. Oncol. 7, 1327-1332 (1989). 4. Markman, M., Hakes, T., Reichman, B., Hoskins, W., Rubin, S., Almadrones, L., Yordan, E. L., Jr., Eriksson, J., and Lewis, J. L., Jr. Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma, J. Clin. Oncol. 9,204210 (1991). 5. Alberts, D. S., and Mason-Liddil, N. Carboplatin in the treatment of ovarian cancer, Semin. Oncol. 16(2, suppl. S), 19-26 (1989). 6. Speyer, J. L., Beller, U., Colombo, N., Sorich, J., Wernz, J. C., Hockster, H., Green, M., Porges, R., Muggia, F. M., Canetta, R., and Beckman, E. M. Intraperitoneal carboplatin: Favorable results in women with minimal residual ovarian cancer after cisplatin therapy, J. Clin. Oncol. 8, 1335-1341 (1990). 7. Pfeiffer, P., Bennedaek, O., and Bertelsen, K. Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer, Gynecol. Oncol. 36, 306-311 (1990). 8. Alberts, D., Green, S., Hannigan, E., O’Toole, R., Mason-Liddll, N., Surwit, E., Stock-Novack, D., Goldberg, R., Malviya, V., and Nahhas, W. Improved efficacy of carboplatin/cyclophosphamide vs cisplatin/cyclophosphamide: Preliminary report of a phase III, randomized trial in stages III-IV suboptimal ovarian cancer, Proc. Am. Sot. Clin. Oncol. 8, 1.51 (1989). 9. Pater, J. Cyclophosphamide/cisplatin versus cyclophosphamide/ carboplatin in macroscopic residual ovarian cancer: Initial results of a National Cancer Institute of Canada Clinical Trials Group trial, Proc. Am. Sot. Clin. Oncol. 9, 155 (1990). 10. Advanced Ovarian Cancer Trialists Group. Chemotherapy in ad-
AND ETOPOSIDE
357
vanced ovarian cancer: An overview of randomized clinical trials, J. 303, 884-893 (1991). Casper, E. S., Kelsen, D. P., Alcock, N. W., and Lewis, J. L. Ip cisplatin in patients with malignant ascites: Pharmacokinetic evaluation and comparison with the iv route, Cancer Treat. Rep. 67, 325-328 (1983). Lopez, J. A., Krikorian, J. G., Reich, S. D., Smyth, R. D., Lee, F. H., and Issell, B. F. Clinical pharmacology of intraperitoneal cisplatin, Gynecol. Oncol. 20, l-9 (1985). Howell, S. B., Pfeifle, C. E., Wung, W. E., Olshen, R. A., Lucas, W. E., Yon, J. L., and Green, M. Intraperitoneal cisplatin with systemic thiosulfate protection, Ann. Intern. Med. 97, 845-851 (1982). DeGregorio, M., Lum, B. L., Holleran, W. M., Wilbur, B. J., and Sikic, B. I. Preliminary observations of intraperitoneal carboplatin pharmacokinetics during a phase 1 study of the Northern California Oncology Group, Cancer. Chemother. Pharmacol. 18, 235-238 (1986). Elferink, F., van der Vijgh, W. J. F., Klein, I., ten Bokkel Huinink, W. W., Dubbelman, R., and McVie, J. G. Pharmacokinetics of carboplatin after intraperitoneal administration, Cancer Chemother. Br. Med.
11.
12.
13.
14.
15.
Pharmacol.
21, 57-60(1988).
16. Howell, S. B., Zimm, S., Markman, M., Abramson, I. S., Cleary, S., Lucas, W. E., and Weiss, R. J. Long term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy, J. Clin. Oncol. 5,16071612 (1987). 17. Los, G., Mutsaers, P. H. A., van der Vijgh, W. J. F., Baldew, G. S., de Graaf, P. W., and McVie, J. G. Direct diffusion of cisdiamminedichloroplatinum(I1) in intraperitoneal rat tumors after intraperitoneal chemotherapy: A comparison with systemic chemotherapy, Cancer Res. 49, 3380-3384 (1989). 18. Los, G., Verdegaal, E. M. E., Mutsaers, P. H. A., and McVie, J. G. Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy, Cancer Chemother. Phnrmacol. 28, 159-165 (1991).
