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Cancer cells have an increased ability to synthesize GTP (guanosine triphosphate) because of increased activity of IMP DH (inosine 5'-phosphate dehydrogenase, EC 1.1.1.205). Because IMP DH activity is rate limiting for de novo biosynthesis of GTP, this enzyme was suggested as a sensitive target for chemotherapy. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted in the cells into the active metabolite, TAD, (thiazole-4-carboxamide adenine dinucleotide) which potently inhibits IMP DH activity. By adding TAD to tissue extracts one can determine the extent of inhibition of IMP DH. We applied the IMP DH assay method to extracts of normal ovaries (N = 11) and epithelial ovarian carcinomas (N = 10). The IMP DH activity (mean +/- SE) in ovarian carcinoma was 21.1 +/- 5.8 which was markedly higher than that observed in normal ovaries (2.9 +/- 0.7 nmol/hr/mg protein) (P < 0.05%). The inhibition by TAD of IMP DH activity in ovarian carcinomas (N = 4) was 81%. The results indicate that IMP DH activity is elevated sevenfold in ovarian carcinomas as compared to normal ovary and can be inhibited by exposure to tiazofurin (TAD). Similar high IMP DH activity and inhibition of the activity by TAD was observed in patients with chronic granulocytic leukemia in blast crisis among whom 70 to 80% remissions were reported. Since there is increased IMP DH activity in human ovarian carcinomas and in OVCAR-5 cells and tiazofurin and TAD inhibit IMP DH activity of these cells and the proliferation of human ovarian carcinoma xenografts in the mouse, tiazofurin may merit serious consideration for a Phase II trial for patients with recurrent/refractory epithelial ovarian carcinoma.

Eighty-eight patients with ovarian malignancy underwent second-look laparotomy as part of their plan of management at Indiana University Hospital. Thirty-five patients (39.8%) were found to have no gross or microscopic evidence of persistent neoplasm, and an additional 16 (18.2%) had only microscopic tumor. Patients with initial Stage III or IV disease were less likely to have negative findings at laparotomy than were patients with Stage I or II disease. A complete initial cytoreductive operation (residual disease = 0 cm) correlated positively with negative findings at laparotomy. Endometrioid histologic findings were associated with a favorable condition at the second look, but tumor grade was associated with superior survival only for patients with grade 0 disease. Eight of 30 patients (26.7%) with invasive carcinoma and negative findings at second-look laparotomy have had tumor recurrence (2 to 63 months), and five of eight have died. Intraperitoneal chromic phosphorus salvage therapy for patients with microscopic disease was promising, with eight of 15 treated patients (53.3%) alive after therapy, with no evidence of disease from 16 to 56 months after the second look. Second-look laparotomy has been the major determinant of continued or alternative therapy for patients with ovarian malignancy. Second-look laparotomy has been incorporated into the standard management plan without a formal clinical trial. The need for a second look may be reduced by identifying patients who do not benefit from the procedure. Patients with persistent disease confirmed by noninvasive means can continue therapy without laparotomy. There is also a subgroup of patients with a favorable prognosis whose therapy could be safely discontinued without laparotomy.

Twenty-nine patients with advanced or recurrent adenocarcinoma of the ovary no longer responsive to standard treatment measures were given maytansine 1.2 mg/m2 I.V. every 3 weeks. None of the 29 patients demonstrated an objective regression of disease. Eighteen (62%) demonstrated stable disease for 1 or more months, while 11 (38%) developed rapid progression of disease. Adverse effects consisted primarily of leukopenia (7/29), thrombocytopenia (9/29), and nausea and vomiting (14/29). Only one patient developed life-threatening toxicity (platelets less than 25,000 microliters), and no drug-related deaths were observed. Maytansine thus appears inactive in the treatment of adenocarcinoma of the ovary at the dose and schedule tested.

Dianhydrogalactitol was administered intravenously to patients with advanced or recurrent gynecologic malignancies on a weekly schedule. The initial dosage was 60 mg/m2 with escalation to 75 mg/m2 if there were no adverse effects. Forty-two patients with ovarian epithelial adenocarcinoma (OEA) and forty-one patients with squamous carcinoma of the cervix (SCC) were entered into this study. Of these, 39 patients with OEA and 36 with SCC were evaluable for toxicity and response. Seven patients (19.4%) with SCC had an objective response, while six patients (15.4%) with OEA had an objective response. Adverse effects were frequent but tolerable. There were no drug-related deaths, and only two patients suffered life-threatening hematologic toxicity. Myelosuppression was observed more frequently among the patients with OEA. A higher percentage of OEA patients had received prior chemotherapy. The level of activity and frequency of adverse effects observed at this dose schedule warrant further studies of this drug in these two tumors.

Between January 1973 and December 1983, 469 patients with carcinoma of the endometrium were seen at this institution. Eighty-one patients were identified with adenocarcinoma involving both the uterine body and the cervix. Patients were divided into three groups for evaluation. Group A (n = 58) had a positive cervical biopsy or endocervical curettage, but a normal-appearing cervix at clinical examination. Group B (n = 18) had gross tumor involving the cervix which was confirmed by biopsy. Group C (n = 5) had unsuspected cervical involvement revealed at hysterectomy. Fourteen Group A patients received preoperative radiation therapy. Thirty of the 44 Group A patients (68.2%) who did not receive preoperative radiation, had no involvement of the cervix by tumor in the hysterectomy specimen. Seventy-six patients were eligible for follow-up of at least 18 months. There were 24 recurrences among these 76 patients. Recurrence was more common with advancing grade and with increasing myometrial invasion. Pelvic failures occurred with comparable frequency in both Groups A and B. Only 4 of 11 patients who were found to have extrauterine disease at surgery are still alive. In this study, we found that endocervical curettage has a significant false-positive rate, both histologic grade and volume of cervical involvement should be considered in treatment planning, primary operation should be considered in the management of selected patients with Stage II endometrial carcinoma, and extrauterine disease is a grave prognostic factor.

Progesterone receptor content was measured in tissue samples from 175 patients with endometrial adenocarcinoma by use of the dextran-charcoal method. The estradiol receptor content was determined in 138 of these samples. Ninety-two tumors (52.6%) tested positive for progesterone receptors (greater than 50 fmol/mg cytosol protein) and 111 (80.4%) tested positive for estradiol receptors (greater than 6 fmol/mg). Median follow-up was 27.3 months (range 1 to 152 months). Progesterone receptor status correlated significantly with grade, histology, adnexal spread, age, and recurrence rate in stage I cancer. There was no correlation between progesterone receptor status and clinical stage, myometrial invasion, peritoneal cytology, retroperitoneal lymph node involvement, or spread to the cervix. Estradiol receptor status correlated with adnexal spread and recurrence rate. Recurrence in patients with stage I disease was significantly more common if tumors were negative for progesterone receptor (16 of 43, 37.2%) than if they were positive (four of 57, 7%; p less than 0.001). Recurrence was also more common if tumors were negative for estradiol receptor (seven of 17, 41.2%) than if they were positive (eight of 63, 12.7%; p = 0.02). In recurrent or advanced disease, response to progestin was independent of estradiol receptor content, but tumors positive for progesterone receptors responded significantly more often than those lacking progesterone receptors. Overall survival was superior for patients with progesterone receptor-positive tumors (p = 0.001). Although survival in clinical stages I and II was also superior in patients with lesions positive for progesterone receptors (p = 0.13), there was no statistical difference in survival between patients with progesterone receptor-positive or -negative cancers and surgical stages I and II disease (p = 0.12). Estradiol receptor status had no apparent correlation with survival.

From 1971-1986, peritoneal washings were obtained for cytologic examination at the time of primary exploratory laparotomy in 340 patients with endometrial adenocarcinoma. Seventy-two samples (21.2%) contained malignant cells. The finding of malignant cytology increased with stage of disease: stage I, 17%; stage II, 19.5%; stage III, 68.7%; and stage IV, 85.7% (P less than .001). In 248 patients with clinical stage I disease for whom uterine evaluation was complete, there was an increasing incidence of malignant cytology with increasing grade (P = .002), depth of myometrial invasion (P = .003), and adnexal spread (P less than .001). Twelve of 41 patients (29.3%) with clinical stage I and positive cytology developed recurrent disease, compared with six of 207 (2.9%) with negative cytology (P less than .001). Survival for all stages together was poorer in patients with positive washings than in those with negative washings (P less than .001). This difference in survival was also observed in patients with clinical stage I disease (P less than .001). Among patients with surgical stage I disease, disease-free survival was also superior in the group with negative cytology. In both clinical and surgical stage I, intra-abdominal recurrences were more common among patients with malignant peritoneal cytology.

Ten patients with ovarian carcinoma whose tumors had progressed on first-trial chemotherapy were treated with cisplatin, vinblastine, and bleomycin (PVB) to determine the efficacy, dose range, and toxicity of this combination. Two dose levels of vinblastine were used. Objective responses occurred in 5/10 patients (3 CR, 2 PR), with a median response duration of 17.0 weeks. Toxicity was appreciable. One patient expired of bleomycin-induced pulmonary fibrosis. With the higher dose of vinblastine, four patients had grade III and three patients had grade IV hematologic toxicity. At the lower dose, two patients had grade II and one patient had grade III hematologic toxicity. PVB has activity in second-trial therapy of ovarian carcinoma at the dose and schedule tested, but the role of this regimen in the future treatment of this disease remains to be determined.

Favorable responses to hexamethylmelamine (HMM) have been documented in untreated as well as in alkylating agent-resistant ovarian epithelial adenocarcinoma (OvCa). Platinum-based combination therapy for OvCa has been used since 1976. Eighteen patients with OvCa were treated with HMM as salvage therapy between February 1979 and October 1981. All patients had histologically confirmed OvCa. Eleven tumors were grade III/III and seven tumors were grade II/III. Sixteen patients had received cisplatin-based combination therapy, whereas two had received doxorubicin/cyclophosphamide because of other medical conditions. HMM was used alone in 16 patients and in combination with other drugs in two patients. The initial dose of HMM was 300 mg/m2/day X 14 days when used alone and 130 mg/m2/day X 14 days when used in combination with other drugs. Six patients were treated at a reduced initial dose because of prior marrow toxicity. Adverse effects were tolerable, with 14 patients experiencing hematologic toxicity (5 mild, 5 moderate, 3 severe, 1 life threatening) and 15 patients experiencing GI toxicity (5 mild, 7 moderate, 3 severe). Only 2 patients experienced no toxicity. No objective tumor responses were observed. Four patients had progression of tumor within 4 weeks of starting therapy and 14 patients had stable disease with a mean progression-free interval of 21 weeks. Although HMM is an active drug in untreated and alkylating agent-resistant OvCa, experience suggests that HMM at the dose and schedule tested has insignificant activity in patients who have failed cisplatin-based combination therapy.

This study was designed to determine whether the presence of progesterone receptors (PR) and/or estradiol receptors (ER) could be used to predict progestin responsiveness of recurrent or advanced endometrial cancers. We have demonstrated the presence of physicochemically similar cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria. All normal endometria contained both PR and ER. Seventy-three percent of endometrial hyperplasias were PR(+) and 93% were ER(+). A decreasing concentration of progesterone receptor activity was observed with increasing tumor anaplasia [grade 1, 84% PR(+); grade 2, 55% PR(+); grade 3, 22% PR(+)] and in irradiated tumors. A statistically significant (p less than 0.001) relationship has been demonstrated between the presence of specific cytoplasmic PR and response to progestin therapy in recurrent or advanced endometrial adenocarcinomas. Thus, we conclude that a PR assay may be used to help select the most appropriate therapy for patients with recurrent or advanced endometrial adenocarcinoma.

The records of 23 patients with confirmed carcinoma of the fallopian tube, treated between 1966 and 1983, were reviewed. Patients ranged in age from 41 to 88 years. A pelvic mass was the most common preoperative finding (61%), followed by abnormal bleeding (43%), and pain (39%). Fifteen patients had stage I or II disease, 8 had Stage III or IV disease. In patients with metastatic disease, involvement of the peritoneal surfaces, bowel, and omentum were noted most often. Lymph nodes were the most common site(s) of recurrent disease. Twelve evaluable patients with measurable disease were treated with cisplatin and cyclophosphamide (PC) +/- doxorubicin (PAC). There were 9 complete and 2 partial responses, a 92% response rate. Incorporation of cisplatin therapy appears to have resulted in improved short-term survival.

Age, clinical stage, histologic grade, depth of myometrial penetration, adnexal status, peritoneal cytology, and progesterone and estrogen receptor status were available for 139 patients with clinical stage IA, IB, or II endometrial adenocarcinoma who had therapy at Indiana University Hospital or St. Vincent Hospital in Indianapolis. These features were analyzed for their association with survival and disease-free survival. Patients treated at Indiana University Hospital were similar to those from St. Vincent Hospital when comparisons were made by chi 2 test for age, clinical stage, grade, adnexal metastases, peritoneal cytologic results, progesterone receptor status, or estrogen receptor status. However, patients treated at Indiana University Hospital had lesions that were deeper (p = 0.03) than those treated at St. Vincent Hospital. Survival differences were observed for patients with progesterone receptor-rich versus progesterone receptor-poor tumors (p = 0.004), grades 1 and 2 versus grade 3 lesions (p = 0.013), and malignant versus benign peritoneal cytologic results (p = 0.01). Differences in disease-free survival were observed for those patients with adnexal metastases versus those with no adnexal disease (p = 0.002), those with estrogen receptor-rich versus estrogen receptor-poor tumors, outer third myometrial invasion (p = 0.002), and patients with clinical stage I versus clinical stage II disease (p = 0.03). A stepwise Cox proportional hazards model was constructed to determine correlates of disease-free survival. In the final model, grade (p = 0.0002), peritoneal cytologic results (p = 0.0002), progesterone receptor status (p = 0.004), and age as a continuous variable (p = 0.008) were most closely associated with disease-free survival.