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The efficacy and tolerability of the combined scheme of administering high dose medroxyprogesterone acetate in advanced breast cancer is evaluated.
High-dose medroxyprogesterone acetate (HD-MPA) has been successfully employed in the treatment of hormone-related tumors, especially advanced breast cancer. However, progestins in general and MPA in particular are considered a useful treatment also in other types of tumors such as endometrial, prostatic and renal cancer. Furthermore, MPA has been evaluated in tumors which are not classically considered hormone-related, such as ovarian cancer. Therapy with one of a number of progestational agents has been the conventional approach to the management of endometrial carcinoma not amenable to surgery or radiation therapy. Among the various synthetic progestins, MPA has been the most widely employed both by i.m. and oral routes, according to a variety of doses and schedules. Objective responses have been obtained in a percentage of women varying between 30 and 50% in the different series. While the role of MPA in the palliative treatment of advanced disease is well accepted, opinion is divided on the role of progestins in the adjuvant setting. On the basis of available data, it should be concluded that the usefulness of adjuvant therapy with progestins in high risk, early-stage endometrial cancer has not yet been clearly demonstrated. As far as prostatic cancer is concerned, data coming from comparative trials show that MPA is less effective than diethylstilbestrol (DES), and therefore should not be considered the first choice for previously untreated patients. However, it can achieve responses in patients who no longer respond or who are refractory to DES, and represents the treatment of choice for those patients who, due to their cardiovascular conditions, cannot be given estrogens.(ABSTRACT TRUNCATED AT 250 WORDS)
Sixty-eight women with metastatic breast cancer occurring less than five years positives after the treatment of the primary tumour, with estrogens and/or progesterone receptors (EPR), were randomized. Sixty-four patients were available for evaluation of efficacy and toxicity. Thirty patients received treatment A: tamoxifen 30 mg per day alternating every two weeks with medroxyprogesterone acetate (MPA) 1 000 mg per day orally. Thirty-four received treatment B: tamoxifen 30 mg per day and after relapse, high dosage of MPA alone. The distribution of the evaluable metastasis and the value of the ER are the same in the two groups. The total responses or the responses by metastatic site were as follows: complete response, one case in each treatment group, partial response, 6 and 10 cases, no change, 14 and 17 cases and progressive disease, 9 and 6 cases respectively. The duration of the response was the same in the two groups with a median of 6 months (extremes of 30 and 19 months). Among the patients under protocol B, 19 received MPA after failure of tamoxifen: eight responded (3 partial responses and 5 no change). Toxicity was slight but 2 treatments in group A were discontinued. Alternated sequential hormonal treatment is theoretically attractive for these patients with known and positive EPR but it is not more efficient than the two hormonotherapies applied successively.
The synthetic progestin medroxyprogesterone acetate (MPA) has previously been shown to be an inducer of hepatic microsomal cytochrome P-450 in both man and the rat. We have assessed the ability of a variety of oral doses of MPA to induce either hepatic cytochrome P-450 as measured by antipyrine clearance or alpha 1-acid glycoprotein (AGP) in beagle dogs. Over the range of 25 mg/d to 400 mg/d, MPA did not induce antipyrine clearance. The concentration of AGP only increased at the 400 mg/d level, and was effected to a much smaller extent than has been previously observed for other inducing agents. MPA was also tested as a promoter of induction by combining it with a course of rifampin capable of substantially elevating both antipyrine clearance and AGP. MPA was without effect. The results of these experiments are discussed in light of the toxicology of MPA in beagles.
A comparison has been made between the absorption of oral medroxyprogesterone acetate (MPA) in an aqueous suspension preparation and in syrup form. Plasma drug profiles were measured after a single administration of the two formulations in 17 advanced cancer patients. On average the standard form (aqueous suspension) gave peak levels which were lower than the syrup mixture. However, the wide intersubject spread in MPA plasma levels observed in both groups did not allow any statistical significance to be assigned to this difference.
A review of all available data including those from the WHO Collaborative Study of Neoplasia and Steroid Contraceptives has shown no increased risk of cancers of the breast, endometrium, ovary or liver in women using depot-medroxyprogesterone acetate (DMPA). The issue of a causal association between DMPA use and cervical cancer is as yet unresolved and will require the accumulation of additional data. To date, in the WHO study only a small number of women have used DMPA for prolonged periods or have had a long interval since first use. Information on cancer risk in these women can only be gained by continuing the present study or by initiating additional studies focused on these specific topics.
A phase II study of high-dose medroxyprogesterone acetate (MPA) was performed in 18 patients with advanced breast cancer. MPA was administered at a dosage of 1,200mg orally per day. Of the 15 evaluable patients, partial response was obtained in 3, minor response in 1, no change in 5 and progressive disease in 6 patients. The response rate was 20%, which was as effective as that of tamoxifen. As the responders had been previously treated with tamoxifen, the result suggested that MPA showed no cross-resistance to the latter. Eight patients (53%) experienced weight gain which, in 4 cases (27%), necessitated discontinuation of the treatment. One patient exhibited an allergic reaction and the drug was discontinued. Palpitation in 4 patients (27%), vaginal bleeding in 2 (13%), and edema in 1 (7%) were observed, but these effects were tolerable. We therefore conclude that high-dose MPA is an effective therapy for advanced breast cancer, and that further study is warranted.
Lipid metabolic changes under oral treatment with medroxyprogesterone acetate (MPA) were investigated in four groups of patients: group I; 10 patients aged 25-45 (mean 38) years received 50 mg MPA daily for pelvic endometriosis. Group II; 21 patients aged 55-77 (mean 62) years received 200 mg MPA daily for surgically treated endometrial carcinoma stage I. Group III; 14 praemenopausal patients aged 37-52 (mean 47) years received 1000 mg MPA daily for metastasized breast cancer. Group IV; 27 post-menopausal patients aged 53-78 (mean 68) years were treated with 1000 mg MPA daily for metastatic breast cancer as well. A fifth group of initially 86 patients aged 40-86 (mean 63) years after surgery for endometrial carcinoma stage I served as untreated control for groups II and IV. Cholesterol and triglyceride concentrations were measured enzymatically lipoproteins were determined by quantitative electrophoresis and precipitation and apolipoproteins A1 and B were quantified by kinetic rate nephelometry. Whereas in patients of group I no changes of lipid and lipoprotein parameters were observed, daily oral doses of 200 mg MPA and more led to a marked fall in alpha-lipoprotein-, HDL-cholesterol and apolipoprotein A1 levels. beta-Lipoprotein-, LDL-cholesterol and apolipoprotein B concentrations rose significantly in Groups III and IV. The relevance of these findings in terms of athero-genicity is discussed.
Twenty-nine females with metastatic or locally recurrent carcinoma of the breast were treated orally with 1 g of medroxyprogesterone acetate (MPA) daily. This was used as a second- or third-line treatment. Serum concentration of MPA was measured over a 28-day period. We have demonstrated a significantly greater area-under-the-concentration-time curve, peak, and steady-state MPA concentration for Provera at 100- and 200-mg tablets (Upjohn) than for Farlutal at 500-mg tablets (Farmitalia). Relative bioavailability of preparations should be considered when prescribing or assessing treatment results when MPA is used.
Four demented male patients who manifested disruptive sexual behavior, including public masturbation and attempts to molest female patients, and who could not be managed by other means received a therapeutic trial of medroxyprogesterone acetate (MPA) for 1 year and were followed up for an additional year. Their sexual activities were recorded before, during, and after the study, and serum testosterone, luteinizing hormone (LH), and prolactin were monitored regularly. Within 2 weeks of the start of MPA therapy, the sexual acting out had stopped; this was associated with a 90% and a 60% decline, respectively, of serum testosterone and LH. When MPA treatment was stopped, testosterone and LH returned to pretrial levels in all four men. One showed a return of sexual acting out, but this was at a reduced level and was successfully managed by firm nursing. MPA was used without adverse effects. Because of its safety and efficacy, the drug should be considered as a first-line treatment for sexual acting out in demented men.
Wide excision is the recommended primary therapy for retroperitoneal fibromatosis. Radiation therapy and a variety of medications have been used to treat patients with recurrent tumors, but the response to these agents has not been uniform. The patient presented was successfully treated with medroxyprogesterone acetate for recurrent retroperitoneal fibromatosis that was refractory to multiple operative resections and radiation therapy.
32 patients suffering from previously untreated, advanced metastatic or non-metastatic prostatic carcinoma, were studied in an assessment of the effect of high-dose medroxyprogesterone acetate (MPA) on the hormonal parameters testosterone and the luteinizing hormone (LH). The dose used was 500 mg intramuscularly daily for a week, followed by 1000 mg monthly until progression or for a minimal period of 12 months. Full castration was achieved and this effect was maintained during the observation period. Stable disease was seen in 20 patients (63%) whilst progression of disease was found in 12 patients (37%). 4 patients were non-responders. The incidence of side effects was 31%.
30 patients with renal tumours were treated with Depo-Provera (Medroxyprogesterone). Among the 21 patients operated on without metastases and with an parallel metastasis (fibrous capsule, adipose capsule, peritoneum) in the course of 6 to 15 months no one died of a tumour progression. Among the 9 patients with a distant metastasis in one case the regression of the metastasis could be achieved, whereas in another case progesterone stopped the progression of the intraoperatively observed liver metastasis.
The influence of medroxyprogesterone acetate (MPA) and various other steroid hormones on the lateral diffusion of the fluorescent lipid probe 1-acyl-2-(N-4-nitrobenzo-2-oxa-1.3-diazolyl)-aminocarpropylphos phatidylcholine (NBD-PC) in the plasma membrane of intact mammary cancer cells (CAMA-1 cell line) has been studied by fluorescence recovery after photobleaching technique. Incubation of cells with MPA in serum free medium at ambient temperature for 1 hr led to a significant decrease in the lateral diffusion coefficient of NBD-PC. MPA induced this change over a limited concentration range with 10(-7)-10(-5) mol/l near-maximal or maximal effects, and 10(-8) mol/l exhibiting no effect. Exposure of the CAMA-1 cells to 10(-7) mol/l MPA in undiluted serum induced a significant effect following 1.5 hr of treatment with no increase in effectiveness up to 4 hr of incubation. As compared to MPA, the other steroids tested were less effective or ineffective. The influence on lateral lipid mobility diminished as follows: MPA greater than progesterone greater than 5a-DHT approximately 17 beta-estradiol greater than dexamethasone, and roughly seems to parallel their lipid solubility as estimated by partition coefficients in an n-octanol-water system. Any involvement of classical steroid hormone receptors in the mechanism of membrane action could be excluded. Nongenomic steroid effects on the plasma membrane are assumed. As the structure and function of biomembranes are modulated by lipid-bilayer fluidity and membranes crucially participate in nearly all aspects of cell biology, it is concluded that direct interactions of MPA with membranes potentially play a role in the antitumor activity of the compound.
Forty-six patients with advanced breast cancer were treated orally with high-dose medroxyprogesterone acetate (MPA), and a 28% (2 CRs, 11 PRs) response rate was obtained. The patient groups that showed a favorable response to MPA were as follows: patients in a postmenopausal state, with soft tissue or bone metastases, with slow-growing tumors, without prior therapy or with good response to prior endocrine therapy, and with positive estrogen (ER)- and/or progesterone (PgR) receptors. Six of 10 patients who had responded to prior endocrine therapy responded to MPA, while only 2 of 23 who had not responded to prior endocrine therapy showed a good response to MPA. There was a significant difference in response to MPA between patients with positive ER or PgR and those with negative ER or PgR tumors. The ER detected in primary or initially relapsed tumors correlated well with the effects of MPA given as a 2nd-line endocrine therapy for advanced breast cancer. The possible roles of MPA in the treatment of advanced breast cancer were discussed.
Results of clinical studies in advanced and, recently, also in early breast cancer have shown a clear protective effect of high dose medroxyprogesterone acetate (MPA) on the bone marrow toxicity induced by chemotherapy. The underlying mechanism of this phenomenon is unsettled and in vitro studies have yielded contradictory results. The results of these clinical and in vitro studies are summarized. The myeloprotective effect may have important therapeutical implications.
The effect of medroxyprogesterone acetate (MPA) on breast cancer cell proliferation kinetics was investigated in ten human breast cell lines growing as monolayer cultures. Significant inhibition of growth occurred only in the estrogen receptor-positive, progesterone receptor-positive cell lines, T-47D, MCF-7, ZR 75-1, BT 474, and MDA-MB-361. Among these cell lines sensitivity to MPA varied widely; concentrations required for 20% inhibition of growth ranged from 0.04 nM for T-47D to greater than 100 nM for ZR 75-1 cells. Furthermore, although the most sensitive line, T-47D, had the highest level of PR, sensitivity to MPA was not correlated with PR levels among the responsive cell lines. More detailed studies were undertaken with the T-47D cell line. The growth-inhibitory response was confined to the progestins: MPA, ORG 2058, R5020, and progesterone, while androgens, estrogens, and glucocorticoids were without effect over the same concentration range (0.1-100 nM). MPA-induced growth inhibition was associated with a significant decrease in the proportion of S-phase cells with an accumulation of cells in the G0-G1 phase of the cell cycle. Cells began to accumulate in G0-G1 after 12 h of drug treatment and the effect was maximal by 24 h, i.e., maximal effects were observed during the first cell cycle following drug treatment. By contrast, significant accumulation in G0-G1 required exposure of MCF-7 cells to MPA for at least two cell cycle times, i.e., 48 h and the effect was still increasing at 96 h. Stathmokinetic studies revealed that in both cell lines accumulation in the G0-G1 phase was due to an MPA-induced increase in the G1 transit time. These data indicate that MPA and other progestins have direct growth inhibitory effects on estrogen receptor-positive and progesterone receptor-positive human breast cancer cells in vitro and these effects can be accounted for by a decrease in the rate at which cells traverse the G1 phase of the cell cycle.
Forty-six patients with advanced breast cancer were treated with oral high-dose medroxyprogesterone acetate (MPA) as a second line endocrine treatment, with a 28% 13/46) response rate. There was a significant difference in response to MPA between patients with estrogen (ER)- or progesterone (PgR)-receptors and those with negative receptors assayed just before the treatment (ER+, 7/10, ER-, 0/9 of response rates, p = 0.007, PgR+, 4/4: PgR-, 3/15, p = 0.02). The combination of ER and PgR was observed to be best in predicting the response (p = 0.02). The ER status as well as the combination of ER and PgR, but not PgR alone detected in the primary tumors, correlated well with the response (ER+, 10/23: ER-, 0/15, p = 0.0094, PgR+: PgR-, p = 0.13, ER+PgR+, ER+PgR-, ER-PgR-:p = 0.024). The correlation between steroid hormone receptors and response to MPA in advanced breast cancer was established from the literature. Response rate to MPA was shown to be 42% (69/169) in ER+ cancer patients, and 10% (9/90) in ER- cancer patients (p = 0.00004). There was no correlation between PgR status and the response. Changes of receptors were studied in relation to the response. When ER+ or PgR+ tumors retained their positivity until MPA treatment, a good response was obtained, while there were almost no responders if one or both receptors changed from positive to negative, or remained negative. In conclusion, the response to MPA can be predicted by the steroid hormone receptors.