Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer.

BACKGROUND: To evaluate the use of D-methionine(D-met) as a cytoprotectant in the context of clinically relevant doses of cisplatin. MATERIALS AND METHODS: Forty five Fischer rats were injected intraperitoneally with 10(6) NuTu-19 cells and treated as follows: group 1 was the control group and received no treatment, group 2 received cisplatin 4 mg/kg and group 3 received cisplatin 4 mg/kg plus D-met. There were two groups that received high dose cisplatin. Group 4 received cisplatin 8 mg/kg and group 5 received cisplatin 8 mg/kg plus D-met. Treatment was initiated four weeks after injection of the NuTu-19 cells, and consisted of four weekly intraperitoneal injections. Serum BUN and creatinine levels in the high dose groups evaluated nephrotoxicity and clinical outcome was measured by mean survival using Kaplan Meier analysis. RESULTS: There were no significant elevations in serum BUN or creatinine levels in any of the rats treated with high dose cisplatin. In the animals given cisplatin 8 mg/kg plus D-met, death from toxicity was prevented and all animals completed four treatments. In contrast, only two animals in group 4 (cisplatin 8 mg/kg alone) completed 4 treatments. There was a significant improvement in survival for the animals given D-met. (p = .0001) In all treated groups except for group 4, there was an improvement in survival compared to the control group. When comparing groups 2 and 3 (4 mg/kg +/- D-met), there was a subjective decrease in tumor response for group 3 but mean survival was not statistically different. (91 vs. 81 days; p = 0.07) A comparison of groups 2 and 5 revealed no survival benefit using high dose cisplatin with D-met. (91 vs. 79 days; p = 0.10). CONCLUSIONS: Our results indicate that D-methionine provides cytoprotection against cisplatin toxicity without significant compromise of antitumor activity. All though D-methionine allowed for significant dose intensification of cisplatin above standard doses, there was no survival advantage noted in this group of animals. The indications for its use in the treatment of ovarian cancer remain to be determined.

Management of ovarian cancer in patients older than 80 years of Age.

OBJECTIVE: The objective of this study was to examine the treatment, associated morbidity, and survival in very elderly patients with epithelial ovarian cancer. METHODS: A retrospective analysis of patients 80 years of age and older treated for epithelial ovarian cancer by the Gynecologic Oncology faculty at the University of California Irvine was performed. RESULTS: Eighteen patients were older than 80 years of age at the time of diagnosis of ovarian cancer. Median age was 83 years (range 80-86 years). There were 2 stage I, 10 stage IIIC, 4 stage VI, and 2 unstaged patients. One patient had a tumor of low malignant potential, 4 patients had grade II tumors, and 10 patients had tumors that were grade III. Eighty-three percent of patients had one or more preexisting medical illnesses. Cardiac disease, stroke, and hypertension were most common. Sixteen of 18 patients (88%) underwent primary debulking surgery. American Society of Anesthesiologists physical status classification was as follows: 7/16 (44%) class II, 6/16 (38%) class III, and 2/16 (13%) class IV. The procedures performed included 16 bilateral salpingo-oophorectomies, 11 total abdominal hysterectomies, 16 omentectomies, 3 lymph node dissections, and 7 bowel resections. Four (25%) patients were optimally cytoreduced to <1 cm of residual disease. Seventy-five percent of surgical patients received blood transfusions of 2 or more units PRBC. Mean EBL was 600 cc (range 200-4200 cc). Thirty-eight percent of patients experienced major postoperative morbidity. There were 7 patients with postoperative congestive heart failure, 3 with sepsis, 1 with aspiration pneumonia, and 2 postoperative deaths. Seventy-five percent of patients spent time in the intensive care unit. Median number of days was 3 (range 1-22 days). Mean postoperative stay was 8 days (range 6-57 days). Sixty-five percent of patients were discharged to home. The other patients were discharged to intermediate care facilities or nursing homes. Eighty-three percent of patients received chemotherapy. Of the 10 patients (63%) receiving adjuvant chemotherapy, the mean interval from surgery to initiation of therapy was 3 weeks (range 1-4 weeks). Overall median survival was 6 months (range 1-45 months). Median survival in patients with optimal debulking was 32.5 months (range 7-45 months) compared to 3.5 months (range 1-41 months) in patients suboptimally debulked. CONCLUSIONS: In patients older than 80 years of age who undergo debulking surgery for ovarian cancer, serious medical comorbidity and advanced ASA status are common. Despite aggressive surgical effort and frequent blood transfusions, optimal debulking to less than 1 cm is achieved in only 25% of patients. Impressive morbidity and mortality occurs in this group of patients, but most patients are discharged to home and are able to receive postoperative chemotherapy.