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High-dose medroxyprogesterone acetate (MPA) in advanced epithelial ovarian cancer resistant to first- or second-line chemotherapy
GYNECOLOCIC
ONCOLOGY
12, 314-318 (1981)
High-Dose Medroxyprogesterone Acetate (MPA) in Advanced Epithelial Ovarian Cancer Resistant to First- or Second-Line Chemotherapy C. MANGIONI,*
S. FRANCESCHI,*
C. LA VECCHIA,~ AND M. D’INCALCI~.’
“IQ Clinica Ostetrica e Ginecologica dell’llniversitci di Milan0 Via Commenda, 12, Milan, Italy; and ilstituto di Ricerche Farmacologiche “Mario Negri” Via Eritrea, 62 - 20157 Milan, Italy Received January 16, 1981 Out of 33 evaluable patients with advanced ovarian cancer, resistant to extensive polychemotherapy, then treated with high-dose im medroxyprogesterone (MPA), five partial responses (15%) were obtained. No partial response was obtained in a comparable group of 30 patients treated with an oral schedule. Four patients (two po, 2 im) had stable disease for at least 3 months, and 16 experienced subjective improvement. Treatment was very well tolerated. This study shows that high-dose MPA has some activity in ovarian cancer, and is worthy of further investigation.
INTRODUCTION In spite of the promising results achieved with some multidrug regimens in previously untreated advanced ovarian cancer the percentage of patients relapsing after an initial response is still high. Many efforts have been made to try to counteract the initial resistance with either single chemotherapeutic agents or very aggressive polychemotherapy regimens, but the benefits are scant in comparison with the toxic side effects. Hormones, particularly progestins, have low toxicity and are reportedly efficacious in other malignancies originating from hormone-dependent tissues (e.g., breast or endometrial cancer) but no appropriate studies have been conducted as yet to evaluate their activity on epithelial ovarian cancer. Such study appears justified in the light of the reported presence of cytoplasmic receptors to progestin in ovarian cancer cells [l]. In this study we evaluated the efficacy of medroxyprogesterone acetate (MPA) given orally or intramuscularly to patients after first and second line chemotherapeutic failure with no chance of benefit from conventional chemotherapeutic agents. MATERIALS AND METHODS A total of 7.5 patients aged from 28 to 74 years (mean = 59) with advanced epithelial ovarian cancer entered this study. All had received at least one poly’ To whom correspondence and request reprints should be addressed. 0090-8258/81/060314-05$01.00/O Copyright All rights
0 1981 by Academic Press, Inc. of reproduction in any form reserved.
314
MPA
IN
ADVANCED
OVARIAN
315
CANCER
chemotherapy regimen; 53 had received two or more regimens. Only 2 patients had received only cyclophosphamide because old age and low performance status (P.S.) prevented their being treated with other cytotoxic drugs. Twelve patients were not evaluable as they died within 1 month of starting therapy (patients evaluable: 63). The main characteristics of the two groups of patients are listed in Table 1. Stratification was performed according to histological grade (Broder grades 1 and 2, nineteen patients. Broder grades 3 and 4, forty-four patients). Within each stratum patients were allocated at random to one of the following two MPA regimens: (i) 800 mg daily po for at least 4 weeks (30 patients); (ii) 500 mg daily im for the first 4 weeks; 500 mg twice weekly for the second 4 weeks; 500 mg once weekly for the next 4 or more weeks (33 patients). Response was defined according to the following criteria: partial response: >50% regression in size of measurable disease for at least 3 months; stable disease: no change in size of tumor for at least 3 months: progression: 250% increase in size of measurable disease, or appearance of new localizations. Karnofsky’s index was used to evaluate the subjective status at the beginning of therapy: 15 patients had an index of ~50 (23.8%); 34 patients, 60-80 (54.0%); 14 (22.2%), 290. Subjective improvement was defined as a Karnofsky index improvement of at least 20 points. RESULTS As reported in Table 2, there were 5/33 (15%) partial responses in the im treated group. The duration of these responses was 5, 5,6, 8 + , and 6 + months. No partial response was obtained among the po treated patients (P < 0.05). Four patients had stable disease (two po; two im-duration 3, 3, 4, 3 months). TABLE 1 MAIN CHARACTERISTICSOF PATIENTS (po AND im ADMINISTRATION)
Route: Age (mean): Range: Kamofsky index 650 60-80 90-100
PO 56 33-10
im 63 28-14
5 (16.7%) 16 (53.3%) 9 (30%)
10 (30.3%) 18 (54.6%) 5 (15.2%)
Total
30
33
Broder grade l-2 3-4
21
10 23
Histotype Serous Endometrioid Clear cells Mutinous Undifferentiated Total
16 7 4 1 2 30
20 8 2 3 33
Total
Serous Endometrioid Clear cells Mutinous Undifferentiated
Histotype
Partial
-
response
TABLE 2
1
5 (15.1%)
28 (93.3%)
2 (6.7%)
-
2 2
Partial response
15 6 4 1 2
Progression
1 1
Stable disease
Per OS
RESPONSEPER HISTOTYPE AND ROUTE OF ADMINISTRATION
-
-
26 (78.8%)
2 (6.1%)
I
1
Progression 18 5 2 1
Stable disease
Intramuscular
:
rrl
Q 0 3
MPA
IN
ADVANCED
OVARIAN
CANCER
317
The mean duration of survival of partial responders (9.2 months) and stable disease (6.7 months) was longer than that of patients in progression (3.2 months). Among the 44 less differentiated tumors there were three cases of partial responses and four of stable disease; two partial responses were observed among the 18 better differentiated ones. Histotype distribution, analyzed in Table 2, shows a better responsiveness among endometrioid tumors (2 P.R. and 2 S.D. among 15 patients), but the difference is not statistically significant. Overall subjective improvement was noted in 25% of the case list (16/63). MPA treatment was well tolerated both by the im and oral route. No hematological toxicity and no significant alterations in serum electrolytes or liver enzymes were noticed during monthly checks. Only one patient suffered from a gluteal abscess and she was consequently shifted from the parenteral to the oral route. DISCUSSION
High im doses of MPA appear to induce objective responses in 15% of refractory ovarian cancer patients. Such a result, though hardly exciting in absolute terms, can be considered encouraging taking into account that the population of patients in this study had already been extensively treated with other chemotherapeutic regimens and had very poor chances of benefiting from any conventional chemotherapeutic agent. Except for the performance status which was slightly in favor of the orally treated group, the characteristics of the two populations of patients receiving MPA by different routes (Table 1) were well balanced, but none of the patients receiving the drug orally responded to treatment, suggesting that the systemic bioavailability after oral administration is not sufficient to achieve or maintain effective drug levels. Studies by Malkasian, though referring to a very limited group of patients, also suggested the low efficacy of MPA when given orally [2]. The indication existed that high-dose im progesterones could be effective in ovarian cancer but the results of these reports were difficult to evaluate because of the limited number of patients [2-61 or because progestins were combined with other hormones or cytotoxic drugs [7]. The present study thus provides the first report on a progestin used as a single agent in a worthwhile number of ovarian cancer patients. The results justify further studies to better ascertain the efficacy of MPA on endometrioid ovarian cancer, where some activity was to be expected on the basis of its structural analogy to endometrial cancer, and also in the other histotypes where some effect has been observed. Combined investigation of the progestin receptors of ovarian cancer cells and of MPA plasma levels may help better characterize the possible determinants of MPA antitumor activity in ovarian cancer. ACKNOWLEDGMENT The generous contribution of the Italian Association for Cancer Research, Milan, Italy, is gratefully acknowledged.
REFERENCES 1. Holt, J. A., Caputo, T. A., Kelly, K. M., Greenwald, P., and Chorost, S. Estrogen and progestin binding in cytosols of ovarian adenocarcinoma, Obstet. Gynecol. 53, 50-58 (1979). 2. Malkasian, G. D., Jr., Decker, D. G., Jorgensen, E. O., and Webb, M. J. 6-Dehydro-6, 17a-
318
3. 4. 5. 6. 7.
MANGIONI
ET AL.
dimethylprogesterone (NSC-123018) for the treatment of metastatic and recurrent ovarian carcinoma, Cancer Chemofher. Rep. 57, 241-242 (1973). Ward, H. W. Progesteron therapy for ovarian carcinoma, .I. Obsrer. Gynaecol. Brir. Commonw. 79, 555-559 (1972). Malkasian, G. D., Jr., Decker, D. G., Jorgensen, E. O., and Edmonson, J. H. Medroxyprogesterone acetate for the treatment of metastatic and recurrent ovarian carcinoma, Cancer Treat. Rep. 61, 913-914 (1977). Jolles, B. Progesterone in the treatment of advanced malignant tumours of breast, ovary and uterus, Brir. J. Cancer 16, 209-221 (1962). Varga, A., and Henriksen, E. Effect of 17-alpha-hydroxyprogesterone 17-n-caproate on various pelvic malignancies, Obster. Gynecol. 23, 51-62 (1964). Guthrie, D. The treatment of advanced cystadenocarcinoma of the ovary with gestronol and continuous oral cyclophosphamide, Brir. J. Obsrer. Gynecol. 86, 497-500 (1979).
ONCOLOGY
12, 314-318 (1981)
High-Dose Medroxyprogesterone Acetate (MPA) in Advanced Epithelial Ovarian Cancer Resistant to First- or Second-Line Chemotherapy C. MANGIONI,*
S. FRANCESCHI,*
C. LA VECCHIA,~ AND M. D’INCALCI~.’
“IQ Clinica Ostetrica e Ginecologica dell’llniversitci di Milan0 Via Commenda, 12, Milan, Italy; and ilstituto di Ricerche Farmacologiche “Mario Negri” Via Eritrea, 62 - 20157 Milan, Italy Received January 16, 1981 Out of 33 evaluable patients with advanced ovarian cancer, resistant to extensive polychemotherapy, then treated with high-dose im medroxyprogesterone (MPA), five partial responses (15%) were obtained. No partial response was obtained in a comparable group of 30 patients treated with an oral schedule. Four patients (two po, 2 im) had stable disease for at least 3 months, and 16 experienced subjective improvement. Treatment was very well tolerated. This study shows that high-dose MPA has some activity in ovarian cancer, and is worthy of further investigation.
INTRODUCTION In spite of the promising results achieved with some multidrug regimens in previously untreated advanced ovarian cancer the percentage of patients relapsing after an initial response is still high. Many efforts have been made to try to counteract the initial resistance with either single chemotherapeutic agents or very aggressive polychemotherapy regimens, but the benefits are scant in comparison with the toxic side effects. Hormones, particularly progestins, have low toxicity and are reportedly efficacious in other malignancies originating from hormone-dependent tissues (e.g., breast or endometrial cancer) but no appropriate studies have been conducted as yet to evaluate their activity on epithelial ovarian cancer. Such study appears justified in the light of the reported presence of cytoplasmic receptors to progestin in ovarian cancer cells [l]. In this study we evaluated the efficacy of medroxyprogesterone acetate (MPA) given orally or intramuscularly to patients after first and second line chemotherapeutic failure with no chance of benefit from conventional chemotherapeutic agents. MATERIALS AND METHODS A total of 7.5 patients aged from 28 to 74 years (mean = 59) with advanced epithelial ovarian cancer entered this study. All had received at least one poly’ To whom correspondence and request reprints should be addressed. 0090-8258/81/060314-05$01.00/O Copyright All rights
0 1981 by Academic Press, Inc. of reproduction in any form reserved.
314
MPA
IN
ADVANCED
OVARIAN
315
CANCER
chemotherapy regimen; 53 had received two or more regimens. Only 2 patients had received only cyclophosphamide because old age and low performance status (P.S.) prevented their being treated with other cytotoxic drugs. Twelve patients were not evaluable as they died within 1 month of starting therapy (patients evaluable: 63). The main characteristics of the two groups of patients are listed in Table 1. Stratification was performed according to histological grade (Broder grades 1 and 2, nineteen patients. Broder grades 3 and 4, forty-four patients). Within each stratum patients were allocated at random to one of the following two MPA regimens: (i) 800 mg daily po for at least 4 weeks (30 patients); (ii) 500 mg daily im for the first 4 weeks; 500 mg twice weekly for the second 4 weeks; 500 mg once weekly for the next 4 or more weeks (33 patients). Response was defined according to the following criteria: partial response: >50% regression in size of measurable disease for at least 3 months; stable disease: no change in size of tumor for at least 3 months: progression: 250% increase in size of measurable disease, or appearance of new localizations. Karnofsky’s index was used to evaluate the subjective status at the beginning of therapy: 15 patients had an index of ~50 (23.8%); 34 patients, 60-80 (54.0%); 14 (22.2%), 290. Subjective improvement was defined as a Karnofsky index improvement of at least 20 points. RESULTS As reported in Table 2, there were 5/33 (15%) partial responses in the im treated group. The duration of these responses was 5, 5,6, 8 + , and 6 + months. No partial response was obtained among the po treated patients (P < 0.05). Four patients had stable disease (two po; two im-duration 3, 3, 4, 3 months). TABLE 1 MAIN CHARACTERISTICSOF PATIENTS (po AND im ADMINISTRATION)
Route: Age (mean): Range: Kamofsky index 650 60-80 90-100
PO 56 33-10
im 63 28-14
5 (16.7%) 16 (53.3%) 9 (30%)
10 (30.3%) 18 (54.6%) 5 (15.2%)
Total
30
33
Broder grade l-2 3-4
21
10 23
Histotype Serous Endometrioid Clear cells Mutinous Undifferentiated Total
16 7 4 1 2 30
20 8 2 3 33
Total
Serous Endometrioid Clear cells Mutinous Undifferentiated
Histotype
Partial
-
response
TABLE 2
1
5 (15.1%)
28 (93.3%)
2 (6.7%)
-
2 2
Partial response
15 6 4 1 2
Progression
1 1
Stable disease
Per OS
RESPONSEPER HISTOTYPE AND ROUTE OF ADMINISTRATION
-
-
26 (78.8%)
2 (6.1%)
I
1
Progression 18 5 2 1
Stable disease
Intramuscular
:
rrl
Q 0 3
MPA
IN
ADVANCED
OVARIAN
CANCER
317
The mean duration of survival of partial responders (9.2 months) and stable disease (6.7 months) was longer than that of patients in progression (3.2 months). Among the 44 less differentiated tumors there were three cases of partial responses and four of stable disease; two partial responses were observed among the 18 better differentiated ones. Histotype distribution, analyzed in Table 2, shows a better responsiveness among endometrioid tumors (2 P.R. and 2 S.D. among 15 patients), but the difference is not statistically significant. Overall subjective improvement was noted in 25% of the case list (16/63). MPA treatment was well tolerated both by the im and oral route. No hematological toxicity and no significant alterations in serum electrolytes or liver enzymes were noticed during monthly checks. Only one patient suffered from a gluteal abscess and she was consequently shifted from the parenteral to the oral route. DISCUSSION
High im doses of MPA appear to induce objective responses in 15% of refractory ovarian cancer patients. Such a result, though hardly exciting in absolute terms, can be considered encouraging taking into account that the population of patients in this study had already been extensively treated with other chemotherapeutic regimens and had very poor chances of benefiting from any conventional chemotherapeutic agent. Except for the performance status which was slightly in favor of the orally treated group, the characteristics of the two populations of patients receiving MPA by different routes (Table 1) were well balanced, but none of the patients receiving the drug orally responded to treatment, suggesting that the systemic bioavailability after oral administration is not sufficient to achieve or maintain effective drug levels. Studies by Malkasian, though referring to a very limited group of patients, also suggested the low efficacy of MPA when given orally [2]. The indication existed that high-dose im progesterones could be effective in ovarian cancer but the results of these reports were difficult to evaluate because of the limited number of patients [2-61 or because progestins were combined with other hormones or cytotoxic drugs [7]. The present study thus provides the first report on a progestin used as a single agent in a worthwhile number of ovarian cancer patients. The results justify further studies to better ascertain the efficacy of MPA on endometrioid ovarian cancer, where some activity was to be expected on the basis of its structural analogy to endometrial cancer, and also in the other histotypes where some effect has been observed. Combined investigation of the progestin receptors of ovarian cancer cells and of MPA plasma levels may help better characterize the possible determinants of MPA antitumor activity in ovarian cancer. ACKNOWLEDGMENT The generous contribution of the Italian Association for Cancer Research, Milan, Italy, is gratefully acknowledged.
REFERENCES 1. Holt, J. A., Caputo, T. A., Kelly, K. M., Greenwald, P., and Chorost, S. Estrogen and progestin binding in cytosols of ovarian adenocarcinoma, Obstet. Gynecol. 53, 50-58 (1979). 2. Malkasian, G. D., Jr., Decker, D. G., Jorgensen, E. O., and Webb, M. J. 6-Dehydro-6, 17a-
318
3. 4. 5. 6. 7.
MANGIONI
ET AL.
dimethylprogesterone (NSC-123018) for the treatment of metastatic and recurrent ovarian carcinoma, Cancer Chemofher. Rep. 57, 241-242 (1973). Ward, H. W. Progesteron therapy for ovarian carcinoma, .I. Obsrer. Gynaecol. Brir. Commonw. 79, 555-559 (1972). Malkasian, G. D., Jr., Decker, D. G., Jorgensen, E. O., and Edmonson, J. H. Medroxyprogesterone acetate for the treatment of metastatic and recurrent ovarian carcinoma, Cancer Treat. Rep. 61, 913-914 (1977). Jolles, B. Progesterone in the treatment of advanced malignant tumours of breast, ovary and uterus, Brir. J. Cancer 16, 209-221 (1962). Varga, A., and Henriksen, E. Effect of 17-alpha-hydroxyprogesterone 17-n-caproate on various pelvic malignancies, Obster. Gynecol. 23, 51-62 (1964). Guthrie, D. The treatment of advanced cystadenocarcinoma of the ovary with gestronol and continuous oral cyclophosphamide, Brir. J. Obsrer. Gynecol. 86, 497-500 (1979).