Two patients with advanced adenocarcinoma of the fallopian tube were treated with cis-diamminedichloroplatinum, adriamycin, and progestins. Cyclophosphamide was added to the treatment of 1 patient. Both regimens achieved surgically proved complete remission. No severe drug-related toxicity occurred.
Hormone replacement should provide a serum hormone profile similar to that found in normal physiology. This is generally impractical because hormones are usually released episodically and therefore require frequent administration. However, rather than replacing the hormone directly, in theory, one could administer a mimic or amplifier of the pulse generator that controls pulsatile release of the particular hormone. Using growth hormone (GH) as a paradigm we sought such a mimetic that would provide episodic GH release when administered by the oral route. A GH secretagogue MK0677, is described that has these ideal properties; following oral administration MK0677 amplifies episodic GH release. Mechanistically, it synergizes with growth hormone releasing hormone (GHRH) through a receptor and signal transduction pathway distinct from that of GHRH and is a functional antagonist of somatostatin (SRIF). MK0677 also acts on the arcuate nucleus and appears to stimulate GHRH release. By using 35S-MK0677, a new G-protein coupled receptor for MK0677 was characterized in the plasma membrane fraction of pituitary and hypothalamic tissue. The receptor is present in very low abundance and couples to phospholipase C. Other ligands selective for this receptor also cause synchronization of well-defined pathways leading to GH release. Repeated oral treatment of dogs once daily with MK0677 initiates amplified pulsatile GH release accompanied by increases in IGF-1 that are sustained. The unique biological properties of MK0677 and other synthetic ligands that bind to the same receptor force us to predict that these ligands mimic a naturally occurring hormone that regulates pulsatile GH release. Understanding the regulatory mechanisms involved in this paradigm has broad implications for the control of pulsatile rhythms in the endocrine system.
Six patients who took oral contraceptive agents for 5 to 18 years developed endometrial neoplasia. Endometrial adenocarcinoma occurred in 4 of these patients and severe adenomatous hyperplasia occured in 2. Five of the 6 patients took sequential agents; 1 patient used a combined agent. An additional patient who took Premarin and Provera sequentially developed adenocarcinoma of the endometrium. Eighteen cases of endometrial adenocarcinoma and 7 cases of adenomatous hyperplasia in patients with long-term sequential oral contraceptive use have previously been reported by others. Progestogens may not be completely protective against the endometrial cancer-causing potential of the estrogens, especially in the sequential regimens.
Endometrial carcinoma is now the most common gynecologic cancer in the United States and its incidence is increasing. Many investigators attribute this to exogenous factors over which little control has been exerted in the western world. Obesity, dietary fat content, and changing patterns of parity and lifestyle seem significant. Moreover, there appears to be an emerging virulence noted, particularly in some centers. Improved surgical staging and a better understanding of virulence factors will increase the number of patients requiring treatment to fields larger than heretofore recognized. We can expect that one third of the patients with endometrial cancer will require treatment for widespread disease or recurrent disease. Progestational treatment is useful in approximately one-third of all patients with recurrent disease. Thus, systemic nonhormonal chemotherapy must be developed if cure rates in this disease are to improve appreciably. In 1974, only 126 patients had been reported to have been treated with cytotoxic chemotherapy for endometrial cancer. Since that time, experience has demonstrated that the most active single agents are adriamycin, cisplatin, and hexamethylmelamine. These drugs produce a 30-40% response rate when used individually. Multidrug regimens employing various combinations have achieved responses of 15-85% with and without the inclusion of a progestational agent. The median duration of response has been increased but cures are still relatively few. Adverse effects are tolerable and age is not a contraindication to the administration of cytotoxic chemotherapy. Adjuvant treatment is being tested and optimism for future success is justified.
Twenty-four patients who had stage III or IV ovarian adenocarcinoma and had failed prior chemotherapy were treated with cyclophosphamide, adriamycin, and cis-dichlorodiammineplatinum(II) every 3 weeks. Twelve patients had objective responses and an additional six had subjective improvement. The median duration of survival for responders is 9 months. There were no instances of nephrotoxicity. Fluid management consisted of 1000-2000 ml of iv fluid without Lasix- or mannitol-induced diuresis. Patients responded after having failed radiotherapy or multiple-drug chemotherapy, including some who were 70-75 years of age or were greater than 50% bedridden. Patients with one- or two-drug prior chemotherapy had a higher response rate (ten responses among 17 patients) than those previously treated with three or more drugs (two responses among seven patients).
Combination chemotherapy can produce a rapid and frequent therapeutic effect against advanced endometrial adenocarcinoma regardless of the tumor distribution. A new treatment program is described. Melphalan, 5-fluorouracil, and medroxyprogesterone acetate achieved 6 of 7 objective responses in patients. This result with combination chemotherapy is substantially better than results with single agents or hormones alone and justifies further evaluation of combinations of cytotoxic chemotherapy as part of the initial treatment of choice for patients with advanced endometrial adenocarcinoma.
The fetoplacental allograft and the malignant neoplasm represent the only 2 biologic conditions in which antigenic tissue is tolerated by a seemingly intact immune system. Recent investigations in the fields of tumor and pregnancy immunology have resulted in the recognition of a variety of immunologic mechanisms which are common to both systems. These common denominators are reviewed and a thesis suggesting a common mechanism in the nonrejection of pregnancy and malignancy, based on the presence of embryonic antigens in both systems, is presented.
