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Phase II evaluation of peroral carmofur, cyclophosphamide, and hexamethylmelamine as a second-line therapy in advanced epithelial ovarian carcinoma
GYNECOLOGICONCOLOGY34, 27-29 (1989)
Phase II Evaluation of Peroral Carmofur, Cyclophosphamide, and Hexamethylmelamine as a Second-Line Therapy in Advanced Epithelial Ovarian Carcinoma PIRKKO SIPILA, *Department
M.D. ,* SEPIA KIVINEN, M.D., * PENTTI GROHN, M.D.,? JAAKKO VESALA, PH.D.& AND ERKKI HEINONEN, M.D.S
of Gynecology and Obstetrics, Oulu University Central Hospital, Oulu, Finland; Kuopio University Central Hospital, Kuopio, Finland; and $Orion Pharmaceutics,
fDepartment of Radiotherapy and Oncology, Research Center, Espoo, Finland
Received December 3, 1987
MATERIAL AND METHODS
A prospective phase II study was performed to evaluate the
effect and tolerability of a peroral combination chemotherapy consisting of hexamethyhnelamine, cyclophosphamide, and carmofur in patients with epithelial ovarian cancer previously heavily treated by cisplatin-based chemotherapy but no longer responding to it. Of the 27 patients 1 showed a clinical complete remission lasting 15+ months and 4 a partial remission of 6 + to 21 months. A further 7 patients had an unchanged situation of 4 to 13+ months. The median survival of the nonresponders was 3 months. The side effects were tolerable, mostly nausea and vomiting. Only 4 of 27 patients suffered from severe vomiting causing discontinuation of the therapy. The peroral ambulatory chemotherapy prolonged markedly the overall survival of about one-half of the patients with ovarian cancer who previously failed to respond to cisplati-based chemotherapy. o 1989 Academic PIW, IX.
Twenty-seven patients with a histologically confirmed epithelial ovarian cancer (stages III-IV, FIGO) were included in the study. They had been operated on previously and had received cisplatin-melphalan or cisplatin-doxorubicin-cyclophosphamide combination chemotherapy as primary treatment and had become resistant to it [6]. The patient characteristics are given in Table 1. The treatment consisted of cyclophosphamide 150 Days l-5; hexamethylmelamine 150 w/m2/W, mg/m2/day, Days 1-21; and carmofur 500 mg/m2/day divided into three doses, Days 1-21, and was recycled every 6 weeks. The peroral therapy was started immediately after failure to cisplatin. Clinical examination, abdominal ultrasound, and labINTRODUCTION oratory tests consisting of urine analysis, renal and liver function tests, blood count, and chest X ray were perCisplatin-based combination chemotherapy is mostly formed before entering the study and every 6 weeks used as primary treatment of advanced ovarian carcinoma. before a new course of treatment. In addition, the bioIn the majority of patients, an objective response can be chemical response was measured by using the S-CA125 maintained for several years. Second-line chemotherapy monoclonal antibody test [7]. Response and toxicity were after cisplatin is often hopeless and of palliative nature; evaluated according to the criteria of the World Health these patients seldom achieve any further response to Organization [8]. other combinations [ 1,2]. Carmofur (HCFU , 1-hexylcarbamo yl-S-fluorouracil) , RESULTS cyclophosphamide, and hexamethyhnelamine are all active The clinical outcome of the patients is given in Table in single-agent chemotherapy of ovarian cancer and can be administered orally. The side effects are tolerable and 2. So far, 21 out of 27 patients have completed three or treatments can be accomplished on an ambulatory basis more courses of treatment. One patient achieved complete clinical remission of 15+ months. She had visible met[3-51. We undertook this study to evaluate the effect of a astatic nodes less than 1 cm in diameter which were left combination of these three drugs as a salvage chemo- intact in the third-look laparotomy but only cytologically therapy in previously heavily treated and relapsed ovarian positive tumor cells in the peritoneal washing in the fourthlook operation. Four patients showed a partial response cancer patients. 27 0090-8258/89$3.00 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
28
SIPILA ET AL. TABLE 1 Patient Characteristics Characteristics
Number of patients 27 4
Total Discontinuations (vomiting) Age at entry Median Range Prior therapy
57.9 years 32-76 years
Surgery
27
Cisplatin-based chemotherapy
27
of 11, 21, 6 + and 6+ months. Seven more patients exhibited stable disease for over 3 months (4, 6, 6, 7, 8, 9, and 13+ months). Only 11 of 27 patients did not respond to the therapy. Mean survival of the nonresponders was 3 months (Table 1). The treatment was well tolerated by most of the patients. There were four discontinuations due to vomiting and abdominal pain. Nausea, vomiting, and tiredness were the most common side effects. Bone marrow toxicity occurred in three patients, whereas no renal or liver toxicity was observed. CA125 marker showed increased values in all patients with measurable disease, the elevations being in accord with clinical response.
1
5
10
cyclesof the therapy
FIG. 1. CA125 values of the responding ovarian cancer patients (normal value < 30 IU/liter).
DISCUSSION Chemotherapy of recurrent ovarian carcinoma after failure to cisplatin-based combinations is very controversial and the possible benefits of a treatment with other combinations must be evaluated especially with regard to the toxicity. Patients seldom tolerate another equally heavy chemotherapy. The oral combination cyclophosphamide-hexamethylmelamine-carmofur was unexpectedly effective in TABLE
CA124 (Wi) 10000
2
Clinical Outcome of the Ovarian Cancer Patients Treated by Peroral Cytotoxic Chemotherapy Outcome Response to therapy Complete (4%) Partial (15%) No change (26%) Progression (41%) Discontinuation (15%) Toxicity Bone marrow (WHO grade >l) Renal Liver Nausea (WHO grade >2) Alopecia Dizziness
Number of patients 1 4 7
11 4 3
None None 8 None 1
1
10 cycles Of the therapy
FIG. 2. CA125 values of the nonresponding ovarian cancer patients (normal value < 30 IU/liter).
PERORAL CHEMOTHERAPY
this phase II study with previously heavily treated patients. The overall response rate was 19% with one complete and four partial responses. Stabilization of the disease was seen in six other patients (22%). The side effects were minimal. The therapy was well tolerated by most patients with only four discontinuations and no reduction of doses. The drugs used have a different mode of action and, thus, the doses could be kept low. All the treatments were accomplished on an ambulatory basis. Our results demonstrate clearly that an oral three-drug combination chemotherapy can be effective in previously heavily treated ovarian cancer patients. REFERENCES 1. Omura, G., Blessing, J., Ehrlich, C., et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma, Cancer 57, 1725-1730 (1986).
OF OVARIAN CANCER
29
2+Neijt, J. P., Ten Bokkel Huinink, W. W., van der Burg, M. E. L.,
et al. Randomized trial comparing two combination chemotherapy regimens (hexa-CAF vs CHAP-5) in advanced ovarian carcinoma, Lancet 1, 594-600 (1984). 3. Koyama, Y. I-HexyIcarbamoyl-5-fluorouracil (HCFU)-A masked 5-fluorinated pyrimidine, Cancer Treat. Rev. 8, 147-156 (1981). 4. Noda, T., Kosakai, H., Tsujimura, K., et al. A clinical trial of carmofur (HCFU) in the treatment of ovarian carcinoma-The first report, Japan. J. Cancer Chemother. 10(9), 1972-1979 (1983). 5. Rosen, Cl., Lurain, J., and Newton, M. Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple-agent chemotherapy, Gynecol. Oncol. 27, 173-179 (1987). 6 International Federation of Gynecology and Obstetrics. Classification ’ and staging of malignant tumors in female pelvis, Acta Obstet. Gynecol. Scnnd. 50, 1 (1971). I. Bast, R. C., Jr., Klug, T. L., St. John, E., et al. A radioimmunoassay using monoclonal antibody to monitor the course of epithelial ovarian cancer, N. Engt. J. Med. 309, 883 (1983). 8. WHO. World Health Organization handbook of reporting results of cancer treatment, WHO Offset Publication Co., Geneva, p. 48 (1979).
Phase II Evaluation of Peroral Carmofur, Cyclophosphamide, and Hexamethylmelamine as a Second-Line Therapy in Advanced Epithelial Ovarian Carcinoma PIRKKO SIPILA, *Department
M.D. ,* SEPIA KIVINEN, M.D., * PENTTI GROHN, M.D.,? JAAKKO VESALA, PH.D.& AND ERKKI HEINONEN, M.D.S
of Gynecology and Obstetrics, Oulu University Central Hospital, Oulu, Finland; Kuopio University Central Hospital, Kuopio, Finland; and $Orion Pharmaceutics,
fDepartment of Radiotherapy and Oncology, Research Center, Espoo, Finland
Received December 3, 1987
MATERIAL AND METHODS
A prospective phase II study was performed to evaluate the
effect and tolerability of a peroral combination chemotherapy consisting of hexamethyhnelamine, cyclophosphamide, and carmofur in patients with epithelial ovarian cancer previously heavily treated by cisplatin-based chemotherapy but no longer responding to it. Of the 27 patients 1 showed a clinical complete remission lasting 15+ months and 4 a partial remission of 6 + to 21 months. A further 7 patients had an unchanged situation of 4 to 13+ months. The median survival of the nonresponders was 3 months. The side effects were tolerable, mostly nausea and vomiting. Only 4 of 27 patients suffered from severe vomiting causing discontinuation of the therapy. The peroral ambulatory chemotherapy prolonged markedly the overall survival of about one-half of the patients with ovarian cancer who previously failed to respond to cisplati-based chemotherapy. o 1989 Academic PIW, IX.
Twenty-seven patients with a histologically confirmed epithelial ovarian cancer (stages III-IV, FIGO) were included in the study. They had been operated on previously and had received cisplatin-melphalan or cisplatin-doxorubicin-cyclophosphamide combination chemotherapy as primary treatment and had become resistant to it [6]. The patient characteristics are given in Table 1. The treatment consisted of cyclophosphamide 150 Days l-5; hexamethylmelamine 150 w/m2/W, mg/m2/day, Days 1-21; and carmofur 500 mg/m2/day divided into three doses, Days 1-21, and was recycled every 6 weeks. The peroral therapy was started immediately after failure to cisplatin. Clinical examination, abdominal ultrasound, and labINTRODUCTION oratory tests consisting of urine analysis, renal and liver function tests, blood count, and chest X ray were perCisplatin-based combination chemotherapy is mostly formed before entering the study and every 6 weeks used as primary treatment of advanced ovarian carcinoma. before a new course of treatment. In addition, the bioIn the majority of patients, an objective response can be chemical response was measured by using the S-CA125 maintained for several years. Second-line chemotherapy monoclonal antibody test [7]. Response and toxicity were after cisplatin is often hopeless and of palliative nature; evaluated according to the criteria of the World Health these patients seldom achieve any further response to Organization [8]. other combinations [ 1,2]. Carmofur (HCFU , 1-hexylcarbamo yl-S-fluorouracil) , RESULTS cyclophosphamide, and hexamethyhnelamine are all active The clinical outcome of the patients is given in Table in single-agent chemotherapy of ovarian cancer and can be administered orally. The side effects are tolerable and 2. So far, 21 out of 27 patients have completed three or treatments can be accomplished on an ambulatory basis more courses of treatment. One patient achieved complete clinical remission of 15+ months. She had visible met[3-51. We undertook this study to evaluate the effect of a astatic nodes less than 1 cm in diameter which were left combination of these three drugs as a salvage chemo- intact in the third-look laparotomy but only cytologically therapy in previously heavily treated and relapsed ovarian positive tumor cells in the peritoneal washing in the fourthlook operation. Four patients showed a partial response cancer patients. 27 0090-8258/89$3.00 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
28
SIPILA ET AL. TABLE 1 Patient Characteristics Characteristics
Number of patients 27 4
Total Discontinuations (vomiting) Age at entry Median Range Prior therapy
57.9 years 32-76 years
Surgery
27
Cisplatin-based chemotherapy
27
of 11, 21, 6 + and 6+ months. Seven more patients exhibited stable disease for over 3 months (4, 6, 6, 7, 8, 9, and 13+ months). Only 11 of 27 patients did not respond to the therapy. Mean survival of the nonresponders was 3 months (Table 1). The treatment was well tolerated by most of the patients. There were four discontinuations due to vomiting and abdominal pain. Nausea, vomiting, and tiredness were the most common side effects. Bone marrow toxicity occurred in three patients, whereas no renal or liver toxicity was observed. CA125 marker showed increased values in all patients with measurable disease, the elevations being in accord with clinical response.
1
5
10
cyclesof the therapy
FIG. 1. CA125 values of the responding ovarian cancer patients (normal value < 30 IU/liter).
DISCUSSION Chemotherapy of recurrent ovarian carcinoma after failure to cisplatin-based combinations is very controversial and the possible benefits of a treatment with other combinations must be evaluated especially with regard to the toxicity. Patients seldom tolerate another equally heavy chemotherapy. The oral combination cyclophosphamide-hexamethylmelamine-carmofur was unexpectedly effective in TABLE
CA124 (Wi) 10000
2
Clinical Outcome of the Ovarian Cancer Patients Treated by Peroral Cytotoxic Chemotherapy Outcome Response to therapy Complete (4%) Partial (15%) No change (26%) Progression (41%) Discontinuation (15%) Toxicity Bone marrow (WHO grade >l) Renal Liver Nausea (WHO grade >2) Alopecia Dizziness
Number of patients 1 4 7
11 4 3
None None 8 None 1
1
10 cycles Of the therapy
FIG. 2. CA125 values of the nonresponding ovarian cancer patients (normal value < 30 IU/liter).
PERORAL CHEMOTHERAPY
this phase II study with previously heavily treated patients. The overall response rate was 19% with one complete and four partial responses. Stabilization of the disease was seen in six other patients (22%). The side effects were minimal. The therapy was well tolerated by most patients with only four discontinuations and no reduction of doses. The drugs used have a different mode of action and, thus, the doses could be kept low. All the treatments were accomplished on an ambulatory basis. Our results demonstrate clearly that an oral three-drug combination chemotherapy can be effective in previously heavily treated ovarian cancer patients. REFERENCES 1. Omura, G., Blessing, J., Ehrlich, C., et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma, Cancer 57, 1725-1730 (1986).
OF OVARIAN CANCER
29
2+Neijt, J. P., Ten Bokkel Huinink, W. W., van der Burg, M. E. L.,
et al. Randomized trial comparing two combination chemotherapy regimens (hexa-CAF vs CHAP-5) in advanced ovarian carcinoma, Lancet 1, 594-600 (1984). 3. Koyama, Y. I-HexyIcarbamoyl-5-fluorouracil (HCFU)-A masked 5-fluorinated pyrimidine, Cancer Treat. Rev. 8, 147-156 (1981). 4. Noda, T., Kosakai, H., Tsujimura, K., et al. A clinical trial of carmofur (HCFU) in the treatment of ovarian carcinoma-The first report, Japan. J. Cancer Chemother. 10(9), 1972-1979 (1983). 5. Rosen, Cl., Lurain, J., and Newton, M. Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple-agent chemotherapy, Gynecol. Oncol. 27, 173-179 (1987). 6 International Federation of Gynecology and Obstetrics. Classification ’ and staging of malignant tumors in female pelvis, Acta Obstet. Gynecol. Scnnd. 50, 1 (1971). I. Bast, R. C., Jr., Klug, T. L., St. John, E., et al. A radioimmunoassay using monoclonal antibody to monitor the course of epithelial ovarian cancer, N. Engt. J. Med. 309, 883 (1983). 8. WHO. World Health Organization handbook of reporting results of cancer treatment, WHO Offset Publication Co., Geneva, p. 48 (1979).