Pharmacokinetic studies of 4'-epi-doxorubicin in cancer patients with normal and impaired renal function and with hepatic metastases.
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Biomedical subjects
Publications and source records attributed to F Pannuti.
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A pharmacokinetic evaluation of medroxyprogesterone acetate (MAP, 6 alpha-methyl-17 alpha-hydroxyprogesterone acetate) was undertaken in 70 patients with advanced cancer treated either orally or im with single high doses. MAP plasma levels were determined by gas chromatography (63Ni electron capture detector) after derivatization with heptafluorobutyric anhydride, using 17 alpha-hydroxyprogesterone caproate as internal standard. Plasma levels after oral administration can be approximated by a triexponential function in agreement with a pharmacokinetic two-compartment open model with first-order absorption; peak levels are dose-related, but high interindividual variance is present. Following the administration, both decay phases are masked by prolonged absorption; peak levels are lower than after oral administration, but long-term bioavailability is higher, as demonstrated by comparison of the values for areas under curves in the 0-146-hour interval. The high interindividual ranges in the observed MAP plasma levels indicate that if any significant clinical evaluation is to be made, routine analysis of plasma MAP is mandatory.
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The authors treated three groups of rats with medroxyprogesterone acetate (MAP) at different dosages (0, 2.5, 5, 10, 20, 40, 80 mg/kg) i.p. and orally for 7 days to evaluate its anabolic and its androgenic/antiandrogenic effect. 70 rats had been previously castrated and 35 were intact. The anabolic effect is evident in all groups of animals which were treated. The androgenic action predominates in castrated animals, while the antiandrogenic action predominates in intact animals. The above-mentioned actions are more marked when very high doses are used. After suggesting the possible mechanism of action of MAP, the authors point out that the anabolic effect confirms what has already been reported in clinical oncology after treatment with very high doses of MAP (1,000-2,000 mg orally or i.m. for 30 days) in different types of tumors (breast, kidney, prostate).
The Authors have studied total urinary hydroxyproline (TUH), together with other hematochemical analyses, in 104 patients suffering from advanced breast cancer with or without bone metastases. TUH escretion is higher in patients with osseous lesions and, if simultaneous pathologic values of TUH and serum alcaline phosphatase occur, the presence of bone metastases is statistically even more probable. Moreover TUH seems to vary in accordance with the clinical response of the disease at osseous level in 46 patients treated with Medroxyprogesterone acetate (MPA) at high doses, showing itself as a possible marker of not negligible clinical value.
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The results obtained with a new hormonal treatment schedule involving the administration of medroxyprogesterone acetate in single and total doses never before used in the treatment of advanced breast cancer are reported. The results concern 100 patients, 13 of which in premenopause and 87 in postmenopause stage. 79 patients were treated with a single daily dose of 1500 mg i.m. for 30 days, subdivided into 2 equal doses administered at intervals of 12 hours, while 21 patients were treated with a dose of 2000 mg/day using the same modalities. In the 13 premenopausal patients, complete or partial objective remission was observed in 12/13 (92%) of cases, while the disease advanced in one of the patients (8%). Of the 87 postmenopausal patients, complete or partial objective remission was observed in 40/87 (46%) of cases, minimal remission in 9/87 (10%), while 18/87 (21%) remained stationary. The disease advanced in 20/87 (23%) of patients. In patients where metastasis mainly affected the bones and soft tissues complete or partial remission occurred in 41/52 (79%) of cases. Those where visceral metastasis was prevalent showed remission in 3/33 (9%) of cases. Median duration of remission was 6 months (range: 3--27). A significant reduction of pain was noticed in 68/74 (92%) of cases, of dyspnea in 20/25 (80%), of anorexia in 45/53 (85%), of asthenia in 49/70 (70%) and of restriction of movement in 24/39 (62%). On the basis of the present results, treatment with massive doses of medroxyprogesterone acetate should be considered: a) as first therapeutic measure in the treatment of postmenopausal patients with prevalent lesions in soft tissues and bones; b) as a subject of a particular study in premenopausal patients with breast cancer in an advanced stage, and c) as a possible alternative to polychemotherapy in the treatment of micrometastasis following mastectomy.
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A detailed code for the evaluation of side-effects due to antiblastics in accordance with clinical, pharmacological and chronobiological parameters is described. Eight types of toxicity are recognised: systemic or local, cutaneous and adnexal, gastroenteric, haematochemical, cardiovascular, respiratory, genital and urinary, and nervous. Improvement of the objectivity and comparability of results in clinical oncology is proposed by means of a balanced points system for the expression of such effects, and methods for the summary expression of the toxicity of a single case or a uniform group of cases. The method of evaluation proposed also permits statistical comparison between different treatment protocols.
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The results obtained with a new hormone therapy using medroxyprogesterone acetate (MAP) in previously untested single and total doses in the treatment of advanced breast cancer are reported. Fifty-two postmenopausal patients were treated with an average total dose of 40 g of MAP for a period of 30 days. Nineteen of 44 patients (43%) had complete or partial remission, while the disease remained unchanged in nine of 44 patients (20%). Disease progression occurred in 12 of 44 patients (27%). Partial or complete remission occurred in 12 of 18 (67%) and four of six (67%) of the patients with dominant osseous and soft tissue metastases respectively. Three of ten (16%) of those with visceral metastases had remission. The average duration of remission was 7 months. Average survival times were 15.5 months for patients with remission, 8 months for those with no change, and 2.5 months for those with disease progression. From a subjective standpoint, pain was reduced significantly or disappeared in 34 of 36 patients (94%); this was also the case with respect to dyspnea (13 of 16 patients [81%]), anorexia (24 of 29 [83%]), asthenia (28 of 35 [80%]), and walking impairment (15 of 24 [63%]). When relapse occurred, patients previously treated with massive doses of MAP received further treatment with higher doses of MAP; four of 22 (18%) of the patients attained partial remission once again. Positive effects were also seen in subjective performance status, body weight, and EKG. We also describe the new clinical and toxicologic features of this treatment.
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