GYNECOLOCX
ONCOLOGY 46,
230-232 (1992)
Phase II Trial of Amonafide in Previously Treated Patients with Advanced Ovarian Cancer: A Southwest Oncology Group Study’ p2 HOLLY H. GALLION, M.D.,* P. Y. LIU, PH.D. ,t DAVID E. ALBERTS, M.D. ,$ ROBERT V. O’TOOLE, M.D. ,§ JANET O’SULLIVAN, M.S. ,t GLENN MILLS, M.D. ,I) HARRIET 0. SMITH, M.D. ,# AND HARRY E. HYNES, M.D.7 *University of Kentucky Medical Center, Lexington, Kentucky; tsouthwest Oncology Group Statistical Center, Seattle, Washington; $lJniversity Arizona Cancer, Tucson, Arizona; $Ohio State Universi@ Health Center, Columbus, Ohio; IlLouisiana State University Medical Center, New Orleans, Louisiana; ‘University of New Mexico, Albuquerque, New Mexico; and l/Wichita CCOP, Wichita, Kansas
of
Received December 3, 1991
Twenty-three patients with metastatic or recurrent Stage III or IV epithelial ovarian cancer who were refractory to or relapsed following previous chemotherapy with cisplatin or a cisplatin analog were entered into a phase II study of amonr&de. The starting dose of amonaflde was 300 mg/m* delivered daily over 1 hr by intravenous infusion. In the absenceof myelosuppression, the dose of amonafide was escalated by increments of 75 mg/m* to a maximum of 450 mg/m*. There were 19 eligible and 17 fully evaluable patients. Grade 3 or 4 leukopenia occurred in 14 (74%) patients and grade 3 or 4 thrombocytopenia in 6 (32%) patients. No objective complete or partial responses were observed. Four patients had stable disease for 3, 4, 4.5, and 6 months, respectively. Therefore, amonalide in the dosesused in the present trial does not have significant activity in previously treated patients with ovarian cancer. o IWZ Academic press, IIIC. INTRODUCTION Ovarian cancer is currently the leading cause of death from gynecologic cancer in the United States. It has been estimated that in 1991 over 20,000 women will develop this malignancy [l]. Due to the lack of early symptoms and effective screening methods, the majority of women with ovarian cancer have disease spread beyong the ovary at the time of diagnosis. Despite aggressive tumor debulking and platinum-based combination chemotherapy, ’ This investigation was supported in part by the following PHS Cooperative Agreement Grants awarded by the National Cancer Institute, DHHS; CA-46136, CA-37429, CA-13612, CA-04920, CA-36020, CA12213, CA-35431, CA-35261, CA-22433, CA-46441, CA-46282, CA35176, CA-35117, CA-37981, CA-45807, CA-35200, CA-35178, CA32734, CA-35281, CA-35119, CA-35128, CA-45450, CA-03096, CA45560, CA-32102. * Reprint requests should be addressed to Southwest Oncology Group (SWOG-8717), Operations Office, 5430 Fredericksburg Road, Suite 618, San Antonio, TX 78229-6196.
the long-term prognosis for these patients is poor, with S-year survival rates of only 10 to 15% for patients with Stage III or IV disease [2]. Amonafide is one of a new series of antineoplastic agents which has been synthesized from imide derivatives. Since antitumor activity was observed in phase I trials, the Southwest Oncology Group (SWOG) conducted a phase II trial of amonafide in patients with metastatic or recurrent ovarian cancer following primary chemotherapy with cisplatin or cisplatin analogs [3,4]. MATERIALS Patient Selection
Patients with histologically confirmed advanced metastatic or recurrent Stage III or IV epithelial ovarian cancer who were refractory to or relapsed following chemotherapy with cisplatin or a cisplatin analog were eligible for this study. Additional eligibility criteria included bidimensionally measurable disease, estimated life expectancy of at least 8 weeks, and a SWOG performance status of O-2. Evidence of adequate major organ function, including a granulocyte count >1500/mm3, platelet count ~100,000/mm3, serum bilirubin 61.5 mg%, and serum creatinine ~1.5 mg/dl, was also required. For patients who had undergone prior chemotherapy or radiotherapy, an interval of at least 4 weeks must have elapsed since completion of that therapy. Patients who had received more than one prior chemotherapy regimen were ineligible. Treatment Plan
The starting dose of amonafide was 300 mg/m* delivered daily by intravenous infusion over 1 hr for 5 con230
CWO-8258/92 $4.00
Copyright 0 1992by AcademicPress,Inc. All rights of reproductionin any form reserved.
AND METHODS
231
PHASE II TRIAL OF AMONAFIDE
secutive days. Treatment cycles were repeated every 21 days provided there had been adequate recovery from hematologic toxicity. In subsequent cycles, doses were modified according to the nadir granulocyte and platelet counts from the previous cycle. Dose reductions of 25 and 50% were allowed if significant myelosuppression occurred. If the nadir platelet count was >100,000/mm3 and the nadir granulocyte count was >1500/mm3 the dose of amonafide was escalated by increments of 75 mg/m2 to a maximum of 450 mg/m’. Amonafide was not administered if the serum bilirubin was >2.0 mg/dl, the creatinine was >2.0 mg/dl, or the SGOT was greater than three times the baseline value. A complete blood count, serum creatinine, SGOT, and CA-125 were obtained on the first day of each treatment cycle. Complete blood counts with platelets were obtained on Day 15. Chest X ray and radiographic studies for tumor measurement were obtained every 6 weeks to evaluate tumor response. Response and toxicity were defined according to standard SWOG criteria [5]. A complete response was defined as complete disappearance of all evidence of disease for at least 1 month. A partial response consisted of a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least 1 month and no increase in the size of an existing lesion or appearance of any new lesion. Progression was defined as a 50% increase or an increase of 10 cm2 (whichever is smaller) in the sum of the products of measurable lesions over the smallest sum observed or the appearance of any new lesion within 1 month of study entry. Disease not qualifying for complete response, partial response, or progression was classified as stable disease. Patients were withdrawn from the study if progression occurred or if toxicity necessitated more than a 2-week delay in the next course of treatment. RESULTS
Twenty-three patients were entered into this Southwest Oncology Group study from June 1988 to June 1990. Four patients were ineligible; three did not have bidimensionally measurable disease and one did not have epithelial ovarian cancer. Two of the 19 eligible patients were not evaluable for response. One patient died 13 days after entry into the study and no assessmentof tumor response was made in the remaining patient. The median age of the 19 eligible patients was 63 years (range, 38-77 years). The SWOG performance status at the initiation of amonafide therapy was 0 or 1 in 17 patients and 2 in 2 patients. Twelve patients had Stage III disease and seven patients had Stage IV tumor. Disease status was refractory in 7 patients and relapsing in 12. A total of 63 treatment cycles was administered. The mean number of cycles per patient was 3 (range, 1 to 7).
TABLE 1 Toxicity Data for AmonaGde (IV = 19) Grade Toxicity
0
1
2
3
4
Hematopoietic Granulocytopenia Leukopenia Anemia Thrombocytopenia
3 0 6 9
1 1 1 2
3 4 6 2
3 5 3 2
9 9 3 4
Gastrointestinal Vomiting Nausea Constipation Stomatitis
7 7 16 15
4 4 2 2
4 4 0 2
4 4 1 0
0 0 0 0
Miscellaneous Alopecia Creatinine Allergy Bilirubin increase Malaise/fatigue, lethargy
16 18 18 18 14
1 0 0 0 4
2 1 1 0 0
0 0 0 1 1
0 0 0 0 0
The number of courses of amonafide received by the 17 evaluable patients was as follows; 5 patients received one course, 4 received two courses, 3 received four courses, 1 received five courses, 3 received six courses and 1 received seven courses. Fourteen patients were treated at an amonafide dose of 300 mg/m2, one patient at 400 mg/m2, and two patients at 450 mg/m2. No objective complete or partial responses were observed. Four patients had stable disease for 3, 4, 4.5, and 6 months, respectively, and the remainder had disease progression. Fourteen patients have expired; all deaths were tumor related. The median survival after initiation of the protocol was 5.6 months (range, 0.2 to 13 months). Toxicity data are presented in Table 1. The most common toxicity of amonafide was hematologic. Grade 3 or 4 leukopenia occurred in 14 (74%) patients and grade 3 or 4 thrombocytopenia in six (32%) patients. Seven patients experienced no nausea or vomiting during the course of treatment. Only four patients developed grade 3 nausea or vomiting. DISCUSSION
The majority of previously untreated patients with advanced ovarian cancer will initially respond to cisplatinbased chemotherapy [6]. In fact, a complete response to cisplatin can be documented pathologically in up to 50% of patients with advanced-stage disease [7]. However, despite the absence of microscopically detectable disease at second-look surgery, as many as 50% of these patients will subsequently develop recurrent tumor [S]. Unfortunately, the response to second-line chemotherapy in pa-
232
GALLION
tients who have failed primary chemotherapy is disappointingly low [9,10]. For these reasons, it is imperative to search for effective second-line agents in ovarian cancer. Amonafide is one of a new series of antineoplastic agents originally synthesized from imide derivatives of 3nitro-l,&napthalic acid as part of a drug development program which attempted to combine the structural entities responsible for the antitumor activity of aristocholic acid, cycloheximide, tilorone, and 1,4(morpholinemethy)4-phthalimidopiperidine-2,6-dione into one molecule [11,12]. The cytotoxic effects of this synthetic agent appear to be mediated through DNA intercalation and inhibition of macromolecular synthesis. Preclinical anticancer activity in murine leukemia and solid tumor models led to the evaluation of amonafide in phase I clinical trials [3,4]. In these initial trials, amonafide demonstrated an acceptable toxicity profile and antitumor activity was observed in a patient with non-small cell lung cancer and in a patient with metastatic prostate cancer [4]. For these reasons, amonafide was released for phase II testing in solid tumors. In the present phase II series of patients with cisplatin resistant or refractory ovarian cancer, amonafide therapy was associated with tolerable grade 3 or 4 myelosuppression in the majority of patients. However, no objective responses were observed. Therefore, it can be concluded that amonafide, in the doses used in the present trial, does not appear to be an active cytotoxic agent in ovarian cancer. REFERENCES 1. Boring, C., Squires, T., and Tong, T. Cancer statistics, 1991, CA 41, 19-36 (1991). 2. Richardson, G. S., Scully, R. E., Nikrui, N., and Nelson, J. H., Jr. Common epithelial cancer of the ovary, N. Engl. J. Med. 3l2(7), 415-424 (1985).
ET AL. 3. Legha, S. S., Ring, S., Raber, M., Felder, T. B., Newman, R. A., and Krakoff, I. H. Phase I clinical investigation of benzisoquinolinedione, Cancer Treat. Rep. 71, 1165-1169 (1987). 4. Saez, R., Craig, J. B., Kuhn, J. G., Weiss, G. R., Koeller, J., Phillips, J., Havlin, K., Harman, G., Hardy, J., Melink, T. J., Sarosy, G. A., and Von Hoff, D. D. Phase I clinical investigation of amonafide, J. Clin. Oncol. 7, 1351-1358 (1989). 5. Weiss, G. R., Green, S., Hannigan, E. V., Boutselis, J. G., Surwit, E. A., Wallace, D. L., and Alberts, D. S. A Phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: A Southwest Oncology Group study, Gynecol. Oncol. 39, 332-336 (1990). 6. Decker, D. G., Fleming, R. R., Malkasian, G. D., Jr., Webb, M. J., Jeffries, J. A., and Edmonson, J. H. Cyclophosphamide plus cis-platinum combination: Treatment program for stage III or IV ovarian carcinoma, Obstet. Gynecol. 60, 481-487 (1982). 7. Cohen, C. J., Goldberg, J. D., Holland, J. F., Bruckner, H. W., Deppe, G., Gusberg, S. B., Wallach, R. C., Kabakow, B., and Rodin, J. Improved therapy with cisplatin regimens for patient with ovarian carcinoma (FIG0 Stages III and IV) as measured by surgical end-staging (second-look operation), Am J. Obstet. Gynecol. 145, 955-966 (1983). 8. Rubin, S. C., Hoskins, W. J., Hakes, T. B., Markman, M., Cain, J. M., and Lewis, J. L., Jr. Recurrence after negative second-look laparotomy for ovarian cancer: Analysis of risk factors, Am. J. Obstet. Gynecol. 159, 1094-1098 (1988). 9. Laufman, L. R., Green, J. B., Alberts, D. S., O’Toole, R., Hilgers, R. D., Young, D. C., Lin, F., and Rivkin, S. E. Chemotherapy of drug-resistant ovarian cancer: A Southwest Oncology Group study, J. Clin. Oncol. 4, 1374-1379 (1986). 10. Stanhope, C. R., Smith, J. P., and Rutledge, F. Second trial drugs in ovarian cancer, Gynecol. Oncol. 5, 52-58 (1977). 11. Brana, M. F., Catellano, J. M., Jimenez, A., Lombart, A., Rabadan, F., Roldan, C., Santos, A., and Vazquez, D. Synthesis and mode(s) of action of a new series of imide derivatives of 3-nitrol,&napthalic acid, Cancer Chemother. Pharmacol. 4,61-66 (1980). 17 Brana, M. F., Catellano, J. M., Jimenez, A., Lombart, A., Rabadan, F. P., Roldan, M., Roldan, C., Santos, A., and Vazquez, D. Synthesis, cytostatic activity and mode of action of a new series of imide derivatives of 3-nitro-1,gnapthalic acid, Current Chemorher. 2. 1216-1217 (1978). \ I AI.
ONCOLOGY 46,
230-232 (1992)
Phase II Trial of Amonafide in Previously Treated Patients with Advanced Ovarian Cancer: A Southwest Oncology Group Study’ p2 HOLLY H. GALLION, M.D.,* P. Y. LIU, PH.D. ,t DAVID E. ALBERTS, M.D. ,$ ROBERT V. O’TOOLE, M.D. ,§ JANET O’SULLIVAN, M.S. ,t GLENN MILLS, M.D. ,I) HARRIET 0. SMITH, M.D. ,# AND HARRY E. HYNES, M.D.7 *University of Kentucky Medical Center, Lexington, Kentucky; tsouthwest Oncology Group Statistical Center, Seattle, Washington; $lJniversity Arizona Cancer, Tucson, Arizona; $Ohio State Universi@ Health Center, Columbus, Ohio; IlLouisiana State University Medical Center, New Orleans, Louisiana; ‘University of New Mexico, Albuquerque, New Mexico; and l/Wichita CCOP, Wichita, Kansas
of
Received December 3, 1991
Twenty-three patients with metastatic or recurrent Stage III or IV epithelial ovarian cancer who were refractory to or relapsed following previous chemotherapy with cisplatin or a cisplatin analog were entered into a phase II study of amonr&de. The starting dose of amonaflde was 300 mg/m* delivered daily over 1 hr by intravenous infusion. In the absenceof myelosuppression, the dose of amonafide was escalated by increments of 75 mg/m* to a maximum of 450 mg/m*. There were 19 eligible and 17 fully evaluable patients. Grade 3 or 4 leukopenia occurred in 14 (74%) patients and grade 3 or 4 thrombocytopenia in 6 (32%) patients. No objective complete or partial responses were observed. Four patients had stable disease for 3, 4, 4.5, and 6 months, respectively. Therefore, amonalide in the dosesused in the present trial does not have significant activity in previously treated patients with ovarian cancer. o IWZ Academic press, IIIC. INTRODUCTION Ovarian cancer is currently the leading cause of death from gynecologic cancer in the United States. It has been estimated that in 1991 over 20,000 women will develop this malignancy [l]. Due to the lack of early symptoms and effective screening methods, the majority of women with ovarian cancer have disease spread beyong the ovary at the time of diagnosis. Despite aggressive tumor debulking and platinum-based combination chemotherapy, ’ This investigation was supported in part by the following PHS Cooperative Agreement Grants awarded by the National Cancer Institute, DHHS; CA-46136, CA-37429, CA-13612, CA-04920, CA-36020, CA12213, CA-35431, CA-35261, CA-22433, CA-46441, CA-46282, CA35176, CA-35117, CA-37981, CA-45807, CA-35200, CA-35178, CA32734, CA-35281, CA-35119, CA-35128, CA-45450, CA-03096, CA45560, CA-32102. * Reprint requests should be addressed to Southwest Oncology Group (SWOG-8717), Operations Office, 5430 Fredericksburg Road, Suite 618, San Antonio, TX 78229-6196.
the long-term prognosis for these patients is poor, with S-year survival rates of only 10 to 15% for patients with Stage III or IV disease [2]. Amonafide is one of a new series of antineoplastic agents which has been synthesized from imide derivatives. Since antitumor activity was observed in phase I trials, the Southwest Oncology Group (SWOG) conducted a phase II trial of amonafide in patients with metastatic or recurrent ovarian cancer following primary chemotherapy with cisplatin or cisplatin analogs [3,4]. MATERIALS Patient Selection
Patients with histologically confirmed advanced metastatic or recurrent Stage III or IV epithelial ovarian cancer who were refractory to or relapsed following chemotherapy with cisplatin or a cisplatin analog were eligible for this study. Additional eligibility criteria included bidimensionally measurable disease, estimated life expectancy of at least 8 weeks, and a SWOG performance status of O-2. Evidence of adequate major organ function, including a granulocyte count >1500/mm3, platelet count ~100,000/mm3, serum bilirubin 61.5 mg%, and serum creatinine ~1.5 mg/dl, was also required. For patients who had undergone prior chemotherapy or radiotherapy, an interval of at least 4 weeks must have elapsed since completion of that therapy. Patients who had received more than one prior chemotherapy regimen were ineligible. Treatment Plan
The starting dose of amonafide was 300 mg/m* delivered daily by intravenous infusion over 1 hr for 5 con230
CWO-8258/92 $4.00
Copyright 0 1992by AcademicPress,Inc. All rights of reproductionin any form reserved.
AND METHODS
231
PHASE II TRIAL OF AMONAFIDE
secutive days. Treatment cycles were repeated every 21 days provided there had been adequate recovery from hematologic toxicity. In subsequent cycles, doses were modified according to the nadir granulocyte and platelet counts from the previous cycle. Dose reductions of 25 and 50% were allowed if significant myelosuppression occurred. If the nadir platelet count was >100,000/mm3 and the nadir granulocyte count was >1500/mm3 the dose of amonafide was escalated by increments of 75 mg/m2 to a maximum of 450 mg/m’. Amonafide was not administered if the serum bilirubin was >2.0 mg/dl, the creatinine was >2.0 mg/dl, or the SGOT was greater than three times the baseline value. A complete blood count, serum creatinine, SGOT, and CA-125 were obtained on the first day of each treatment cycle. Complete blood counts with platelets were obtained on Day 15. Chest X ray and radiographic studies for tumor measurement were obtained every 6 weeks to evaluate tumor response. Response and toxicity were defined according to standard SWOG criteria [5]. A complete response was defined as complete disappearance of all evidence of disease for at least 1 month. A partial response consisted of a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least 1 month and no increase in the size of an existing lesion or appearance of any new lesion. Progression was defined as a 50% increase or an increase of 10 cm2 (whichever is smaller) in the sum of the products of measurable lesions over the smallest sum observed or the appearance of any new lesion within 1 month of study entry. Disease not qualifying for complete response, partial response, or progression was classified as stable disease. Patients were withdrawn from the study if progression occurred or if toxicity necessitated more than a 2-week delay in the next course of treatment. RESULTS
Twenty-three patients were entered into this Southwest Oncology Group study from June 1988 to June 1990. Four patients were ineligible; three did not have bidimensionally measurable disease and one did not have epithelial ovarian cancer. Two of the 19 eligible patients were not evaluable for response. One patient died 13 days after entry into the study and no assessmentof tumor response was made in the remaining patient. The median age of the 19 eligible patients was 63 years (range, 38-77 years). The SWOG performance status at the initiation of amonafide therapy was 0 or 1 in 17 patients and 2 in 2 patients. Twelve patients had Stage III disease and seven patients had Stage IV tumor. Disease status was refractory in 7 patients and relapsing in 12. A total of 63 treatment cycles was administered. The mean number of cycles per patient was 3 (range, 1 to 7).
TABLE 1 Toxicity Data for AmonaGde (IV = 19) Grade Toxicity
0
1
2
3
4
Hematopoietic Granulocytopenia Leukopenia Anemia Thrombocytopenia
3 0 6 9
1 1 1 2
3 4 6 2
3 5 3 2
9 9 3 4
Gastrointestinal Vomiting Nausea Constipation Stomatitis
7 7 16 15
4 4 2 2
4 4 0 2
4 4 1 0
0 0 0 0
Miscellaneous Alopecia Creatinine Allergy Bilirubin increase Malaise/fatigue, lethargy
16 18 18 18 14
1 0 0 0 4
2 1 1 0 0
0 0 0 1 1
0 0 0 0 0
The number of courses of amonafide received by the 17 evaluable patients was as follows; 5 patients received one course, 4 received two courses, 3 received four courses, 1 received five courses, 3 received six courses and 1 received seven courses. Fourteen patients were treated at an amonafide dose of 300 mg/m2, one patient at 400 mg/m2, and two patients at 450 mg/m2. No objective complete or partial responses were observed. Four patients had stable disease for 3, 4, 4.5, and 6 months, respectively, and the remainder had disease progression. Fourteen patients have expired; all deaths were tumor related. The median survival after initiation of the protocol was 5.6 months (range, 0.2 to 13 months). Toxicity data are presented in Table 1. The most common toxicity of amonafide was hematologic. Grade 3 or 4 leukopenia occurred in 14 (74%) patients and grade 3 or 4 thrombocytopenia in six (32%) patients. Seven patients experienced no nausea or vomiting during the course of treatment. Only four patients developed grade 3 nausea or vomiting. DISCUSSION
The majority of previously untreated patients with advanced ovarian cancer will initially respond to cisplatinbased chemotherapy [6]. In fact, a complete response to cisplatin can be documented pathologically in up to 50% of patients with advanced-stage disease [7]. However, despite the absence of microscopically detectable disease at second-look surgery, as many as 50% of these patients will subsequently develop recurrent tumor [S]. Unfortunately, the response to second-line chemotherapy in pa-
232
GALLION
tients who have failed primary chemotherapy is disappointingly low [9,10]. For these reasons, it is imperative to search for effective second-line agents in ovarian cancer. Amonafide is one of a new series of antineoplastic agents originally synthesized from imide derivatives of 3nitro-l,&napthalic acid as part of a drug development program which attempted to combine the structural entities responsible for the antitumor activity of aristocholic acid, cycloheximide, tilorone, and 1,4(morpholinemethy)4-phthalimidopiperidine-2,6-dione into one molecule [11,12]. The cytotoxic effects of this synthetic agent appear to be mediated through DNA intercalation and inhibition of macromolecular synthesis. Preclinical anticancer activity in murine leukemia and solid tumor models led to the evaluation of amonafide in phase I clinical trials [3,4]. In these initial trials, amonafide demonstrated an acceptable toxicity profile and antitumor activity was observed in a patient with non-small cell lung cancer and in a patient with metastatic prostate cancer [4]. For these reasons, amonafide was released for phase II testing in solid tumors. In the present phase II series of patients with cisplatin resistant or refractory ovarian cancer, amonafide therapy was associated with tolerable grade 3 or 4 myelosuppression in the majority of patients. However, no objective responses were observed. Therefore, it can be concluded that amonafide, in the doses used in the present trial, does not appear to be an active cytotoxic agent in ovarian cancer. REFERENCES 1. Boring, C., Squires, T., and Tong, T. Cancer statistics, 1991, CA 41, 19-36 (1991). 2. Richardson, G. S., Scully, R. E., Nikrui, N., and Nelson, J. H., Jr. Common epithelial cancer of the ovary, N. Engl. J. Med. 3l2(7), 415-424 (1985).
ET AL. 3. Legha, S. S., Ring, S., Raber, M., Felder, T. B., Newman, R. A., and Krakoff, I. H. Phase I clinical investigation of benzisoquinolinedione, Cancer Treat. Rep. 71, 1165-1169 (1987). 4. Saez, R., Craig, J. B., Kuhn, J. G., Weiss, G. R., Koeller, J., Phillips, J., Havlin, K., Harman, G., Hardy, J., Melink, T. J., Sarosy, G. A., and Von Hoff, D. D. Phase I clinical investigation of amonafide, J. Clin. Oncol. 7, 1351-1358 (1989). 5. Weiss, G. R., Green, S., Hannigan, E. V., Boutselis, J. G., Surwit, E. A., Wallace, D. L., and Alberts, D. S. A Phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: A Southwest Oncology Group study, Gynecol. Oncol. 39, 332-336 (1990). 6. Decker, D. G., Fleming, R. R., Malkasian, G. D., Jr., Webb, M. J., Jeffries, J. A., and Edmonson, J. H. Cyclophosphamide plus cis-platinum combination: Treatment program for stage III or IV ovarian carcinoma, Obstet. Gynecol. 60, 481-487 (1982). 7. Cohen, C. J., Goldberg, J. D., Holland, J. F., Bruckner, H. W., Deppe, G., Gusberg, S. B., Wallach, R. C., Kabakow, B., and Rodin, J. Improved therapy with cisplatin regimens for patient with ovarian carcinoma (FIG0 Stages III and IV) as measured by surgical end-staging (second-look operation), Am J. Obstet. Gynecol. 145, 955-966 (1983). 8. Rubin, S. C., Hoskins, W. J., Hakes, T. B., Markman, M., Cain, J. M., and Lewis, J. L., Jr. Recurrence after negative second-look laparotomy for ovarian cancer: Analysis of risk factors, Am. J. Obstet. Gynecol. 159, 1094-1098 (1988). 9. Laufman, L. R., Green, J. B., Alberts, D. S., O’Toole, R., Hilgers, R. D., Young, D. C., Lin, F., and Rivkin, S. E. Chemotherapy of drug-resistant ovarian cancer: A Southwest Oncology Group study, J. Clin. Oncol. 4, 1374-1379 (1986). 10. Stanhope, C. R., Smith, J. P., and Rutledge, F. Second trial drugs in ovarian cancer, Gynecol. Oncol. 5, 52-58 (1977). 11. Brana, M. F., Catellano, J. M., Jimenez, A., Lombart, A., Rabadan, F., Roldan, C., Santos, A., and Vazquez, D. Synthesis and mode(s) of action of a new series of imide derivatives of 3-nitrol,&napthalic acid, Cancer Chemother. Pharmacol. 4,61-66 (1980). 17 Brana, M. F., Catellano, J. M., Jimenez, A., Lombart, A., Rabadan, F. P., Roldan, M., Roldan, C., Santos, A., and Vazquez, D. Synthesis, cytostatic activity and mode of action of a new series of imide derivatives of 3-nitro-1,gnapthalic acid, Current Chemorher. 2. 1216-1217 (1978). \ I AI.
