Timing of breast cancer surgery during the luteal menstrual phase may improve prognosis.

A meta-analysis has been performed of available retrospective reports concerning the 5-15 year disease-free survival of 5,353 premenopausal breast cancer patients operated on either during the follicular or luteal phases of the menstrual cycle. Patients with surgery performed during the luteal phase (d 14-23+) had an overall mean 5% benefit compared to those operated on the follicular phase determined by date of onset of their last menstrual period p = 0.02 by Wilcoxon 2-tailed test. When nodal invasion was reported, node-negative patients had a 5 +/- 2% SEM benefit. Patients with positive nodes had a 34 +/- 3% SEM increase in survival (p = .05), including both estrogen and progesterone-receptor negative as well as positive neoplasms. In 3 of 4 reports from major cancer treatment centers, each containing 249-1175 cases, risk of recurrent cancer and/or death increased 5 to 6-fold after 10 years for women receiving surgery during d 7-14 of their cycle, compared to those resected during d 21-36. Improvement in prognosis was greatest for patients with the highest risk of recurrence due to node-invasive disease and receptor dysfunction. Several cell-mediated immunologic factors inimical to metastasis are maximal in the luteal phase of the menstrual cycle, including natural killer cell activity. A new drug which augments natural killer cell activity may extend any beneficial survival results to post-menopausal breast cancer patients in the future. We conclude that accurate menstrual histories should be included in the medical record from now on for all premenopausal women receiving any surgical procedure upon the breast, preferably using an objective method of determining the date of last ovulation. Prospective randomized clinical trials are necessary to determine the full extent of survival benefits of late luteal surgical timing.

Timing of breast cancer surgery during the luteal menstrual phase may improve prognosis.

A meta-analysis has been performed of available retrospective reports concerning the 5-15 year disease-free survival of 5,353 premenopausal breast cancer patients operated on either during the follicular or luteal phases of the menstrual cycle. Patients with surgery performed during the luteal phase (d14-23+) had an overall mean 5% benefit compared to those operated on the follicular phase determined by date of onset of their last menstrual period p=0.02 by Wilcoxon 2-tailed test. When nodal invasion was reported, node-negative patients had a 5 + 2% SEM benefit. Patients with positive nodes had a 34 + 3% SEM increase in survival (p = .05), including both estrogen and progesterone-receptor negative as well as positive neoplasms. In 3 of 4 reports from major cancer treatment centers, each containing 249-1175 cases, risk of recurrent cancer and/or death increased 5 to 6-fold after 10 years for women receiving surgery during d7-14 of their cycle, compared to those resected during d21-36. Improvement in prognosis was greatest for patients with the highest risk of recurrence due to node-invasive disease and receptor dysfunction. Several cell-mediated immunologic factors inimical to metastasis are maximal in the luteal phase of the menstrual cycle, including natural killer cell activity. A new drug which augments natural killer cell activity may extend any beneficial survival results to post-menopausal breast cancer patients in the future. We conclude that accurate menstrual histories should be included in the medical record from now on for all premenopausal women receiving any surgical procedure upon the breast, preferably using an objective method of determining the date of last ovulation. Prospective randomized clinical trials are necessary to determine the full extent of survival benefits of late luteal surgical timing.

Increased catechol estrogen metabolism as a risk factor for nonfamilial breast cancer.

The metabolism of estrone (E1) or estradiol-17 beta (E2) to catechols seldom has been investigated in biochemical studies related to the risk of development of human breast cancer, as a result of the extreme lability and reactivity of these hormones. A method of indirect calculation was developed in which estimated catechol estrogen excretion (ECE) from urinary excretion of E1, E2, and estriol (E3) was used, based on the obligate reciprocal relation between 16 alpha-hydroxylase activity (r3) and estrogen 2/4 hydroxylase function (r2). This relationship is expressed by r2 x r3 = K, the estrogen oxidative constant. From published data relating chiefly to 2-OH estrone excretion, K = 12.4 +/- 0.8 (standard error of the mean). Urinary E1 + E2 excretion rates reflect nonprotein-bound plasma ovarian estrogen concentrations available for cell metabolism, which influence the value of K. The equation: r2 = [E1 + E2] K/[E3 + 16 alpha OH E1] = ECE gives a median correlation coefficient between actual catechol estrogen excretion and ECE in micrograms/24 hours of +0.88 (range, 0.61 to 0.97). When tested against the best product isolation analysis of catechol estrogen excretion, ECE was 95% accurate. Using this method a metaanalysis was conducted of published fractional estrogen excretion collected from 2846 healthy women worldwide aged 15 to 59 years, with a risk of breast cancer varying fivefold. Overall ECE was 78% to 97% higher in high-risk women of all ages and menstrual cycle phases (P less than 0.001, by Wilcoxon test). With increasing cancer risk (as estimated by the authors), ECE rose linearly exponentially with a slope of 0.149 (follicular phase) and 0.136 (luteal phase). The correlation coefficient (R2) between the two variables was 0.77 and 0.57, respectively (P less than 0.05). These data derived from calculations of ECE in healthy women confirmed recent analytic results of a twofold increase in the ratio of 2-OH E1/4-OH E1 in healthy Finnish women compared with recent Japanese migrants to Hawaii. In Finnish women with breast cancer, this ratio increased further (almost twofold). Metaanalysis supported the conclusion that increased rates of oxidation of estradiol 17-beta to 2-OH catechols supply the principal proximal human mammary carcinogens active after menarche.

A method for estimating catechol estrogen metabolism from excretion of noncatechol estrogens.

The relationship of catechol estrogen metabolism to disease has seldom been investigated because of analytic difficulties. Estradiol (E2) and estrone (E1) are oxidized simultaneously at either ring A or ring D, and the rate of catechol estrogen formation (r2) is reciprocally related to the rate of 16 alpha-hydroxylation (r3). The rate of ovarian estrogen production (X10) can be summarized as to metabolic outcome: X10 = r10 + r2 + r3 + r(u), where r10 is the loss of E1 and E2 in urine, and ru is the fecal and urinary loss of unknown oxidative products. Assuming a constant r(u) between subjects: constancy of the X10 concentration between subjects during similar menstrual cycle phases. In the absence of xenobiotics, r2 x r3 are reciprocally interrelated: r2 x r3 = K (an oxidation constant whose limiting factor is the biologically available estrogen at the cell surface). To the extent that r10 approximates estrogens available for cellular metabolism, the rate of catechol estrogen metabolism may be determined from (Formula; see text) From published data K = 12.4 +/- 0.8 of the standard error of the mean. Pearson correlation coefficients between actual and estimated catechol estrogen excretion in groups of subjects ranged from 0.61 to 0.97 (median, 0.88). This method has been useful for clinical investigation of the relationship of catechol estrogen metabolism to disease until better methods to measure catechol estrogen directly are available.

Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen.

Mammary carcinomas have been induced by 3.5 Gy whole-body gamma radiation administered at age 40 to 50 days to virgin female Sprague-Dawley rats. In 142 irradiated controls carcinoma incidence averaged 7.8% in survivors observed less than 300 days and 38.3% of those surviving longer (P less than 0.001 by t test). Mammary cancer promotion was inhibited by two methods: estriol (E3) 638 micrograms/month (2.2 microns/mo) subcutaneously for natural life span begun 2 weeks after exposure reduced cancer incidence from 76% in controls to 48% after 331 to 449 mean days observation until neoplasia was palpable (P less than 0.02 by chi-square analysis). Uterine weights were similar in control and treated groups, and were 15% to 18% greater than uteri of nonirradiated controls from other simultaneous experiments. Six monthly 638-micrograms doses of 17 alpha ethinyl estriol (EE3) reduced tumors from 88% in controls to 64% (P less than 0.05 by chi-square analysis) and delayed cancer onset (P less than 0.01-0.04 by life table analysis). Ethinyl estradiol (EE2) after 6 months' treatment similarly delayed mammary tumor development reducing incidence to 75% (NS), with a six-fold increase in nonmammary epithelial malignant tumors. Estriol administration begun between 3 days before to 5 days after radiation did not alter mammary cancer incidence in six experiments. Monthly implantation of 2.5 mg tamoxifen (4.44 microns/mo) started 2 weeks after radiation reduced mammary cancer incidence from 83% to 14% after 307 to 314 days' observation (P less than 0.001 by chi-square analysis). Treated rats had atrophic ovaries and uteri consistent with blockade of endogenous estradiol activity. Short-term parenteral E3 or EE3 therapy using 10 to 30 micrograms/kg/day (35-100 microns/kg/day) rapidly differentiated virgin rat mammary glands without impairment of subsequent estrus cycles and offers an alternative to castration or life-long antiestrogen therapy for reduction of risk of radiogenic mammary carcinoma.

Antimammary carcinogenic activity of 17-alpha-ethinyl estriol.

Both initiation and promotion of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis were inhibited by prophylactic therapy for 1 to 7 months using 17-alpha-ethinyl-estriol in doses as low as 1.0 microgram/d administered to intact virgin female Sprague-Dawley rats at 35 to 65 days of age. Administration of 638-micrograms single or multiple doses 2 to 3 weeks before DMBA induced a 75% to 85% reduction in cancer incidence after 1 year (P less than 0.001). When treatment was begun 2 weeks after DMBA, 1.0 microgram/d infused for 84 days resulted in a 44% reduction in incidence, with higher-dose, more prolonged therapy achieving a 73% reduction, equal to the reduction in carcinoma incidence observed after ovariectomy. Biopsies of nontumorous mammary glands showed a positive correlation between prelactational lobuloalveolar hyperplasia, hormone dose, and reduction in incidence of mammary carcinoma. Similar treatment with 17-alpha-ethinyl-estradiol-17B and diethylstilbestrol did not inhibit the 90% to 100% incidence of carcinoma observed in DMBA-treated control rats, and induced lactational hyperplasia in mammary gland biopsies. Continuous ethinyl estriol infusion subcutaneous (sc) in 2.5 to 7.5 micrograms daily dosage significantly increased uterine weights by as much as 10% to 46% after 2 to 4 weeks. At the time of mammary neoplasm development when rats were necropsied, no significant difference was observed in uterine weights between rats receiving 638 micrograms/mo in a readily soluble pellet implant, and uterine weights of control rats. Ethinyl estriol given seven times monthly in 638-micrograms bolus doses was more inhibitory of mammary carcinogenesis than estriol after a year (P less than 0.1 greater than 0.05). Short-term intermittent administration of ethinyl estriol to young nulliparous women may offer a method of simulating the differentiating effect of pregnancy on mammary tissues, increasing durable resistance to carcinogenesis.

Rat uterine polyamine biosynthetic decarboxylase activities following multiple injections of estradiol-17 beta and/or estriol.

A single injection of 0.5 micrograms estradiol-17 beta (E2) plus 0.5 micrograms estriol (E3) stimulated a different pattern in 22-24 day-old rat uterine ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAMDC) activities than was induced by either a single injection of 0.5 micrograms E2 or multiple injections of 0.5 micrograms E3. Differences included alterations in enzyme activity peak timing as well as activity duration. Every 3 hour injections of 0.05 micrograms E2 induced maximum uterine ODC activity at 4, 24, 32, and 40 hours, intermediate activity at 48, 64, and 72 hours as well as a small peak by 56 hours. When 0.05 micrograms E2 plus 0.05 micrograms E3 were injected simultaneously every 3 hours, the ODC activity pattern was similar except that activity fell to intermediate levels by 40 hours. It is suggested that E3 alterations of E2 induced uterine enzyme activities (when monitored at frequent intervals) could be physiological alterations in uterine growth responses due to E2-E3 hormone interactions. However, there appeared to be no differences between E2 or E2 plus E3 induction of DNA synthesis and luminal epithelial cell height and cross-sectional area or ODC and SAMDC activities when measured at 24, 48, or 72 hours.

Chronic phenytoin administration and the hepatic mixed function oxidase system in female rats.

The long term effects of phenytoin administration on mixed function oxidase activities and serum estradiol in female rats were examined. No induction of hepatic mixed function oxidases was seen until 8 days after the administration of 100 mg phenytoin/kg/day either orally or intraperitoneally. Maximum increase in aniline hydroxylase, aryl hydrocarbon hydroxylase (AHH) and ethylmorphine-N-deethylase activities occurred between days 8 and 16 of treatment and decreased thereafter. No induction of lung or intestinal AHH activity was observed. Serum levels of estradiol were significantly decreased after 16 days of phenytoin treatment. Maximal increases in hepatic cytochrome P-450 and cytochrome c reductase occurred after 8-16 days of treatment. Furthermore, pentobarbital sleeping times were shortest after 16 days of phenytoin administration. The activities of all enzymes after 32 days of phenytoin treatment were less than at the peak activities at 8-16 days.

Therapeutic management of small cell lung cancer. Fewer toxic reactions with lower chemotherapeutic drug dosages.

A treatment protocol for small cell lung cancer used attenuated drug dosages in an attempt to reduce toxic reactions without compromising effectiveness. Treatment consisted of cyclophosphamide, 50 mg orally daily, methotrexate, 1.25 mg orally daily, procarbazine hydrochloride, 50 mg orally daily, and vincristine sulfate, 10 micrograms/kg intravenously weekly, and was continued until relapse or for two years. Patients with limited disease were given concurrent radiation (4,000 to 5,000 rad, using standard fractionation) to the primary lesion and draining nodes. Fifty patients were evaluable for toxic reactions and survival: 22 with limited and 28 with extensive disease. Fifty-four percent of the patients with extensive disease responded; one (4%) had a complete response. Median survival of the patients with extensive disease was 20 weeks. Ninety-five percent of the patients with limited disease responded; 57% had a complete response. Median survival of these patients was 55 weeks; one-year survival was 59%, and 18-month survival was 36%. Three patients have discontinued therapy without relapse for 48, 22, and seven months. One patient remains disease free after undergoing therapy for 84 weeks. There were no treatment-related deaths, and only 4% of patients experienced WBC count nadirs of less than 1,000/cu mm. Patients with limited disease had long-term survivals comparable with those of other more toxic protocols.

Polyamine biosynthetic decarboxylase activities following estradiol-17 beta or estriol stimulation of the immature rat uterus.

Following a single intraperitoneal injection of 0.5 microgram estradiol-17 beta (E2) into immature female rats uterine ornithine decarboxylase (ODC) activity increased to a peak at 4 hours postinjection. It decreased to intermediate levels by 6 hours and remained elevated until returning to control levels by 18 hours. When either 0.5 microgram estriol (E3) or 0.05 microgram E2 was injected, activity increased to a 4 hour ODC peak then decreased to control levels by 10 hours. The decrease to intermediate levels of ODC activity after dosing with 0.5 microgram E2 occurred at the same time activity decreased to control levels following treatment with either 0.05 microgram E2 or 0.5 micrograms E3. S-Adenosyl methionine decarboxylase (SAMDC) activity had increased by 4 hours following an injection of 0.5 microgram E2 and remained elevated until 16 hours then decreased to control levels. An injection of 0.05 microgram E3 stimulated only a 4 hour peak after which time SAMDC decreased to control levels by 14 hours. After an injection of 5.0 microgram E2 SAMDC activity had increased by 4 hours and remained elevated for the remainder of the experiment (16 hours). Decreases in ODC activity following 4 and 10 hours may reflect a decrease in nuclear estrogen receptor levels. The ODC activity seen here following 0.5 microgram E2 injection is similar in timing to that seen in other proliferating systems and may be due to a common mechanism.