Roy Hertz

Five years' experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women

Abstract In 63 women with metastatic trophoblastic disease, intensive chemotherapy with the folic acid antagonist amethopterin supplemented in some by vincaleukoblastine, an oncolytic plant alkaloid, has led to complete remission in 30 patients who have been free of hormonal, radiological, or physical evidence of residual disease for from 6 months to 5 years. Seven patients now in incomplete remission continue on treatment. In addition, of the 26 patients who have died, 22 had obtained substantial but incomplete remission. Such remissions were characterized by marked suppression of tumor, in many instances leaving a persistently elevated hormone titer as the only evidence of persistent disease. Such incomplete remissions have lasted from 1 month to more than 43 months. The hazards of toxicity attendant upon this intensive form of chemotherapy may be largely obviated by proper case selection, by less intensive therapy in patients with liver or renal impairment, and by adequate supportive medical and nursing care, thus rendering the risk involved clinically acceptable. The highly variable clinical course of choriocarcinoma and related trophoblastic disease, with its indeterminate frequency of spontaneous regression, renders an exact appraisal of therapeutic accomplishment very difficult. However, the present data clearly establish the substantial therapeutic value of intensive chemotherapy in women with metastatic tumors of trophoblastic origin.

Clinical and pathophysiologic aspects of adrenocortical carcinoma

Abstract Adrenal cortical carcinoma is a highly malignant cancer that is usually diagnosed late in its course. The presenting complaints may be those due to the mass or those resulting from the secretion of large amounts of physiologically active steroids. Some of the distinctive features of adrenal cortical carcinoma are its large size at the time of diagnosis, the generally large amounts of steroids excreted in the urine when the tumor is functional, the increased excretion of dehydroepiandrosterone (DHEA) when 17-ketosteroid (17-KS) excretion is high, and the increased excretion of tetrahydro substance S (THS) when 17-hydroxycorticosteroid (17-OHCS) excretion is increased. The rate of surgical cure is low. Following an attempt at resection of the carcinoma it is suggested that the excretion of steroids in the urine be examined at frequent intervals so that metastasis may be detected early and treatment initiated.

CHEMOTHERAPY OF ADRENOCORTICAL CANCER WITH o,p′DDD

Excerpt Our approach to the chemotherapy of adrenocortical carcinoma is based upon the original observations of Nelson and Woodard.1They observed that the oral administration to dogs of the insecti...

Therapy of Choriocarcinoma and Related Trophoblastic Tumors with Folic Acid and Purine Antagonists

TUMORS of trophoblastic origin may arise either in the uterus or in the gonads. They are characteristically highly malignant and spread rapidly both by direct extension and by metastasis to lungs a...

Choriocarcinoma of Women Maintained in Serial Passage in Hamster and Rat

Summary 1) Three choriocarcinomata from women have been successfully adapted to serial transplantation in cheek-pouch of the cortisonized hamster and one of these can be carried in previously untreated hamster. This latter strain has also been adapted to subcutaneous growth in the cortisonized, irradiated, hypophysectomized or intact female rat. 2) These heterologously maintained tumors produce in the host gonadotropic effects characteristic of human chorionic gonadotropic hormone. Biologically detectable amounts of hormone are readily demonstrable in homogenates of the growing tumor tissue and in peripheral blood of tumor-bearing hamster. The tumors exhibit no estrogenic, adrenotropic, or thyrotropic effect in the hamster. 3) Each tumor strain presents a quantitatively reproducible growth pattern which renders it adaptable to studies of the effect of chemotherapeutic and other inhibitory agents.

CHEMOTHERAPY OF CHORIOCARCINOMA AND RELATED TROPHOBLASTIC TUMORS IN WOMEN

Our initial experience in the treatment of choriocarcinoma and related trophoblastic tumors with the folic acid antagonist 4-amino-N10-methyl pteroylglutamic acid (methotrexate) has been reported previously.’, We shall now describe additional findings in 27 women whose therapeutic rcsponse to mcthotrexate has been observed over a period of two and onehalf years. Our rationalc in applying antifolic acid therapy in cases of malignant trophoblastic disease of women stems from earlier laboratory and clinical studies. The tissues of the female genital tract have a high requirement for folk acid that became apparent from experimental studies showing that., in the rat or monkey deficient in folic acid, the uterus is incapable of growth in response to administered e~trogens.~ Moreover, Nelson and Evans” demonstrated the high fetal requirement for folic acid in the rat. Indeed, Thiersch6 reported the induction of therapeutic abortion in women by the administration of aminopterin sodium, the folic acid antagonist. In addition, the clinical phenomenon of the macrocytic anemia of pregnancy, responding as it does to folic acid therapy, also appeared to reflect an especially high requirement for folic acid in the rapidly growing fetal and maternal tissues of pregnant women.6 Accordingly, we postulated that choriocarcinoma and related trophoblastic tumors that originated in the fetal chorion and initially involved the uterus might respond to treatment with folic acid antagonists.

CHEMOTHERAPY IN WOMEN WITH TROPHOBLASTIC DISEASE: CHORIOCARCINOMA, CHORIOADENOMA DESTRUENS, AND COMPLICATED HYDATIDIFORM MOLE

The initial report of Li, Hertz and Spencer’ outlined the rationale for and indicated the effectiveness of intensive intermittent therapy with the folic acid antagonist, methotrexate, in women with metastatic trophoblastic disease. The term “trophoblastic disease” is used to designate that spectrum of abnormalities of the chorion which includes hydatidiform mole, chorioadenoma destruens (or invasive mole) and choriocarcinoma. The term “metastatic trophoblastic disease” is applied when there is clinical, radiological o r hormonal evidence of disease outside the uterus. All of these lesions arise initially from an abnormal villus. They may therefore be considered to have a common pathogenetic pathway. In. fact, nearly half of the cases of choriocarcinoma are preceded by a hydatidiform mole. The vagaries of histological diagnosis in this group of tumors2 are well known. Although the histological findings provide a general statistical basis for anticipating the clinical outcome in a large series of cases, the ultimate clinical course in any individual case is not predictable. Moreover, these tumors manifest an inherent variability in biological behavior which may be determined by the graft-like quality of the fetal tumor tissue as it resides in the maternal host. Accordingly, our observations have led us to regard the clinical course of any patient with trophoblastic disease as the result of a precarious balance between factors of host resistance and tumor progression. At any point during this progress the host may rid herself of tumor or the tumor may extend in such a way as to lead to the patient’s death. That we are dealing with a continuous process is clearly evident from those instances in which the entire gamut of histological diagnoses from hydatid mole to metastatic choriocarcinoma may be seen in a single individual. Thus, of eight patients whose diagnosis during life was either hydatid mole or chorioadenoma destruens, seven were found to have extensive choriocarcinoma at autopsy. We therefore consider that we are dealing with a dynamic process, termed trophoblastic disease, rather than with a series of distinctly separable clinic entities. Nevertheless, we have systematically applied the criteria of Novak and SeahS in determining the histological classification of each case of trophoblastic disease. Accordingly, our therapeutic results are presented in relationship to the histopathological findings in each case on the basis of examination of all tissues available to us at the time of the patient’s admission. The data in the literature concerning the survivorship of patients with various forms of trophoblastic disease treated by classical surgical procedures are varied. This applies not only to the presumably less malignant forms of trophoblastic disease but even to metastatic choriocarcinoma. Thus Hreshchyshyn’ describes a mortality of 95 per cent or 40 of 42 cases with metastatic choriocarcinoma collected from the literature. Brewer et aL5 cite the five-year survival of 10 of 52 such cases or a mortality of 81 per cent and Dr. Manahan has reported a mortality of 89 per cent for similar cases of metastatic choriocarcinoma! The variability in these findings results not only from the vagaries of histological diagnosis, but also from the relative availability of such ancillary therapeutic factors as

ENDOCRINE ASPECTS OF TROPHOBLASTIC NEOPLASMS

The trophoblastic cells in both benign and malignant trophoblastic disease secrete a variety of steroid, polypeptide and hormonal agents. Those substances that are known to be elaborated by the neoplastic trophoblastic tissue include hCG, a substance with TSH-like activity, estrogens, progestogens and placental lactogen. The most well characterized of these is hCG, which can be assayed easily. The level of hCG plays an important role in the diagnosis, management and follow-up of patients with trophoblastic disease. Because of this, a sensitive assay that does not cross-react with LH would be ideal. It appears that some of the clinical signs and symptoms seen in these patients (including toxemia, theca lutein cyst, hyperthyroidism and thyrotoxicosis, and galactorrhea) are a direct manifestation or reflection of the level of hCG. There is very little information available at this time on the pathophysiologic role that hCG plays at the cellular level in causing these signs and symptoms. Many questions remain to be answered regarding the role of the other hormones in trophoblastic disease and how they affect the patient. Additionally, very little is known about the potential use of the other hormones in diagnosis, management and follow-up of patients with trophoblastic disease.

Surgical intervention during chemotherapy of gestational trophoblastic neoplasms

The role of surgical intervention during chemotherapy of women with gestational trophoblastic neoplasms has been analyzed in a series of 194 women treated with chemotherapy during the past 10 years. Of the 138 women with metastatic disease 27 (19.6%) required some type of major surgical procedure following the onset of chemotherapy whereas surgery was indicated in only 3 (5.4%) of the 56 women whose disease was limited to the uterus. The most common indications for surgery in patients with metastatic disease were control of hemorrhage, removal of the only apparent site of disease following partial response to chemotherapy, relief of urinary tract obstruction and treatment of infection. Surgical control of complications allowed some of these patients to survive so that they ultimately could be cured by chemotherapy. There was no evidence that surgery carried out during or just prior to a period of drug‐induced leukopenia or thrombocytopenia was associated with any impairment of wound healing or increased incidence of postoperative complications.

The problem of possible effects of oral contraceptives on cancer of the breast.

Available clinical and experimental findings of the potential effect of steroid contraceptives primarily estrogen with respect to breast cancer are appraised in light of the following facts: 1) prolonged latency (usually about 10 years) exists for all known human carcinogens; and 2) carcinogenic agents for man have been shown to also be carcinogenic in animals and frequently in the same site. Both endogenous and exogenous estrogen has been found to modify the activity of breast cancer in women. Epidemiologic findings related to prepubertal females age-specific prevalence rates parity and lactation are not directly enlightening but need further analysis. Past experience with estrogen use has been in predominantly older patients which cannot be equated with what should be anticipated in younger women. Data on effects of long-term estrogen therapy to younger women is limited and fails to provide an adequate epidemiologic basis for the promulgation of a new public health practice affecting millions of women. Studies of carcinogenesis in laboratory animals are discussed with the essential consideration of whether demonstrable carcinogenity in animals is pertinent to the clinical probelm. In view of the serious limitations in knowledge of potential long-term effects of estrogen-progestogen combinations it is mandatory that further clinical experience be gained under properly controlled conditions of observation and follow-up.