Germ cell tumors of the ovary: the experience of the National Cancer Institute of Milan. I. Dysgerminoma.

The experience of the Istituto Nazionale Tumori of Milan on dysgerminoma is presented. Between 1970 and December of 1982, 25 patients were treated with a unique protocol which considered surgery and radiotherapy with different schedules according to the extension of the disease. With this treatment protocol all 13 patients at Stage I were alive and free of disease with a median follow-up of 77 months. Of 12 patients at Stage III (10 retroperitoneal and 2 retroperitoneal and peritoneal) 4 relapsed. The 5-year relapse-free survival of Stage III patients was 61.4% and the overall survival 89.5%. Amenorrhea due to radiation dose absorbed by the contralateral shielded ovary was found in 7.7%. The excellent results in Stage I patients were balanced by the unsatisfactory results in Stage III patients. A more aggressive treatment and the knowledge of other prognostic factors seem necessary.

Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer.

Recent efforts to improve the response rates in advanced ovarian cancer with the use of high-dose cisplatin have been limited by unacceptable toxicity. Based on experimental and clinical studies indicating that reduced glutathione (GSH) is a protective agent against cisplatin-induced toxicity, a new high-dose regimen including GSH as a chemoprotector was designed in an attempt to improve the efficacy and therapeutic index of cisplatin. A total of 40 consecutive patients with stage III (bulky) and IV ovarian carcinoma were treated with cisplatin (40 mg/m2 daily for 4 consecutive days) and cyclophosphamide (600 mg/m2 i.v. on day 4). The treatment was repeated every 3-4 weeks for five courses unless progression or severe toxicity occurred. Before each cisplatin administration, patients received GSH (1,500 mg/m2) i.v. over 15 min, with a standard i.v. hydration (2,000 ml fluid) without diuretics. Debulking surgery was initially attempted in 18 patients and, after 2-3 courses, in 16 patients; it could not be carried out in 6 patients. Three patients were not evaluable for response because they prematurely discontinued their treatment. In all, 23 patients (62%) achieved complete clinical remission (negative second-look laparotomy in 16), with an overall (complete + partial) response rate of 86%; 2 patients achieved disease-free status following second surgery. Nausea/vomiting was the most severe acute toxic effect; myelosuppression was acceptable. Renal impairment was effectively prevented by GSH. Neurotoxicity that was not associated with motor dysfunction was the most significant cumulative toxicity in patients (24/32) receiving 4-5 courses. The results of this study indicate that the use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease and warrants further evaluation.

A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma.

Glutathione (GSH) is a sulfur-containing nucleophile that protects against cisplatin-induced renal toxicity without reducing the antitumor activity of the cytotoxic agent. To document further the clinical role of GSH in improving the outcome of cisplatin-containing regimens, the feasibility of the GSH/cisplatin combination using a low-volume hydration protocol was evaluated in untreated ovarian cancer patients. Twelve patients at stage III (minimal residual disease) and 23 with localized disease at high risk for recurrence were treated with cisplatin (90 mg/m2, i.v. in 250 ml of normal saline over 30 min) and cyclophosphamide (600 mg/m2 i.v.) every 3 weeks. GSH (5 g in 200 ml of normal saline) was administered by a short-term infusion (15 min) prior to cisplatin. The hydration protocol consisted of 1 liter of fluids without diuretics. The treatment was well tolerated; no nephrotoxic or neurotoxic manifestations were observed. The renal excretion of cisplatin (23%) at 24 hours following infusion was lower than expected using a standard i.v. hydration protocol. No reduction of renal elimination of cisplatin could be detected in subsequent courses, thus suggesting a minimal degree of impairment in renal function. In the series of evaluable patients (11) with stage III disease, 9 had complete pathological response. In the series of patients with no clinically detectable disease initially, all were disease-free at treatment completion. Taken together with previous observations, these results support the view that the use of GSH is a successful approach in the attempt to optimize cisplatin treatment, providing a new modality of drug administration for out-patient treatment.

Value of lymph node assessment in ovarian cancer: Status of the art at the end of the second millennium.

Available data on the incidence and the clinical value of lymph node assessment in ovarian cancer are reported. In early ovarian cancer, positive nodes are found in 4-25% of patients. Serous adenocarcinoma and poorly differentiated tumors are characterized by the highest incidence of node metastases. Five-year survival for stage IIIC disease with only retroperitoneal spread is clearly better than for stage IIIC with intraperitoneal dissemination. In advanced ovarian cancer, the rate of node involvement ranges from 55 to 75%. The percentage of positive nodes is significantly related to the amount of residual tumor after cytoreductive surgery, and node status seems to be an important prognostic factor for survival. Although data from retrospective studies advocate a therapeutic effect for systematic lymphadenectomy, results from prospective randomized trials are warranted. After chemotherapy a high percentage of patients (range, 25-77%) are found to have metastatic nodes. In particular, at second-look laparotomy, positive nodes are detected in 17-40% of patients who have no intraperitoneal disease.

Surgical staging for epithelial ovarian tumors of low malignant potential.

From January 1975 to December 1991, 34 patients with a diagnosis of epithelial ovarian tumors of low malignant potential (LMP) were admitted to the Istituto Nazionale Tumori of Milan. Eighteen of them (group 1) underwent complete staging laparotomy and retroperitoneal para-aortic and pelvic lymphadenectomy, as for ovarian cancer. In the remaining 16 cases (group 2), the surgical treatment ranged from unilateral oophorectomy to incomplete staging procedure. In group 1, nine patients (50%) were found to have retroperitoneal nodal involvement. In group 2, all patients had stage I disease. Patients were followed up for 20-222 months (mean 108, median 86). There were two recurrences in group 2 (after 5 years) and none in group 1 (NS). Currently all patients are alive and disease free. Nine of 18 group 1 patients were upstaged to stage III on the basis of lymph node involvement only. However, at least in this retrospective series, lymph node metastases did not affect prognosis or survival.

Cisplatin and cyclophosphamide in advanced ovarian carcinoma: activity and toxicity of an ambulatory regimen.

Chemotherapy with cisplatin (CDDP, 90 mg/m2) and cyclophosphamide (CTX, 600 mg/m2) was administered to 54 consecutive patients with advanced epithelial ovarian cancer (37 stage III and 17 stage IV). In 51 patients, surgery was performed prior to chemotherapy. Of the 37 stage III patients, 13 had only minimal residual disease after surgical debulking. The overall response rate was 69%, with 44% patients achieving clinical (cCR; n = 2) or pathological (pCR; n = 20) complete response. Median follow-up and overall survival time was 26 months, and median CR duration was 30 months. CR was achieved in 6 of 14 patients (43%) who were partial responders after five cycles of chemotherapy and had continued treatment for three to five more cycles. Severe bone marrow toxicity or renal function impairment was never observed, but eight patients presented peripheral signs of dose-related neurotoxicity. These findings indicate that CDDP and CTX in combination are an effective treatment for patients with advanced ovarian carcinoma, and can be administered with tolerable toxicity. In selected cases, prolonged chemotherapy administration can result in durable complete remissions.

A preliminary clinical experience with reduced glutathione as protector against cisplatin-toxicity.

A total of 16 consecutive patients (15 with ovarian cancer and 1 with unknown adenocarcinoma) were treated with a standard regimen including cisplatin and cyclophosphamide or with the same regimen in combination with reduced glutathione as potential protective agent against cisplatin nephrotoxicity, in a non-randomized study. Reduced glutathione (1500 mg/m2) was administered prior to each cisplatin administration (90 mg/m2) to seven patients for a maximum of five consecutive courses. A standard hydration protocol without diuretics was used. The patients received a total of 33 courses with glutathione. Glutathione was well tolerated, since it did not produce appreciable side effects. Cisplatin and glutathione combination did not produce unexpected toxicity. Two patients treated with standard regimen without glutathione developed a transient nephrotoxicity. The severity of myelosuppression was reduced following glutathione administration. Moreover, the therapeutic efficacy was not impaired by glutathione pretreatment.

Fc receptor-like structures on in vitro-cultured human ovarian tumor cells.

Four ovarian cystadenocarcinomas cultured in vitro were tested by a radioisotopic method with sera from cancer patients or healthy donors to search for a possible specific antitumor immune response of patients bearing ovarian tumors. However, the ovarian tumor cells were found to bear on their membrane surface structures able to bind immunoglobulins from any tested serum, thus making impossible the detection of a hypothetical specific antitumor antibody. These structures were demonstrated to bind the Fc portion of the Ig and were therefore similar to the Fc receptors described on various normal cells, particularly of the immunocompetent compartment.

An intensive treatment with mitoxantrone and ifosfamide in second-line therapy of epithelial ovarian cancer.

AIMS AND BACKGROUND: Both mitoxantrone (DHAD) and ifosfamide (IFO) have given promising results when administered as single agents in advanced ovarian cancer pretreated with platinum compounds. The aim of this I.T.M.O. group pilot trial was to evaluate, in a selected population of ovarian cancer patients, the efficacy and tolerability of the following intensive second-line regimen: DHAD, 12 mg/m2 i.v., day 1; IFO, 4,000 mg/m2 i.v., days 1 and 2; Mesna, 800 mg/m2 i.v. t.i.d., days 1 and 2. Filgrastim (5 micrograms/kg/day i.m.) was given from day 6 to day 19 to reduce the expected neutropenia. Cycles were repeated every 21 days. METHODS: Nineteen platinum-pretreated patients were enrolled and 14 were evaluated for tumor response; the disease of 5 patients was not measurable clinically or radiologically. RESULTS: Seven responses were observed (3 CRs), with a median response duration of 5 months. The median time to treatment failure and overall survival for all 19 patients was respectively 8 and 13 months. Anemia was observed in all of the treated patients (grade 3-4 in 9 cases). Only 6 of the 19 patients ended the five planned cycles of chemotherapy without any delay. CONCLUSIONS: Although DHAD plus IFO induced a considerable number of objective responses, the limited response duration time to treatment failure, and overall survival as well as the reported side effects suggest that this is not a recommended regimen for the palliative treatment of ovarian cancer patients undergoing second-line chemotherapy.

[Study of the retroperitoneal lymphatic spread of müllerian ovarian carcinoma, using lymphography]. / Studio sulla diffusione linfatica retroperitoneale del carcinoma ovarico mülleriano mediante l'impiego della linfografia

From January 1973 to May 1974, 117 patients with ovarian carcinomas were evaluated with lymphography. The tumors were staged and classified histopathologically according to FIGO (1971). Considering all cases, lymphography showed nodal metastases in 44 patients (38%). Lymphography was positive in 36% of serous cystoadenocarcinomas, in 26% of mucinous cystoadenocarcinomas, in 15% of endometrioid carcinomas and in 36% of unclassified carcinomas. Of the 10 cases not identified by cell type, lymphography was positive in 40% of cases. In 68% of cases bilateral involvement was found. The site of metastatic nodes was in 32% of cases only in the iliac chains were both involved. Considering the single node chains we found 36% of para-aortic, 27% of common iliac, 35% of external iliac and 2% of inguinal involvement. Metastases were observed, regardless of histological type, in 25% of cases in stage III, 62% iin stage IV, 54% in recurrences and only in 5% of cases in stage I. Therefore the lymphatic spread seems to occur in more advanced stages and in recurrences. In 28 of 117 patients node biopsy was performed. Histological-lymphographic correlation was correct in 7/7 positive cases and in 19/21 negative cases (93%). These results show that lymphography is a reliable tool in the evaluation of ovarian cancer.

Randomized comparison of cyclophosphamide, doxorubicin and cisplatin (CAP) versus cyclophosphamide and doxorubicin (CA) for the treatment of advanced ovarian cancer (ADOVCA). A EORTC Gynecological Cancer Cooperative Group Study.

The possible advantage of adding cisplatin (P) to cyclophosphamide (C) + adriamycin (A) in the management of stages III and IV ovarian cancer of epithelial origin was tested in a trial in which 149 patients were randomized to receive, after initial surgery, either CAP (C = 600 mg/sqm, A = 45 mg/sqm, P = 50 mg/sqm) or CA (C = 600 mg/sqm, A = 45 mg/sqm) every 4 weeks for 6 to 12 cycles, at which time follow-up laparotomoy was to be performed in responding or clinically disease-free patients. Fifteen patients were not included in the final analysis and the remaining 134 patients were considered fully or partially evaluable and are used in analysis of response and survival. The complete and partial response rates were 45.6% in the CAP arm and 45.4% in the CA arm, but the CAP regimen is of special importance in patients with bulky disease. Median survival CAP = 24 m and CA = 24.2 m), time to progression and survival was found not significantly different when CAP and CA were compared. However, more patients in the CA regimen had no macroscopic disease left after surgery than in CAP regimen (11 versus 6) and more patients in the CAP arm dose reductions and schedule delays than in the CA arm (61.1% versus 38.2%).

Therapeutic and staging operations for endometrial carcinomas.

A staging error can lead to a treatment failure in the management of patients with malignant diseases. The actual progression of endometrial carcinoma was postoperatively examined in twenty patients with clinical stage II disease classified by FIGO (International Federation of Gynecology and Obstetrics) criteria. In seven of 20 patients (35%), extrauterine lesions were revealed at surgery. These seven stage-up tumors included three grade 3 endometrioid cancers, three uterine papillary serous carcinomas (UPSC) and one grade 2 endometrioid tumor with deep myometrial invasion. The sites of the extrauterine lesions were determined. The grade 2 cancer was associated with parametrial invasions and positive pelvic lymph nodes. One grade 3 endometrioid tumor and two UPSCs had positive periaortic lymph nodes. Omental involvements were revealed in one grade 3 cancer and two UPSCs, indicating that the pattern of spreading of endometrial cancer with a malignant histology is similar to the spreading of ovarian cancer. Since the both endometrium and ovarian surface epithelium have a common histologic origin in the early embryonic stage, a similar biological characteristics of these tumors are suggested. From the results, it is recommended that a radical hysterectomy with periaortic lymph node dissection, omentectomy and peritoneal washing cytology be performed for endometrial cancer with a malignant histology or deep myometrial invasion to obtain the actual staging which is necessary for maximal curative potential.