Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials.

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.

Effects of progestational agents in treatment of endometrial carcinoma.

Progestational agents induced an objective response in 11.2% of 155 patients with advanced primary or recurrent endometrial carcinoma. Response rates decreased with decreasing tumor differentiation from 40% with Broders grade 1 lesions to 17.5, 2.4, and 0%, respectively, with grades 2, 3, and 4. 17 alpha-Hydroxyprogesterone caproate (Delalutin), 6,17 alpha-dimethyl-6-dehydroprogesterone (Colprone), and 6-methyl-6-dehydroprogesterone acetate (Megace) were the progestogens used; there was no significant advantage for any one agent. Overall, survival after initiation of hormone therapy was 40% at one year, 19% at two years, and 8% at five years. Survival was highly dependent on the degree of tissue differentiation (P less than .001) and was influenced significantly by the estimated tumor volume at the start of therapy (P less than .01) and by the time interval from primary treatment to the beginning of hormone therapy (P less than .01).

Staging laparotomy in early ovarian cancer.

Systematic restaging was performed prospectively in 100 patients referred to the Ovarian Cancer Study Group institutions with a diagnosis of "early" (stage Ia-IIb) ovarian cancer. Before referral, only 25% of patients had an initial surgical incision that was adequate to allow complete examination of the pelvis and abdominal cavity. In patients referred to member institutions, 31 (31%) of 100 were found to have a more advanced stage and 23 (77%) of 31 of these actually had stage III disease. Sixty-one percent of the patients had their advanced stage detected by procedures other than a second laparotomy-nine (29%) of 31 by peritoneoscopy, six (19%) of 31 by peritoneal washings, and six (19%) of 31 by lymphangiography. Sites of unsuspected disease are most likely to be pelvic peritoneum, ascites fluid, other pelvic tissue, para-aortic nodes, and the diaphragms. Based on these data, we conclude that the initial staging approaches traditionally used in clinical evaluation of patients with early ovarian cancer are often incomplete and inadequate.

Mayo Clinic experience with epithelial ovarian cancer.

Clinical investigation of epithelial ovarian cancer must involve the precise definition of the lesion, careful application of new techniques, the objective evaluation of such techniques, the comparison of results in a randomized fashion with prior forms of therapy, careful pathological evaluation of the tumour, and the evaluation of toxicity to the patient. The interdisciplinary team approach to the treatment of epithelial ovarian cancer and the development of randomized, prospective trials are essential. Utilizing these two elements, a better integration of surgery, chemotherapy and radiation therapy can be accomplished. Of great importance is the evaluation of response patterns by an observer who is skilled in pelvic examinations and familiar with the natural history of epithelial ovarian cancer. The increasingly important role of surgery in the treatment of this cancer is now more clearly defined. The psychological effects of chemotherapy as well as the response patterns to chemotherapy must be evaluated. During the past 20 years, considerable progress has been made in prolonging the useful, functional life of the patient. The ultimate cure is still a matter for the future and is predicated on more effective combinations of potent chemotherapeutic combinations and a clearer definition of the role of radiation therapy.

Cyclophosphamide plus cis-platinum in combination: treatment program for stage III or IV ovarian carcinoma.

A randomized prospective comparison of treatment with cyclophosphamide and that with cyclophosphamide and cisplatinum, each in 21 patients with advanced ovarian cancer, has shown that the time to progression of tumor and the duration of survival were markedly improved in the patients receiving the combination chemotherapy. Cytoreductive surgery was performed in most of the patients in the study before the chemotherapy regimen was initiated. Second-look surgery was performed after a year of chemotherapy. The chemotherapy was administered on an outpatient basis, without excessive toxicity. At 2 years, 52.4% of the patients receiving combination therapy had no progression of tumor, whereas 9.5% had no progression of tumor inthe group of patients receiving a single alkylating agent. Survival at 2 years was 61.9% for the combination chemotherapy group and 19.0% for those treated with cyclophosphamide alone. The study demonstrates a striking superiority of combination chemotherapy over single-agent chemotherapy in patients with advanced ovarian cancer.

Ovarian cancer: incidence and case-control study.

The incidence of ovarian cancer in Rochester, Minnesota over the 40-year period 1935 through 1974 was determined; and risk factors for epithelial ovarian cancer occurring in Rochester from 1945 to 1974 were examined in 116 patients and 464 controls. Among the characteristics studied, only nulliparity was found to be a significant risk factor--relative risk 1.8. Other suspected risk factors--including hypertension, obesity, age at menopause, prior therapeutic pelvic radiation, and prior exposure to exogenous estrogen--were found not to differ significantly between patients and controls. The ovarian cancer patients were found to have a significantly lower frequency of prior hysterectomy and of unilateral oophorectomy than the control group. Thus out data show that hysterectomy, even when one or both ovaries are preserved, is associated with a lower risk of subsequent ovarian cancer.

Different chemotherapeutic sensitivities and host factors affecting prognosis in advanced ovarian carcinoma versus minimal residual disease.

Treatment of patients with advanced ovarian carcinoma (stages IIIB and IV) using either cyclophosphamide alone (1 g/m2) or cyclophosphamide (500 mg/m2) plus adriamycin (40 mg/m2) by iv injection every 3 weeks each produced partial regression in approximately one third of the patients. Survival curves and time-to-progression curves for the two regimens were nearly identical in these patients with advanced disease. These same regimens produced different results when used monthly in patients who had minimal residual disease (stages II and IIIA). In patients with minimal residual disease the therapeutic index of the combination regimen was superior to that of cyclophosphamide alone. Prognosis was better overall among patients with minimal residual disease than among patients with advanced disease. Within the minimal-disease group grossly complete excision of tumor prior to chemotherapy was associated with still better prognosis. Among patients with advanced disease, prognosis was significantly better for older patients despite their generally less favorable performance scores. Much of this prognostic superiority appeared to be related to menopausal status and presumably to the depletion of endogenous estrogens in the older patients.

Design and preliminary observations of National Cooperative Diethylstilbestrol Adenosis (DESAD) Project.

The National Cooperative Diethylstilbestrol Adenosis (DESAD) Project has completed the major portion of its enrollment phase with the examination of more than 3000 daughters of women taking synthetic nonsteroidal estrogens (denoted DES) during pregnancies occurring from the early 1940s to the mid-1960s. The aims of the Project are to fill urgent needs for information on the prevalence and incidence of structural and epithelial abnormalities or neoplastic changes and their complications in these young women. Participants are grouped by mode of entry as identified by prenatal record review (40.1%), documented as DES-exposed but walking in (25.1%), or referred (22.8%) to the DESAD Project for examination, and not documented as exposed but having gynecologic abnormalities typical of those associated with DES exposure (12.0%). This study cohort, in part having paired controls, will be examined annually for at least 5 years. Details of the design and selected preliminary findings are reported.

Phase II evaluation of cytembena (NSC-104801) in patients with advanced ovarian carcinoma resistant to alkylating agents: brief communication.

Seventeen patients with stages III and IV alkylating agent-resistant ovarian carcinomas were treated with cytembena, which was given in doses of 200 mg/m2 twice daily for 5 consecutive days every 5 weeks. Sixteen patients completed at least one course of treatment; 11 of them experienced objective progression of disease or failed to continue treatment because of a continuing symptomatic deterioration within the first two treatment cycles. Three patients remained objectively stable after two courses of treatment, but were symptomatically worse and stopped treatment for that reason. Another patient experienced progression after three courses, and the final patient voluntarily withdrew after three courses. No objective regression of disease occurred during treatment with cytembena. Nausea and vomiting occurred at some time in all except 1 patient, and 3 patients experienced mild diarrhea. Two patients had alopecia.

Medroxyprogesterone acetate for the treatment of metastatic and recurrent ovarian carcinoma.

PIP: On a random basis, 19 patients with metastatic and recurrent ovarian carcinoma received 100, 200, or 400 mg daily of medroxyprogesterone acetate orally. All patients had previously failed to respond to cytotoxic therapy. None of the 5 patients receiving 100 mg/day had an objective response. 1 of the 9 patients receiving 200 mg/day had an objective response for 4 months and 2 had their disease remain static for 4 and 5 months. None of the 5 patients who received 400 mg/day had an objective response but 1 had her disease remain static for 7 months. All epithelial ovarian cell types were included in the study. During drug therapy no change was found in hemoglobin levels, leukocyte counts, platelet counts, serum levels of creatinine, bilirubin, alkaline phosphatase, glutamic oxaloacetic transaminase, fasting blood sugar, or urine. Data from these 19 patients indicate that this drug, as used, had no significant benefit.^ieng

Clear-cell adenocarcinoma of the vagina and cervix: survival data.

Survival data on 36 patients with clear-cell adenocarcinomas are reported: seven with vaginal lesions and 29 with cervical lesions. Although the tumor responds to present treatment modalities, it tends to be associated with early lymph node involvement, thus making early diagnosis essential. Radiation as a primary therapeutic measure has often been followed by late recurrence, though many patients with these tumors were treated by older, low-energy modalities.

Prognostic importance of histologic grading in ovarian carcinoma.

Our data on ovarian epithelial carcinoma show that within a given stage, regardless of the histologic cell type, the increasingly higher grades have an increasingly poorer prognosis. This suggests that more intensive therapy be considered for all patients with ovarian epithelial carcinomas than is currently undertaken. Specifically, this means that, in addition to the standard modalities, chemotherapy should be considered for all tumors beyond grade 1, stage 1a.