George C. Lewis

Adjuvant progestogen therapy in the primary definitive treatment of endometrial cancer

Abstract On the basis of reported successful hormone therapy for recurrent cancer of the endometrium, a multi-institutional program was established in 1963 and terminated in 1968 to study the adjuvant use of a progestogen in the primary definitive treatment of uterine carcinoma. The research protocol restricted entry to patients with disease limited to the uterine corpus as established by clinical evaluation, surgery, and pathology. Option of surgery alone or surgery plus irradiation was permitted. Depo-Provera and placebo given over 14 wk were randomly assigned in such a way that 285 patients received hormone; 287 served as controls. Survival analysis at 4 yr indicated no significant contribution to results by the adjuvant therapy. Overall excellent survival for treated patients and controls appeared to be the result of the high degree of patient selection incorporated in the protocol design. The influence of patient selection and of variations of disease-related parameters upon the results is discussed especially as it may affect future programs dealing with comparable patient material.

The management of stage III carcinoma of the endometrium.

Ten percent of all patients with endometrial carcinoma have Stage III disease at the time of presentation. The management, the features of their disease, and their prognosis are quite different than those of patients with Stage I disease. This report is based on 37 patients with Stage III carcinomas. For their treatment, a program of definitive radiation therapy was applied. Eleven patients had a prior total abdominal hysterectomy (TAH) and bilateral salpingo‐oopho‐rectomy (BSO). On the basis of the tumor extension, three main patterns were identified: 1) downward into the vagina or the vagina and the cervix; 2) lateral into the parametrium and the pelvic wall; and 3) to the ovaries. This classification carries therapeutic and prognostic significance. Ovarian extension has the best prognosis when treated by TAH and BSO followed by postoperative radiotherapy. Extension to the vagina or to the vagina and the cervix can be treated successfully by a combination of external beam and local radium placements. Patients with pelvic wall extension have the poorest prognosis. They comprise more than 50% of all cases with Stage III tumors and have exhibited persistent or recurrent disease even when treated at high dose levels. The cumulative survival rates for the entire stage were 50% at the end of the first year, 32% at the end of the second year, and 25% at the end of the fifth year.

Low dose bleomycin and methotrexate in cervical cancer.

Twenty patients with recurrent and disseminated carcinoma of the cervix were treated with Bleomycin, 10 mg/m2 weekly and Methotrexate, 10 mg/m2 every fourth day. Twelve of the 20 (60%) had a greater than 50% shrinking of measured tumor masses lasting a median remission time of 7.5 months. The data suggest that combination protracted chemotherapy with these drugs of metastatic cervical cancer might improve the outlook of patients with this condition.

Endometrial cancer. Therapeutic decision and the staging process in “early” disease

An all inclusive, widely accepted system for correlation of indices of pathophysiology in endometrial cancer with a spectrum of therapeutic management has yet to be developed. Improved understanding of tumor growth should lead to more logical, individualized treatment especially in terms of irradiation. To support these philosophies a brief review of past reports and studies, especially the Endometrial Adjuvant Study is provided. From an analysis of 574 patients in this study, it is apparent that prognostic factors could be separated as major, differentiation, and tumor penetration and minor, number of capsules of radium and depth of uterus. A pilot study under the Gynecologic Oncology Group suggests the correlation of the major factors with lymph node involvement. Since depth of penetration and lymph node involvement are most accurately determined by surgery and pathology, surgical staging is suggested as a guide for therapeutic decision.

Evolution of radiotherapeutic techniques

Abstract Adenocarcinoma is the most common kind of tumor involving the uterine corpus, occurring in a frequency of 90% or better and found predominantly in postmenopausal women. Because of vaginal bleeding, diagnosis is made early and control rates are good. Regional lymph node metastases are found to occur in about 20% of all operable patients and more frequently in those with advanced lesions near the cervix. Surgery alone fails not only because of metastases but also because of persistence in the vaginal vault and in the periurethral region. From a theoretical and practical viewpoint, preoperative irradiation is a valuable and important role in the treatment of carcinoma of the endometrium. Treatment calls for a technique that will effectively irradiate the uterine tissue, the vaginal vault, and the immediate extrauterine tissues in which postsurgical persistence is known to appear. From the standpoint of survival, both preoperative external therapy and preoperative radium therapy are effective with equivalent survival figures. The incidence in our experience of vaginal recurrence in those patients who were irradiated preoperatively with external beam therapy techniques would indicate the need for supplemental radium within the vaginal vault.

Malignant mixed mesodermal tumors of the ovary. A report of 13 cases.

The surgical pathology tiles at Thomas Jefferson University Hospital (TJUH) were reviewed for the period 1973–1984. Thirteen cases of primary ovarian malignant mixed mesodcrmal tumor (MMT) were found; however, material from only seven of these cases could he obtained for repeat review. No conclusions can be drawn regarding any impact on survival based on the histology. Treatment was highly varied reflecting the mix of physicians rendering treatment and the range of modalities used. Overall, survival was miserable. Six of the 13 patients (46.2%) survived 6 months or less, 10 of the 13 (76.9%) survived 12 months or less. No particular treatment modality seemed to offer enhanced survival unless aggressive cytoreductive surgery was performed. A plea is made for national cooperative groups to develop treatment protocols for this aggressive ovarian cancer. The surgical pathology tiles at Thomas Jefferson University Hospital (TJUH) were reviewed for the period 1973–1984. Thirteen cases of primary ovarian malignant mixed mesodcrmal tumor (MMT) were found; however, material from only seven of these cases could he obtained for repeat review. No conclusions can be drawn regarding any impact on survival based on the histology. Treatment was highly varied reflecting the mix of physicians rendering treatment and the range of modalities used. Overall, survival was miserable. Six of the 13 patients (46.2%) survived 6 months or less, 10 of the 13 (76.9%) survived 12 months or less. No particular treatment modality seemed to offer enhanced survival unless aggressive cytoreductive surgery was performed. A plea is made for national cooperative groups to develop treatment protocols for this aggressive ovarian cancer.

Uterine choriocarcinoma with negative specific serum radioimmunoassay for human chorionic gonadotropins

Abstract A case of uterine choriocarcinoma complicating gestational trophoblastic disease is presented. Following chemotherapy, there seemed to be an apparent cure as indicated by follow-up monitoring of the beta subunit of human chorionic gonadotropin (B-HCG assay) when the assay demonstrated three consecutive weekly negative results. At the same period when the assays were negative, the patient was manifesting irregular vaginal bleeding for which diagnostic D&C was done revealing persistant disease which was not detected by measurement with the sensitive quantitiative B-HCG assay. The case is discussed to confirm the fact that clinical assessment is necessary for the follow-up of trophoblastic disease in addition to quantitative B-HCG.

Ovarian cancer. Use of multiple modality programs involving surgery, radiation therapy and chemotherapy

Appreciating the past reports of effectiveness for various therapeutic modalities in ovarian cancer, the Gynecologic Oncology Group activated eight protocols. Three involved epithelial lesions with randomized multimodality trials alone or in combination. The other protocols were devoted to registration of rare tumor case reports. Conclusions are still difficult to reach due to inconsistencies in pathologic diagnoses and deficiencies in radiation therapy, chemotherapy and surgery inherent in the initial phases of group development by diverse specialists in oncology. Adjuvant therapy for early cancer seems to have no advantage. Single drug, melphalan therapy may be as effective as multi‐drug, irradiation or combined drug‐irradiation therapy and less toxic. For the rare tumors, preliminary results suggest therapeutic advantage for at least one triple drug program in malignant teratoma. With the lessons of the past, it is anticipated that new studies briefly described herewith may be more effectively applied. Cancer 40:588–594, 1977.

ICRF-159 (razoxane) in patients with advanced squamous cell carcinoma of the uterine cervix: For the gynecologic oncology group

THIRTY-ONE PATIENTS WITH ADVANCED SQUAMOUS cell carcinoma of the cervix were entered onto this phase II study evaluating the efficacy of ICRF-159 (razoxane). Three of these patients were excluded; one had no tumor, one had a second primary, and one received no therapy.ICRF-159 was administered orally at a dose of 2.5 g/m2 weekly until progression, unacceptable toxicity, or death. Adverse effects were primarily hematologie in nature. Twenty-three of the 28 patients exhibited leukopenia which in ten instances was severe (below 2000/mm3). Seven cases had thrombocytopenia (one case below 50,000/mm3). Other toxicity, including fever and anorexia, was mild to moderate. There was tumor response in five (18%) patients (one CR, four PRs) ranging from 1 to 5 months. Fifteen patients with stable disease and eight with progressive disease had a median survival duration of 3.8+ and 3.5+ months, respectively.ICRF-159 showed limited activity in this patient population. However, it might be considered for combination with other low myelosuppressive agents.

Postoperative pelvic irradiation of stage II ovarian carcinoma

Abstract Clinical Stage II carcinoma of the ovary (1964 FIGO classification) represents a small proportion of total patients and has not been studied extensively. Even though the disease apparently is localized, end-results have been poor. Between 1960 and 1970, 24 patients with clinical Stage II disease received postoperative megavoltage pelvic irradiation following surgical procedures of varying extent. All patients but one received between 5000 and 6000 rad tumor dose to the whole pelvis and all patients were evaluable at a minimum of 5 years. Of 4 Stage II-A patients one was alive without disease. No patients were alive with recurrent tumor. Recurrences in the pelvis occurred only in 2 patients; 4 patients had recurrent disease in the pelvis and upper abdomen. A total of 8 patients developed upper abdominal recurrences in the apparent absence of pelvic disease. These results and those of others which are discussed in this paper suggest that surgery and irradiation to the pelvis only will not eradicate disease completely in over 60% of patients with clinical Stage II ovarian carcinoma.