A 5-year strategic research network with a diverse base of industry, government, and academic partners was approved for support by National Sciences and Engineering Research Council of Canada (NSERC) on January 3, 2005. This Metals in the Human Environment Strategic Network (MITHE-SN) builds on, and further extends, science knowledge developed by the NSERC-sponsored Metals in the Environment Research Network (MITE-RN, 1999-2004). In addition to the initial award, the MITHE-SN received an additional 2-year grant specifically targeted to (1) enhance training opportunities for internships with international organizations, (2) increase international networking and linkages, and (3) optimize knowledge dissemination and technology transfer. The research program is comprised of three themes and represents a cascade of effects along food webs, from the lowest trophic levels to the highest consumers. Each of the themes addresses issues related to distinguishing the magnitudes and roles of natural background and anthropogenic metal inputs in biotic exposure to metals; estimating the bioavailable fraction of metals in the exposure media, thus better quantifying the true exposure concentration; and determining the factors that influence bioavailability of metals in media, so that predictive models can be developed for use in the development of site-specific metals criteria.

BACKGROUND:This study reviews the experience at the University of Texas M.D. Anderson Cancer Center with elderly patients treated for advanced epithelial ovarian cancer with cisplatin-based combination chemotherapy.METHODS:From 1978 through 1988, 215 patients with Stage III or IV, Grade 2 or 3 epithelial ovarian cancer were entered onto one of three consecutive trials involving cisplatin-based combination chemotherapy. The treatment plans were as follows: Trial 1: 12 cycles of cisplatin-melphalan (75 patients); Trial 2: 12 cycles of cisplatin-cyclophosphamide (49 patients); and Trial 3: 6 cycles of cisplatin-cyclophosphamide (91 patients). End-points of analysis included the effect of age on other prognostic factors, clinical response rate, surgical response rate, toxicity, progression-free survival, and survival.RESULTS:Of the entire study group, 57 patients (27%) were 65 years of age and older at diagnosis. There was no effect of age on FIGO stage or histologic grade distribution, but 61% of patients younger than 65 years of age had residual tumors less than or equal to 2 cm compared with only 33% of patients 65 years of age and older (P = 0.00027). There were no differences between the two age groups with respect to response rates, recurrence rate after negative second-look surgery, toxicity, or progression-free survival. Patients in the younger than 65 years of age group, however, had a significantly longer median survival time than those 65 years of age and older (30 versus 19 months, respectively) (P = 0.0038).CONCLUSIONS:This analysis suggests that elderly patients are more likely to begin chemotherapy with bulky residual disease and to have a significantly shorter survival time than their younger counterparts.

BACKGROUND:Paclitaxel is a diterpenic plant product that has significant activity in several solid tumors, including epithelial ovarian cancer. After promising results in Phase I and II studies, its use has increased dramatically. With this increased use, isolated reports of local tissue reactions to paclitaxel have been described. The purpose of this study was to characterize further the presentation and clinical course of this toxic effect. METHODS:Nine hundred fifty-five courses of paclitaxel were administered to patients with gynecologic malignancies at M. D. Anderson Cancer Center during a 13-month period. Nineteen (2%) local infusion-site injuries in 17 patients were observed. RESULTS:The primary disease site was the ovary in 13 patients, the peritoneum in 2, and the endometrium in 2. Paclitaxel was administered as initial therapy in 6 patients and as salvage therapy in 11. Clinical evidence of infiltration was documented during infusion in 8 of 19 (42%) reported episodes. Immediate reactions consisting of mild discomfort, erythema, and edema were observed in six patients, three of whom had complete resolution of the lesion within 1 month. The remaining patients noted initial development of injury between 3 and 13 days after paclitaxel infusion. The typical injury was a discolored, raised, rounded, and indurated lesion that was moderately painful. Two patients (11%) had Grade 1 lesions, 13 (68%) had Grade 2 lesions, and four (21%) had Grade 3 lesions with central ulceration. Cellulitis requiring intravenous antibiotic therapy was associated with two lesions. At last follow-up, 13 injuries had persistent discoloration and induration; one patient had persistent ulceration present at the time of her death 6 months after presentation and one patient underwent excision of a persistent lesion at 12 months. CONCLUSIONS:Given the incidence of Grade 2 and Grade 3 local reactions, it appears that paclitaxel should be considered a vesicant.

Purpose. The primary goal of this trial was to evaluate the clinical activity and the toxicity of a combination of cisplatin and carboplatin for women with advanced-stage epithelial ovarian cancer. Patients and methods. Fifty-one consecutive evaluable patients with untreated stage III and IV epithelial ovarian cancer received 360 mg/m2 carboplatin on Day 1 and 50 mg/m2 cisplatin on Day 2 administered intravenously every 28 days for six cycles. Drug doses were adjusted for hematologic toxicity based on nadir counts during the prior therapy course. Dose levels included 300-400 mg/m2 carboplatin and 50-75 mg/m2 cisplatin. Second-look surgery was optional. Endpoints were clinical response, surgical response, progression-free survival, and survival. Results. Of 8 patients with measurable disease, 3 (37.5%) had a clinical compete response, and 3 (37.5%) had a clinical partial response, for an overall clinical response rate of 75%. Of 39 patients who began chemotherapy with abnormal serum levels of CA 125, 31 (79%) achieved normalization of CA 125 at the completion of chemotherapy. Thirteen patients underwent second-look laparotomy. Of these, 7 (54%) had a pathological compete response, and 2 (15%) had a partial response. The median progression-free survival was 14 months, and the overall median survival was 32.5 months. Neutropenia and thrombocytopenia were the main dose-limiting toxicities. In addition, 9 patients developed grade 2 and 3 developed grade 3 ototoxicity. Conclusion. This regimen is very active against advanced-stage epithelial ovarian cancer. The degree of ototoxicity observed is worrisome, but such toxicity may be ameliorated by limiting the dose of cisplatin and increasing the dose of carboplatin.

From 1978 until 1988, 116 patients with epithelial ovarian cancer were entered onto one of three consecutive prospective clinical trials involving cisplatin-based combination chemotherapy. They had the following characteristics: (1) stage III or IV disease, (2) grade 2 or 3 tumors, and (3) optimally debulked tumors (residual disease ⩽2 cm). The purpose of the study was to investigate the influence of duration of chemotherapy on survival. The treatment plans were as follows: Trial 1, 12 cycles of cisplatin/melphalan (43 patients); Trial 2, 12 cycles of cisplatin/cyclophosphamide (24 patients); and Trial 3, 6 cycles of cisplatin/cyclophosphamide (49 patients). The total dose of cisplatin was 60 mg/m2 in the first trial and 50 mg/m2 in the second and third trials. Median survival times for the three groups were 58, 29, and 35 months, respectively (NS). Median progression-free survival (PFS) times were 37, 23, and 15 months, respectively (P = 0.0008). Combining patients from the first two trials, the median PFS for patients receiving 12 planned cycles of chemotherapy was 30 months versus 15 months for patients receiving 6 planned cycles (P = 0.0004). Using a forward stepwise Cox proportional hazard model, the use of 12 cycles of therapy and melphalan predicted increased PFS (P = 0.0001 and P = 0.0002, respectively). In view of these results, the lack of published data supporting the superiority of 6 over 12 cycles of chemotherapy, and the rather recent availability of less toxic maintenance therapy (i.e., carboplatin), we believe that a multiinstitutional trial comparing the 6-cycle regimen with more prolonged chemotherapy is justifiable.