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Past, present and future of gestational trophoblastic diseases
astir
Journal of Gynecobgy & Obstetrics 60 SuppI. No. 1 (1998) SlZl-S127
Past, present and future of gestational ~ophob~asti~ diseases J.L. Lewis Jr Gynecology Service Memorial Sloan-Kettering Cancer Center New York New York U.S.A.
When asked to give a relatively brief presentation on such a complex subject, my fast concern was how to divide it into segments which were meaningful in relation to the subject of this congress: Gestational TrophobIastic Disease (GTD), I propose that more useful time frames and subjects are GTD Prior to Effective Chemotherapy, Developments Following Demonstration of Effectiveness of Chemo~empy in GTD, and GTD in the Future. Rather than repeat many of the observations made by Professor Bag&awe in his opening address to the V&h World Congress on Gestational Trophoblastic Diseases [l]. I have chosen to describe the work carried out by Dr. Roy Hertz and his colleagues who worked in the Endocrinology Branch of the National Cancer Institute (NCI) of the National Institutes of Health (NIH) in Bethesda, Maryland. Although known to many because of its early use of Methotrexate in the latent of patients with me&static gestational trophoblastic diseases [2], this group of investigators studied many other malignancies and carried out many studies related to reproductive and developmen~l endocrinology. My interest and information for this presentation come from three personal contacts with the group. In 1959- 1961 I was a clinical associate on the service, during which time I did the chart research for the 1961 paper reporting the fmt 5 year survivors of ~20-7292/96/~.50 @ In~e~ati~aiFederation of Gynwology SSDl 0020-7292(96)02403-Y
metastatic GTD cured by chemotherapy [3]. Then in 1965~ 1%7 I returned to Bethesda and worked as a Senior Investigator in the Surgery Branch, NCI, and carried out laboratory research related to the GTD patients. Finally, in 1967 I was a member of the NC1 Choriocarcinoma Task Force [4]. 1. GTD prior to effective chemotherapy According to Smalbraak [S] the clinical entity of hy~ti~fo~ moIe was recognized by Hippocrates and was carefully described in the Sixth Century by Aetius of Amida, who was the first to use the term hydatide. However, it was not until 1903 that Marchand identified uterine choriocarcinoma as a chorionic malignancy rather than a uterine malignancy arising in the decidua
PI.
In the first hatf of this century several renowned pathologists described the histopathology of the categories of GTD: hydatidiform mole, invasive mole, and choriocarcinoma. Novak and Seah [6] described the characteristics of these three entities based on the presence of villi and invasion. Hertig and Manse11published their descriptions of these diseases and illustrated them in the Armed Forces Institute of Pa~olo~ Fascicle on “Tumors of the female sex organs” [7]. Hertig and Obstetrics
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J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. 1 (1998) S121-S127
and Sheldon [8] published a grading scheme for molar tissue which predicted the likelihood of malignant sequelae based on the degree of neoplastic change in the trophoblastic epithelium overlying the villi. Park and Lees [9] reported on a series of 516 patients with choriocarcinoma in 1950. Information concerning the clinical course and prognosis of patients with these categories of GTD was often obtained from publications by consulting pathologists who reported the outcome of patients whose histopathologic material had been sent to them for review and whose clinical information was obtained from the referring physician. Similar information came from some institutions whose obstetrical services were large enough that they could generate meaningful numhers from their own experience. In the United States the Albert Mathieu Chorionepithelioma Registry provided the most useful data. The Registry studied clinical histories, pathology material and x-rays on patients cared for in all parts of the country. By verifying the diagnosis and following the outcome of care, the Registry could generate survival data on patients with the various diagnoses according to the presence of metastases and the type of surgery they underwent. Brewer and colleagues [lo] reported that the cure rate by hysterectomy of choriocarcinoma limited to the uterus was 41%. The mortality rate of invasive mole was approximately 15%. Park and Lees [9] noted that the survival rate of women with me&static gestational choriocarcinoma was approximately 5%. All of these data were obtained before effective chemotherapy was used. One of the most useful studies carried out prior to the use of Methotrexate was reported by Dr. Eleanor Delfs at Johns Hopkins [ 111. She followed patients post-evacuation of molar pregnancies with serial determinations of serum hCG using a relatively insensitive bioassay. Surgery was carried out only if there was a clinical indication, usually severe bleeding. All tests were positive in the first week after evacuation. Of 119 patients studied, 26 (2 1.8%) still had measurable hCG 60 days after evacuation. Of these 26 patients 11 had clinical progression requiring surgery. Of the 11, 6 had invasive mole and 5
had choriocarcinoma. Only two died. This established the usefulness of following hCG production to detect tumor activity and the likelihood of tumor progression after evacuation of a molar pregnancy. 2. Developments following demonstration of effectiveness of chemotherapy in GTD Although isolated responses of GTD to nitrogen mustard had been reported at about the same time [l], the fitst significant series of patients with metastatic GTD who went into complete remission following chemotherapy with Methotrexate therapy began in 1955 when three patients received MTX, in Bethesda, Maryland [2] Because of the leadership role played by this group in the development of effective treatment of GTD in the United States and its contributions in other areas of oncologic and endocrinologic research this unit will be described in some detail. The Endocrinology Branch, NCI, was established as a clinical research unit at George Washington University Hospital by Dr. Roy Hertz in 1949. It was a clinical and laboratory research unit which focused on patients with cancers which produced hormones, those which were treated with hormones and those caused by hormones. Patients with a wide variety of cancers were studied: breast cancer, germ cell tumors of the ovary and testis, prostate cancer, endometrial cancer, adrenal carcinomas, pituitary tumors and gestational trophoblastic diseases. In addition to this work in cancer endocrinology, Dr. Hertz continued his work in reproductive endocrinology and vitamin/hormone interactions which had followed his Ph.D. studies in biology and physiology at the University of Wisconsin. He received his M.D. degree there in 1939, six years after receiving his Ph.D. One of Dr. Hertz’s achievements was the recruitment of a remarkable group of senior investigators who participated in the clinical and laboratory research projects of the Endocrinology Branch. This group included Drs. Min Chiu Li, Delbert Bergenstal, Mortimer Lipsett and Griff T.
J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. 1 (1998) S121-S127
Ross. Dr. Li was first author on the first two clinical papers [2,12] reporting the effectiveness of methotrexate in the treatment of patients with metastatic GTD. William W. Tullner, Ph.D. played an important role in all of the Branch’s research which utilized various bioassays. Finally, there was a series of clinical associates who spent two years assigned to the Endocrinology Branch, NCI, while serving as commissioned officers in the U.S. Public Health Service to satisfy their Uniformed Services Draft obligations. As noted before, the first patients with metastatic GTD to receive methotrexate were treated in 1955 [2]. However, many GTD patients had received at least one of more than a dozen agents there prior to this, including nitrogen mustards, without achieving a complete remission. The first three patients who received methotrexate went into complete remission as determined by physical examination, diagnostic x-ray and hCG assays. When these results were reported in 1956, they created great excitement and resulted in patients with metastatic GTD being referred to the NIH from all over the country. By 1961 a total of 63 patients with metastatic GTD had received methotrexate therapy and 13 of them had also received Vincaleucoblastin after their tumor had become resistant to Methotrexate. Several observations could be made at the time this experience was reported: [3]
(4)
(5)
(6)
(7) (1) Complete remissions were obtained in 48% of the patients. (2) Although MTX was first given as an IV bolus followed by 3 days of oral Methotrexate, this regimen soon was changed to intermittent 5 day courses of MTX given intramuscularly and repeated after recovery from acute toxicity. Irreversible toxicity was avoided by altering drug administration during a course if abnormalities of renal, hepatic or marrow function developed during the 5 days on which drug was given. Drug toxicity played at least some part in the death of 5 patients in the first 23 treated with methotrexate but in none after that. (3) hCG assays on 24 hour urine collections were critical to monitor response to therapy. A very
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slow (5 day), laborious, expensive bioassay was Llxd2) Its advantage was that it could measure levels of gonadotropin down to the range of normal pituitary production of FSH and LH. It did not discriminate between FSH, LH and hCG. Therapy was discontinued when three consecutive weekly assays were within the range of normal pituitary gonadotropin excretion. Of patients who entered remission by this defmition, 10% recurred, most within 8 weeks. Radiologic responseswere slower than hormonal responses: Therapy was not continued because of persistence of a radiologic image if it had decreased when the hCG levels were reaching “normal” (i.e., consistent with pituitary origin). At autopsy all patients had choriocarcinoma regardless of initial histologic diagnosis unless drug toxicity contributed to their death and they had persistent molar tissue. only three prognostic factors could be identified: duration of disease prior to chemotherapy; site of metastases; and prior oophorectomy. The prognostic significance of height of gonadotropin, prior chemotherapy and type of antecedent pregnancy were identified only later when the number of patients in the series was expanded. The importance of ovariectomy has not been subsequently confined. In discussing the unusual response of these tumors to chemotherapy the authors raised the question of histoincompatibility between the maternal host and fetal tissue. “In addition, the inherent capacity of the host to resist and in some cases to throw off this usually highly invasive type of tumor is considered by some to arise from a genetically determined incompatibility between the fetal tissue and the internal environment of the maternal host. In this light, chemotherapy may simply augment or facilitate this factor of resistance.” [3]
In the summer of 1960 two events occurred which had a major impact on the Endocrinology Branch’s work in GTD. The first was the return of Dr. M.C. Li to give a lecture on the treat-
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ment of metastatic germ cell tumors of the testis. In 1958 he left Bethesda and returned to Memorial Hospital for Cancer and Allied Diseases in New York where he had worked as a medical oncologist before joining Dr. Hertz’s group in 1955. Working with Drs. Whitmore, Grabstald and Golbey he had developed a treatment protocol consisting of methotrexate, Actinomycin D and an alkylating agent which resulted in complete remission in a large percentage of men with metastatic germ cell malignancies of the testis. [ 131 In addition to dispelling the theory that the reason for cure of GTD patients with chemotherapy was the synergism between cytotoxicity and immune rejection, it also suggested that Actinomycin D might be useful in GTD patients whose tumor had developed resistance to MTX. Dr. Hertz and his colleagues subsequently showed that responses of metastatic GTD to Actinomycin were equivalent to that obtained with MTX and that there was no cross-resistance.‘4’ The other significant event was the recruitment in 1960 of Griff T. Ross, M.D., Ph.D. to the senior staff. He brought his expertise in clinical endocrinology and developed a particular interest in the correlation of structure and function of hCG and its sub-units as well as gaining expertise in the study and treatment of patients with GTD. Between 1960 and 1966 several changes took place in regards to patients with GTD treated in Bethesda: (1) Patients whose disease was limited to the uterus were treated initially with chemotherapy and underwent surgery only if chemotherapy failed. This change took place after a patient was referred in 1959 with non-metastatic choriocarcinoma following a term delivery and the decision was made that she should have a hysterectomy rather than chemotherapy. She developed pulmonary metastaseswithin 3 months and was cured with Methotrexate. At that time the decision was made to treat similar patients who were referred with initial chemotherapy and to use surgery only for persistent disease. (2) Actinomycin D was fust shown to be effec-
tive in patients with MTX-resistant tumors and then was demonstrated to be equally effective as MTX as initial therapy [ 141. They did not, however, use combination chemotherapy even though Bagshawe, [15] Li [ 131 and others were proving its efficacy. It is logical that this was due to their background as clinical endocrinology investigators and thus oriented towards studying single agents rather than medical oncologists who were developing multi-agent chemotherapy combinations. (3) The NIH Clinical Classification of patients with metastatic GTD was modified to include initial height of hCG and prior chemotherapy as “poor prognosis” factors.
WI (4) In 1966 the members of the Endocrinology Branch transferred from the National Cancer Institute to the National Institute of Child Health and Human Development (NICHHD). The exception was Mortimer Lipsett, M.D. who became Chief of the Endocrinology Branch, NCI, and subsequently became Director of the Clinical Center of the NIH. Dr. Hertz became Scientific Director and Dr. Ross became Clinical Director of the NICHHDD. Although this shift meant the end of recruiting new GTD patients to the NIH, Griff Ross’s work with hCG continued. He developed close collaboration with Dr. Robert E. Canfield whose laboratory at the NIH and later at the Columbia-Presbyterian Medical Center in New York isolated and defined the structure of hCG and its alpha and beta sub-units. [17] This allowed Dr. Judy Vaitukaitis, working under Griff Ross’s tutelage, to develop the radioimmunoassay of the beta sub-unit of hCG which measured this sub-unit of hCG in the presence of pituitary LH [ 181 She also demonstrated its potential as a “tumor marker” in several solid tumors of non-gestational origin. [19] In 1977 Ross published a summary of the clinical relevance of various portions of the hCG molecule. [20] (5) In 1966 Dr. Hertz and Dr. Kenneth Endicott, Director of the National Cancer Institute
J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. I (1998) S121-S127
planned a Choriocarcinoma Task Force [4] which was to continue the NCI’s GTD activities by decentralizing the work in 8 regional centers. Although in a new institute, Drs. Hertz and Ross would coordinate the overall program. The work was to be done in two main areas: a) establish laboratories to carry out hCG assays for surveillance after molar pregnancies and the monitoring of therapy of patients with GTD, and; b) clinical and laboratory research directed to understanding the disease and improving the cure rate. In addition to Drs. Hertz and Ross, the Task force members were Dr. John I Brewer, Chicago; Dr. Donald P. Goldstein, Boston; Dr. Charles B. Hammond, Durham; Dr. John L. Lewis, Jr., New York; Dr. William Odell, San Diego; Dr. Alvin Paulsen, Seattle; and Dr. Julian Smith, Houston. Their diverse backgrounds are of interest. Drs. Goldstein, Hammond, and I were in Obstetrics and Gynecology and had worked in Dr. Hertz’s group as Clinical Associates. Drs. Ode11 and Paulsen were medical endocrinologists and Ode11 had spent two years as a member of the senior staff of the Endocrinology Branch. Dr. Brewer was chairman of the Department of Obstetrics and Gynecology at Northwestern and Director of the Albert Mathieu Chorionepithelioma Registry and Dr. Smith was a gynecologic oncologist on the staff at the M.D. Anderson Hospital. The group developed clinical and laboratory research protocols and developed hCG assay labs. The funding was originally to have come from the Office of the Director, NCI, as a demonstration project to show the progress being made in the control of cancer. When Dr. Endicott resigned to become Director of Memorial Hospital in New York, the grant was divided into two parts: one went to a study section involved in cancer screening (hCG assays) and the other to a chemotherapy study section. Only the hCG assay portion was funded. Thus came to an end the active clinical involvement of Dr. Hertz and the remarkable staff of the Endocrinology Branch, NCI, with GTD patients. It is hard to believe that the interval of
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time during which GTD patients received effective chemotherapy at the NC1 was only 11 years, for its influence on the organization of care and research related to GTD in the United States has been enormous. This unit has, however, made equally significant contributions to other areas of endocrinology related both to oncology and to normal development and physiology. This is best represented by the citation which accompanied the Fred Conrad Koch Award which Dr. Hertz received in 1996. [21] This is the highest award given by the Endocrine Society. The citation listed six areas of scientific work in which Dr. Hertz had made major contributions. His work with GTD was only one of them. Similarly, the list of academic investigators he had tutored was dominated by reproductive endocrinologists rather than individuals working in the field of GTD. I am pleased to report that Dr. Hertz is still active as a consultant to the NICHHD. It would be inappropriate to discuss this clinical and laboratory research unit in such detail without also acknowledging the importance of the contributions of Professor Kenneth Bagshawe and his colleagues at Charing Cross Hospital in London. For four decades this most innovative and instructive unit has not only led the way in treatment but also generated basic research fmdings that have helped us to understand the biology of gestational trophoblastic diseases. Just a few of their many original contributions are: (1) First report of the use of combination chemotherapy as initial therapy of GTD, methotrexate and 6 Mercaptopurine. [ 151 (2) Establishment of a national network for hCG testing and clinical follow-up of patients following evacuation of a molar pregnancy, thus defining the rate of patients needing chemotherapy and also essentially preventing death of patients after molar pregnancy. [22] (3) Development of multiple combinations of chemotherapeutic agents based on their various modes of action and toxicity. [23] (4) Evaluation of the unit’s extensive clinical experience in a manner that allowed the assignment of relative value scores for prognostic factors in GTD patients. [24]
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J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. 1 (1998) S121-S127
(5) Demonstration of the effectiveness of a scheme for treating patients in the various risk categories with chemotherapy that produces the least toxicity without decreasing it’s therapeutic effectiveness. [25] (6) Collaboration with several basic scientists on critical scientific studies directed towards answering questions related to the etiology and biology of trophoblastic tumors. [23] Most important of these scientific collaborations was his work with his wife, the immunobiologist, Sylvia Lawler. They worked together in a series of research projects designed to explore the role of immunologic factors in the etiology, clinical course and response to therapy of various forms of GTD. [26] Many other investigators brought about developments which deserve more attention than can be given here: identification of the two forms of hydatidiform moles; recognition of a new form of GTD, placental site trophoblastic tumors; utilization of new chemotherapeutic agents; re-evaluation of the clinical importance of surgery in some patients; and the demonstration of the importance of specialized treatment centers. 3. GTD in the future The dramatic scientific advances being reported in all fields of biology and medicine almost certainly will lead to new breakthroughs in our knowledge of GTD. The questions are easier to ask than the predictions of the answers. What is the “carcinogenic activity” that can transform normal-appearing trophoblastic tissue to a malignancy even in the first few weeks after the tissue is formed ? If the trophoblastic cords of an implanting blastocyst prior to vascularization (as Hertig says) look exactly like choriocarcinema, what causes this tissue to mature and stop invading ? What is the mechanism that explains why malignant trophoblastic tissue that makes little or no hCG (such as placental site trophoblastic tumor or some drug-resistant tumors) is not responsive to cytotoxic chemotherapy ? Is there a substance that can be identified in appar-
ently normal placentas or aborted trophoblastic tissue which ultimately develop choriocarcinoma that is not present in similar tissues that do not undergo this malignant change ? If such a substance could be found and detected easily in urine or blood, such a substance would give the promise of our being able to carry out surveillance for choriocarcinoma after a term or aborted pregnancy just as hCG tests have proved useful after molar pregnancies. The scientific presentations at this VIII World congress on Gestational Trophoblastic Diseases are representative of the many scientific techniques which are available to study GTD. I am encouraged by the volwne and quality of the basic research being reported, for its critical mass makes it more likely that significant breakthroughs will be achieved. References [l] Bagshawe KD. Review article. 40 Years of Trophoblastic Turnouts. Trophoblastic Disease Update 1996; 1: 3-5. [2] Li MC, Hertz R, Spencer DB. Effects of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Sac Exp Biol Med 1956; 93: 361- 6. [3] Hertz R, Lewis JL Jr, Lipsett MB. Five years’ experience with the chemotherapy of metastatic choriocarcinema and related trophoblastic tumors in women. Am J Obst Gynec 1961; 82: 631-40. [4] Lewis JL. Choriocarcinoma Task Force: Transactions of the Annual Meeting of the Society of Alumni of the Sloane Hospital for Women. Bull Sloane Hasp Women 1969; 15: 75-7. [5] Smalbraak J. Trophoblastic Growths. Amsterdam : Elsevier. 1957; 3-8. [6] Novak E, Seah CS. Am J Obst Gynec 1954; 67: 933 - 963. [7] Hertig AT, Manse11 H. “Tumors of the female sex organs.” Part I Hydatidiform mole and choriocarcinema. Sect. 9, fascicle 33. Atlas of tumor pathology. Armed Forces Institute of Pathology, Washington 1956. [8] Hertig AT. Sheldon WH. Hydatidifonn mole-a pathological-clinical correlation of 200 cases. Am J Obst Gynec 1947; 53: l-36. [9] Park WW, Lees JC. Choriocarcinoma. A general review, with analysis of 516 cases. Arch Path (Chicago) 1950; 49: 73-104 and 204-241. [lo] Brewer JI, Smith RT, Pratt GB. Choriocarcinoma: absolute survival rates of 122 patients treated by
J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. I (1998) S121S127 hysterectomy. Am J Obst Gynec 1963; 85: 841- 3. [l 1] Delfs E. Chorionic gonadotropin determination in patients with hydatidiform mole and choriocarcinoma. Ann N Y Acad Sci 1957; 80: 125-39. [12] Li MC, Hertz R, Bergenstal DM. Therapy of Choriocarcinoma and related trophoblastic tumors with folic Acid and purine antagonists. New Engl J Med 1958; 66: 259. [13] Li MC, Whitmore WF, Golbey R et al. Effects of combined drug therapy on metastatic cancer of the testis. JAMA 1960, 174: 1291-9. [ 141 Ross GT, Goldstein DP, Hertz R et al. Sequential use of Methotrexate and Actinomycin D. in the treatment of me&static choriocarcinoma and related trophoblastic diseases in women. Am J Obst Gynec 1965; 93: 223 - 229. [15] Bagshawe KD. Treatment of choriocarcinoma with a combination of cytotoxic drugs. Brit Med J 1960 II; 426-431. [16] Hammond CB, Borchert LG, Tyrey L et al. Treatment of metastatic trophoblastic disease : good and poor prognosis. Am J Obst Gynec 1973; 115: 451-7. [17] Morgan FJ, Canfield RC. Nature of the sub-units of human chorionic gonadotropin. Endocrinology 1971; 88: 1045-53. [18] Vaitukaitis JL, Braunstein GD, Ross GT. A radioimmu-
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nossay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obst Gynec 1972; 113: 751-8. [19] Vaitukaitis JL. Human chorionic gonadotropin as a tumor marker. Ann Clin Lab Science 1974; 4: 276-80. [20] Ross CT. Clinical relevance of research on the structure of human chorionic gonadotropin. Am J Obst Gynec 1977; 129: 795-805. [21] The Endocrine Society 1996 Annual Awards. Endocrinology 1996; 137: 3608- 3609. [22] Bagshawe KD, Wilson H, Dublon P et al. Follow-up after hydatidifotm mole: studies using radioimmunoassays for urinary human chorionic gonadotropin (hCG). Br J Obst Gynec 1973; 80: 461-8. [23] Bagshawe KD. Choriocarcinoma. The clinical biology of the trophoblast and its tumours. 1969. Edward Arnold (Publishers) Ltd. London. [24] Bagshawe KD. Risk and prognostic factors in trophoblastic neoplasia. Cancer 1976; 38: 1373-85. [2.5] World Health Organization Scientific Group on Gestational Trophoblastic Diseases Technical Report Series: no. 692. Geneva: the World Health Organization, 1983. [26] Lawler SD. HL-A and trophoblastic tumours. Br Med Bull 1978: 34: 305-308.
Journal of Gynecobgy & Obstetrics 60 SuppI. No. 1 (1998) SlZl-S127
Past, present and future of gestational ~ophob~asti~ diseases J.L. Lewis Jr Gynecology Service Memorial Sloan-Kettering Cancer Center New York New York U.S.A.
When asked to give a relatively brief presentation on such a complex subject, my fast concern was how to divide it into segments which were meaningful in relation to the subject of this congress: Gestational TrophobIastic Disease (GTD), I propose that more useful time frames and subjects are GTD Prior to Effective Chemotherapy, Developments Following Demonstration of Effectiveness of Chemo~empy in GTD, and GTD in the Future. Rather than repeat many of the observations made by Professor Bag&awe in his opening address to the V&h World Congress on Gestational Trophoblastic Diseases [l]. I have chosen to describe the work carried out by Dr. Roy Hertz and his colleagues who worked in the Endocrinology Branch of the National Cancer Institute (NCI) of the National Institutes of Health (NIH) in Bethesda, Maryland. Although known to many because of its early use of Methotrexate in the latent of patients with me&static gestational trophoblastic diseases [2], this group of investigators studied many other malignancies and carried out many studies related to reproductive and developmen~l endocrinology. My interest and information for this presentation come from three personal contacts with the group. In 1959- 1961 I was a clinical associate on the service, during which time I did the chart research for the 1961 paper reporting the fmt 5 year survivors of ~20-7292/96/~.50 @ In~e~ati~aiFederation of Gynwology SSDl 0020-7292(96)02403-Y
metastatic GTD cured by chemotherapy [3]. Then in 1965~ 1%7 I returned to Bethesda and worked as a Senior Investigator in the Surgery Branch, NCI, and carried out laboratory research related to the GTD patients. Finally, in 1967 I was a member of the NC1 Choriocarcinoma Task Force [4]. 1. GTD prior to effective chemotherapy According to Smalbraak [S] the clinical entity of hy~ti~fo~ moIe was recognized by Hippocrates and was carefully described in the Sixth Century by Aetius of Amida, who was the first to use the term hydatide. However, it was not until 1903 that Marchand identified uterine choriocarcinoma as a chorionic malignancy rather than a uterine malignancy arising in the decidua
PI.
In the first hatf of this century several renowned pathologists described the histopathology of the categories of GTD: hydatidiform mole, invasive mole, and choriocarcinoma. Novak and Seah [6] described the characteristics of these three entities based on the presence of villi and invasion. Hertig and Manse11published their descriptions of these diseases and illustrated them in the Armed Forces Institute of Pa~olo~ Fascicle on “Tumors of the female sex organs” [7]. Hertig and Obstetrics
s122
J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. 1 (1998) S121-S127
and Sheldon [8] published a grading scheme for molar tissue which predicted the likelihood of malignant sequelae based on the degree of neoplastic change in the trophoblastic epithelium overlying the villi. Park and Lees [9] reported on a series of 516 patients with choriocarcinoma in 1950. Information concerning the clinical course and prognosis of patients with these categories of GTD was often obtained from publications by consulting pathologists who reported the outcome of patients whose histopathologic material had been sent to them for review and whose clinical information was obtained from the referring physician. Similar information came from some institutions whose obstetrical services were large enough that they could generate meaningful numhers from their own experience. In the United States the Albert Mathieu Chorionepithelioma Registry provided the most useful data. The Registry studied clinical histories, pathology material and x-rays on patients cared for in all parts of the country. By verifying the diagnosis and following the outcome of care, the Registry could generate survival data on patients with the various diagnoses according to the presence of metastases and the type of surgery they underwent. Brewer and colleagues [lo] reported that the cure rate by hysterectomy of choriocarcinoma limited to the uterus was 41%. The mortality rate of invasive mole was approximately 15%. Park and Lees [9] noted that the survival rate of women with me&static gestational choriocarcinoma was approximately 5%. All of these data were obtained before effective chemotherapy was used. One of the most useful studies carried out prior to the use of Methotrexate was reported by Dr. Eleanor Delfs at Johns Hopkins [ 111. She followed patients post-evacuation of molar pregnancies with serial determinations of serum hCG using a relatively insensitive bioassay. Surgery was carried out only if there was a clinical indication, usually severe bleeding. All tests were positive in the first week after evacuation. Of 119 patients studied, 26 (2 1.8%) still had measurable hCG 60 days after evacuation. Of these 26 patients 11 had clinical progression requiring surgery. Of the 11, 6 had invasive mole and 5
had choriocarcinoma. Only two died. This established the usefulness of following hCG production to detect tumor activity and the likelihood of tumor progression after evacuation of a molar pregnancy. 2. Developments following demonstration of effectiveness of chemotherapy in GTD Although isolated responses of GTD to nitrogen mustard had been reported at about the same time [l], the fitst significant series of patients with metastatic GTD who went into complete remission following chemotherapy with Methotrexate therapy began in 1955 when three patients received MTX, in Bethesda, Maryland [2] Because of the leadership role played by this group in the development of effective treatment of GTD in the United States and its contributions in other areas of oncologic and endocrinologic research this unit will be described in some detail. The Endocrinology Branch, NCI, was established as a clinical research unit at George Washington University Hospital by Dr. Roy Hertz in 1949. It was a clinical and laboratory research unit which focused on patients with cancers which produced hormones, those which were treated with hormones and those caused by hormones. Patients with a wide variety of cancers were studied: breast cancer, germ cell tumors of the ovary and testis, prostate cancer, endometrial cancer, adrenal carcinomas, pituitary tumors and gestational trophoblastic diseases. In addition to this work in cancer endocrinology, Dr. Hertz continued his work in reproductive endocrinology and vitamin/hormone interactions which had followed his Ph.D. studies in biology and physiology at the University of Wisconsin. He received his M.D. degree there in 1939, six years after receiving his Ph.D. One of Dr. Hertz’s achievements was the recruitment of a remarkable group of senior investigators who participated in the clinical and laboratory research projects of the Endocrinology Branch. This group included Drs. Min Chiu Li, Delbert Bergenstal, Mortimer Lipsett and Griff T.
J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. 1 (1998) S121-S127
Ross. Dr. Li was first author on the first two clinical papers [2,12] reporting the effectiveness of methotrexate in the treatment of patients with metastatic GTD. William W. Tullner, Ph.D. played an important role in all of the Branch’s research which utilized various bioassays. Finally, there was a series of clinical associates who spent two years assigned to the Endocrinology Branch, NCI, while serving as commissioned officers in the U.S. Public Health Service to satisfy their Uniformed Services Draft obligations. As noted before, the first patients with metastatic GTD to receive methotrexate were treated in 1955 [2]. However, many GTD patients had received at least one of more than a dozen agents there prior to this, including nitrogen mustards, without achieving a complete remission. The first three patients who received methotrexate went into complete remission as determined by physical examination, diagnostic x-ray and hCG assays. When these results were reported in 1956, they created great excitement and resulted in patients with metastatic GTD being referred to the NIH from all over the country. By 1961 a total of 63 patients with metastatic GTD had received methotrexate therapy and 13 of them had also received Vincaleucoblastin after their tumor had become resistant to Methotrexate. Several observations could be made at the time this experience was reported: [3]
(4)
(5)
(6)
(7) (1) Complete remissions were obtained in 48% of the patients. (2) Although MTX was first given as an IV bolus followed by 3 days of oral Methotrexate, this regimen soon was changed to intermittent 5 day courses of MTX given intramuscularly and repeated after recovery from acute toxicity. Irreversible toxicity was avoided by altering drug administration during a course if abnormalities of renal, hepatic or marrow function developed during the 5 days on which drug was given. Drug toxicity played at least some part in the death of 5 patients in the first 23 treated with methotrexate but in none after that. (3) hCG assays on 24 hour urine collections were critical to monitor response to therapy. A very
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slow (5 day), laborious, expensive bioassay was Llxd2) Its advantage was that it could measure levels of gonadotropin down to the range of normal pituitary production of FSH and LH. It did not discriminate between FSH, LH and hCG. Therapy was discontinued when three consecutive weekly assays were within the range of normal pituitary gonadotropin excretion. Of patients who entered remission by this defmition, 10% recurred, most within 8 weeks. Radiologic responseswere slower than hormonal responses: Therapy was not continued because of persistence of a radiologic image if it had decreased when the hCG levels were reaching “normal” (i.e., consistent with pituitary origin). At autopsy all patients had choriocarcinoma regardless of initial histologic diagnosis unless drug toxicity contributed to their death and they had persistent molar tissue. only three prognostic factors could be identified: duration of disease prior to chemotherapy; site of metastases; and prior oophorectomy. The prognostic significance of height of gonadotropin, prior chemotherapy and type of antecedent pregnancy were identified only later when the number of patients in the series was expanded. The importance of ovariectomy has not been subsequently confined. In discussing the unusual response of these tumors to chemotherapy the authors raised the question of histoincompatibility between the maternal host and fetal tissue. “In addition, the inherent capacity of the host to resist and in some cases to throw off this usually highly invasive type of tumor is considered by some to arise from a genetically determined incompatibility between the fetal tissue and the internal environment of the maternal host. In this light, chemotherapy may simply augment or facilitate this factor of resistance.” [3]
In the summer of 1960 two events occurred which had a major impact on the Endocrinology Branch’s work in GTD. The first was the return of Dr. M.C. Li to give a lecture on the treat-
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ment of metastatic germ cell tumors of the testis. In 1958 he left Bethesda and returned to Memorial Hospital for Cancer and Allied Diseases in New York where he had worked as a medical oncologist before joining Dr. Hertz’s group in 1955. Working with Drs. Whitmore, Grabstald and Golbey he had developed a treatment protocol consisting of methotrexate, Actinomycin D and an alkylating agent which resulted in complete remission in a large percentage of men with metastatic germ cell malignancies of the testis. [ 131 In addition to dispelling the theory that the reason for cure of GTD patients with chemotherapy was the synergism between cytotoxicity and immune rejection, it also suggested that Actinomycin D might be useful in GTD patients whose tumor had developed resistance to MTX. Dr. Hertz and his colleagues subsequently showed that responses of metastatic GTD to Actinomycin were equivalent to that obtained with MTX and that there was no cross-resistance.‘4’ The other significant event was the recruitment in 1960 of Griff T. Ross, M.D., Ph.D. to the senior staff. He brought his expertise in clinical endocrinology and developed a particular interest in the correlation of structure and function of hCG and its sub-units as well as gaining expertise in the study and treatment of patients with GTD. Between 1960 and 1966 several changes took place in regards to patients with GTD treated in Bethesda: (1) Patients whose disease was limited to the uterus were treated initially with chemotherapy and underwent surgery only if chemotherapy failed. This change took place after a patient was referred in 1959 with non-metastatic choriocarcinoma following a term delivery and the decision was made that she should have a hysterectomy rather than chemotherapy. She developed pulmonary metastaseswithin 3 months and was cured with Methotrexate. At that time the decision was made to treat similar patients who were referred with initial chemotherapy and to use surgery only for persistent disease. (2) Actinomycin D was fust shown to be effec-
tive in patients with MTX-resistant tumors and then was demonstrated to be equally effective as MTX as initial therapy [ 141. They did not, however, use combination chemotherapy even though Bagshawe, [15] Li [ 131 and others were proving its efficacy. It is logical that this was due to their background as clinical endocrinology investigators and thus oriented towards studying single agents rather than medical oncologists who were developing multi-agent chemotherapy combinations. (3) The NIH Clinical Classification of patients with metastatic GTD was modified to include initial height of hCG and prior chemotherapy as “poor prognosis” factors.
WI (4) In 1966 the members of the Endocrinology Branch transferred from the National Cancer Institute to the National Institute of Child Health and Human Development (NICHHD). The exception was Mortimer Lipsett, M.D. who became Chief of the Endocrinology Branch, NCI, and subsequently became Director of the Clinical Center of the NIH. Dr. Hertz became Scientific Director and Dr. Ross became Clinical Director of the NICHHDD. Although this shift meant the end of recruiting new GTD patients to the NIH, Griff Ross’s work with hCG continued. He developed close collaboration with Dr. Robert E. Canfield whose laboratory at the NIH and later at the Columbia-Presbyterian Medical Center in New York isolated and defined the structure of hCG and its alpha and beta sub-units. [17] This allowed Dr. Judy Vaitukaitis, working under Griff Ross’s tutelage, to develop the radioimmunoassay of the beta sub-unit of hCG which measured this sub-unit of hCG in the presence of pituitary LH [ 181 She also demonstrated its potential as a “tumor marker” in several solid tumors of non-gestational origin. [19] In 1977 Ross published a summary of the clinical relevance of various portions of the hCG molecule. [20] (5) In 1966 Dr. Hertz and Dr. Kenneth Endicott, Director of the National Cancer Institute
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planned a Choriocarcinoma Task Force [4] which was to continue the NCI’s GTD activities by decentralizing the work in 8 regional centers. Although in a new institute, Drs. Hertz and Ross would coordinate the overall program. The work was to be done in two main areas: a) establish laboratories to carry out hCG assays for surveillance after molar pregnancies and the monitoring of therapy of patients with GTD, and; b) clinical and laboratory research directed to understanding the disease and improving the cure rate. In addition to Drs. Hertz and Ross, the Task force members were Dr. John I Brewer, Chicago; Dr. Donald P. Goldstein, Boston; Dr. Charles B. Hammond, Durham; Dr. John L. Lewis, Jr., New York; Dr. William Odell, San Diego; Dr. Alvin Paulsen, Seattle; and Dr. Julian Smith, Houston. Their diverse backgrounds are of interest. Drs. Goldstein, Hammond, and I were in Obstetrics and Gynecology and had worked in Dr. Hertz’s group as Clinical Associates. Drs. Ode11 and Paulsen were medical endocrinologists and Ode11 had spent two years as a member of the senior staff of the Endocrinology Branch. Dr. Brewer was chairman of the Department of Obstetrics and Gynecology at Northwestern and Director of the Albert Mathieu Chorionepithelioma Registry and Dr. Smith was a gynecologic oncologist on the staff at the M.D. Anderson Hospital. The group developed clinical and laboratory research protocols and developed hCG assay labs. The funding was originally to have come from the Office of the Director, NCI, as a demonstration project to show the progress being made in the control of cancer. When Dr. Endicott resigned to become Director of Memorial Hospital in New York, the grant was divided into two parts: one went to a study section involved in cancer screening (hCG assays) and the other to a chemotherapy study section. Only the hCG assay portion was funded. Thus came to an end the active clinical involvement of Dr. Hertz and the remarkable staff of the Endocrinology Branch, NCI, with GTD patients. It is hard to believe that the interval of
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time during which GTD patients received effective chemotherapy at the NC1 was only 11 years, for its influence on the organization of care and research related to GTD in the United States has been enormous. This unit has, however, made equally significant contributions to other areas of endocrinology related both to oncology and to normal development and physiology. This is best represented by the citation which accompanied the Fred Conrad Koch Award which Dr. Hertz received in 1996. [21] This is the highest award given by the Endocrine Society. The citation listed six areas of scientific work in which Dr. Hertz had made major contributions. His work with GTD was only one of them. Similarly, the list of academic investigators he had tutored was dominated by reproductive endocrinologists rather than individuals working in the field of GTD. I am pleased to report that Dr. Hertz is still active as a consultant to the NICHHD. It would be inappropriate to discuss this clinical and laboratory research unit in such detail without also acknowledging the importance of the contributions of Professor Kenneth Bagshawe and his colleagues at Charing Cross Hospital in London. For four decades this most innovative and instructive unit has not only led the way in treatment but also generated basic research fmdings that have helped us to understand the biology of gestational trophoblastic diseases. Just a few of their many original contributions are: (1) First report of the use of combination chemotherapy as initial therapy of GTD, methotrexate and 6 Mercaptopurine. [ 151 (2) Establishment of a national network for hCG testing and clinical follow-up of patients following evacuation of a molar pregnancy, thus defining the rate of patients needing chemotherapy and also essentially preventing death of patients after molar pregnancy. [22] (3) Development of multiple combinations of chemotherapeutic agents based on their various modes of action and toxicity. [23] (4) Evaluation of the unit’s extensive clinical experience in a manner that allowed the assignment of relative value scores for prognostic factors in GTD patients. [24]
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(5) Demonstration of the effectiveness of a scheme for treating patients in the various risk categories with chemotherapy that produces the least toxicity without decreasing it’s therapeutic effectiveness. [25] (6) Collaboration with several basic scientists on critical scientific studies directed towards answering questions related to the etiology and biology of trophoblastic tumors. [23] Most important of these scientific collaborations was his work with his wife, the immunobiologist, Sylvia Lawler. They worked together in a series of research projects designed to explore the role of immunologic factors in the etiology, clinical course and response to therapy of various forms of GTD. [26] Many other investigators brought about developments which deserve more attention than can be given here: identification of the two forms of hydatidiform moles; recognition of a new form of GTD, placental site trophoblastic tumors; utilization of new chemotherapeutic agents; re-evaluation of the clinical importance of surgery in some patients; and the demonstration of the importance of specialized treatment centers. 3. GTD in the future The dramatic scientific advances being reported in all fields of biology and medicine almost certainly will lead to new breakthroughs in our knowledge of GTD. The questions are easier to ask than the predictions of the answers. What is the “carcinogenic activity” that can transform normal-appearing trophoblastic tissue to a malignancy even in the first few weeks after the tissue is formed ? If the trophoblastic cords of an implanting blastocyst prior to vascularization (as Hertig says) look exactly like choriocarcinema, what causes this tissue to mature and stop invading ? What is the mechanism that explains why malignant trophoblastic tissue that makes little or no hCG (such as placental site trophoblastic tumor or some drug-resistant tumors) is not responsive to cytotoxic chemotherapy ? Is there a substance that can be identified in appar-
ently normal placentas or aborted trophoblastic tissue which ultimately develop choriocarcinoma that is not present in similar tissues that do not undergo this malignant change ? If such a substance could be found and detected easily in urine or blood, such a substance would give the promise of our being able to carry out surveillance for choriocarcinoma after a term or aborted pregnancy just as hCG tests have proved useful after molar pregnancies. The scientific presentations at this VIII World congress on Gestational Trophoblastic Diseases are representative of the many scientific techniques which are available to study GTD. I am encouraged by the volwne and quality of the basic research being reported, for its critical mass makes it more likely that significant breakthroughs will be achieved. References [l] Bagshawe KD. Review article. 40 Years of Trophoblastic Turnouts. Trophoblastic Disease Update 1996; 1: 3-5. [2] Li MC, Hertz R, Spencer DB. Effects of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Sac Exp Biol Med 1956; 93: 361- 6. [3] Hertz R, Lewis JL Jr, Lipsett MB. Five years’ experience with the chemotherapy of metastatic choriocarcinema and related trophoblastic tumors in women. Am J Obst Gynec 1961; 82: 631-40. [4] Lewis JL. Choriocarcinoma Task Force: Transactions of the Annual Meeting of the Society of Alumni of the Sloane Hospital for Women. Bull Sloane Hasp Women 1969; 15: 75-7. [5] Smalbraak J. Trophoblastic Growths. Amsterdam : Elsevier. 1957; 3-8. [6] Novak E, Seah CS. Am J Obst Gynec 1954; 67: 933 - 963. [7] Hertig AT, Manse11 H. “Tumors of the female sex organs.” Part I Hydatidiform mole and choriocarcinema. Sect. 9, fascicle 33. Atlas of tumor pathology. Armed Forces Institute of Pathology, Washington 1956. [8] Hertig AT. Sheldon WH. Hydatidifonn mole-a pathological-clinical correlation of 200 cases. Am J Obst Gynec 1947; 53: l-36. [9] Park WW, Lees JC. Choriocarcinoma. A general review, with analysis of 516 cases. Arch Path (Chicago) 1950; 49: 73-104 and 204-241. [lo] Brewer JI, Smith RT, Pratt GB. Choriocarcinoma: absolute survival rates of 122 patients treated by
J.L. Lewis Jr / International Journal of Gynecology & Obstetrics 60 Suppl. No. I (1998) S121S127 hysterectomy. Am J Obst Gynec 1963; 85: 841- 3. [l 1] Delfs E. Chorionic gonadotropin determination in patients with hydatidiform mole and choriocarcinoma. Ann N Y Acad Sci 1957; 80: 125-39. [12] Li MC, Hertz R, Bergenstal DM. Therapy of Choriocarcinoma and related trophoblastic tumors with folic Acid and purine antagonists. New Engl J Med 1958; 66: 259. [13] Li MC, Whitmore WF, Golbey R et al. Effects of combined drug therapy on metastatic cancer of the testis. JAMA 1960, 174: 1291-9. [ 141 Ross GT, Goldstein DP, Hertz R et al. Sequential use of Methotrexate and Actinomycin D. in the treatment of me&static choriocarcinoma and related trophoblastic diseases in women. Am J Obst Gynec 1965; 93: 223 - 229. [15] Bagshawe KD. Treatment of choriocarcinoma with a combination of cytotoxic drugs. Brit Med J 1960 II; 426-431. [16] Hammond CB, Borchert LG, Tyrey L et al. Treatment of metastatic trophoblastic disease : good and poor prognosis. Am J Obst Gynec 1973; 115: 451-7. [17] Morgan FJ, Canfield RC. Nature of the sub-units of human chorionic gonadotropin. Endocrinology 1971; 88: 1045-53. [18] Vaitukaitis JL, Braunstein GD, Ross GT. A radioimmu-
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nossay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obst Gynec 1972; 113: 751-8. [19] Vaitukaitis JL. Human chorionic gonadotropin as a tumor marker. Ann Clin Lab Science 1974; 4: 276-80. [20] Ross CT. Clinical relevance of research on the structure of human chorionic gonadotropin. Am J Obst Gynec 1977; 129: 795-805. [21] The Endocrine Society 1996 Annual Awards. Endocrinology 1996; 137: 3608- 3609. [22] Bagshawe KD, Wilson H, Dublon P et al. Follow-up after hydatidifotm mole: studies using radioimmunoassays for urinary human chorionic gonadotropin (hCG). Br J Obst Gynec 1973; 80: 461-8. [23] Bagshawe KD. Choriocarcinoma. The clinical biology of the trophoblast and its tumours. 1969. Edward Arnold (Publishers) Ltd. London. [24] Bagshawe KD. Risk and prognostic factors in trophoblastic neoplasia. Cancer 1976; 38: 1373-85. [2.5] World Health Organization Scientific Group on Gestational Trophoblastic Diseases Technical Report Series: no. 692. Geneva: the World Health Organization, 1983. [26] Lawler SD. HL-A and trophoblastic tumours. Br Med Bull 1978: 34: 305-308.