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The currently accepted therapies for ovarian cancer have produced only limited numbers of extended complete remissions in advanced-stage disease. Studies of high-volume intraperitoneal chemotherapy have been initiated to define the toxicology, pharmacokinetics, and the therapeutic effectiveness of this treatment modality. This technique has been virtually ignored until recently, because little success has been achieved with it except in one study (Rutledge, 1966), in which large intraperitoneal fluid volumes were used. The general lack of success probably reflects inadequate attention to physiologic and pharmacologic principles of drug distribution and absorption in a space as large as the peritoneal cavity. Biomedical engineers, pharmacologists, and clinicians at the NCI have cooperated in the development of a rational chemotherapy for ovarian cancer. Following mathematical pharmacokinetic modeling and toxicologic studies in rat, a Phase I clinical trial of intraperitoneal methotrexate administered in large volumes of dialysis fluid was initiated. Results in three patients confirm the practicality of this approach, and further investigation is warranted.

Peritoneoscopy was done within 1 month of exploratory laparotomy in 30 consecutive patients, with ovarian carcinoma as part of their pretreatment evaluation. Six of the 7 patients who were thought to have ovarian carcinoma localized to the pelvis (stages I and II) were found to have advanced disease (stage III) at peritoneoscopy and thus required a change in therapy. Metastatic diaphragmatic involvement in ovarian carcinoma is common and was found in 77 percent of all patients studied. The routine shielding if the liver area ordinarily used with total abdominal radiotherapy would select these patients for therapeutic failure. Peritoneoscopy supplied reevaluable finding in 2 of 7 patients having normal physical, roentgenologic, and laboratory examinations, as well as in 93 percent of all patients stuided. "Second look" peritoneoscopy precluded the need the laparotomy in 5 to 13 patients achieving as apparent clinical remission.

Twenty-four fully staged, previously untreated patients with advanced ovarian carcinoma were prospectively randomized to either intensive intravenous cyclophosphamide or conventional oral Melphalan therapy. The median durations of initial remissions (5 and 6 mo) and the median durations of survival (15 and 14 mo) were similar for the two regimens but the toxicity of the intensive regimen was excessive. Followup indicates that long term disease free survivals are possible in those patients who achieve complete remissions on chemotherapy alone as three of the four patients achieving complete remission in the present study remain free of disease with a median survival in excess of 30 mo. High dose intensive alkylating agent therapy in the manner used in the present study fails to enhance the response to chemotherapy and produces unacceptable toxicity.

Forty patients with ovarian adenocarcinoma had peritoneoscopy within 1 month of their exploratory laparotomy as part of their pretreatment evaluation. Of 12 patients (58%) believed to have disease localized to the pelvis (stage 1 or II) at laparotomy staging 7 were found to have more advanced disease (stage III) at peritoneoscopy and thus required a change in therapy. Involvement of the diaphragm with metastatic ovarian carcinoma was found in 63% of all patients. This finding again necessitated a change in therapy, since the right hemidiaphragm is shielded along with the liver when abdominal radiotherapy is used. Peritoneoscopy supplied the only followable findings with which to gauge response to therapy in 40% of the patients and also supplied followable findings in 78% of all patients studied. Second-look peritoneoscopy was performed in all patients achieving an apparent clinical remission with chemotherapy. Active disease was found in 43% of these patients, which thus precluded the need for laparotomy.

A search for improved forms of systemic chemotherapy in advanced ovarian carcinoma has resulted in two prospective trials at the Medicine Branch National Cancer Institute. The first trial compared high-dose, split-course intravenous cyclophosphamide with conventional treatment with an oral alkylating agent, melphalan [also called L-phenylalanine mustard (PAM)]. While both regimens were essentially equal in therapeutic efficacy, the former was considerably more toxic and the latter was therefore preferred. The second trial employed a 4-drug combination (5-fluorouracil, methotrexate, cyclophosphamide, and hexamethylmelamine); the results indicated a higher overall response rate (85%) and a higher complete remission rate (31%) with the combination therapy than with the PAM therapy, although the study is short and the observations are preliminary.

The use of high-volume i.p. chemotherapy with methotrexate (7.5 to 50 microM methotrexate administered via peritoneal dialysis technique) was studied in four patients with ovarian cancer and one patient with malignant melanoma. All had tumor localized to the peritoneal cavity or liver. Methotrexate concentration in the peritoneum could be maintained 18- to 36-fold higher than corresponding plasma concentrations using this method, plasma levels remaining in the range of 0.2 to 3 microM. While local toxicity was generally limited and manageable, mild aseptic peritoneal irritation was commonly seen, and one episode of bacterial peritonitis did occur. Because of the concentration difference between peritoneum and the systemic circulation, systemic toxicity was moderate with only six of 29 treatment cycles resulting in myelosuppression. No definite therapeutic benefit was seen, but the tumors of four of five patients had demonstrated resistance to a methotrexate-containing chemotherapeutic regimen prior to this study. Further investigation of this novel treatment modality is warranted. In addition, this study provides the first measurement of peritoneal methotrexate clearance and the ratio of peritoneal in total body clearance.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.