Disposition and metabolism of pentamethylmelamine and hexamethylmelamine in rabbits and humans.
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The disposition and metabolism of pentamethylmelamine (PMM) and hexamethylmelamine (HMM) were studied in the rabbit, and the disposition of PMM was studied in humans. Parent compound and metabolites were identified by thin-layer chromatography, gas chromatography, and gas chromatography/mass spectrometry analyses. Plasma elimination in both species following i.v. administration of each drug was best described by a two-compartment open model. Both compounds were extensively demethylated with less than 1% of the total dose administered recovered in the urine over 24 hr. The areas under the plasma time-concentration curves of PMM and HMM following p.o. administration to rabbits were 5 and 25% of the areas following i.v. administration. Gastrointestinal absorption was rapid and efficient with 75 to 89% of drug equivalents recoverable in the urine after p.o. administration of [ring-14C]PMM or [ring-14C]HMM to rabbits. Reduced bioavailability of PMM and HMM p.o. appears to be a consequence of rapid metabolism presumably in the liver. (+info)
Recurrent ovarian cancer: how important is it to treat to disease progression?
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Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment. (+info)
Pretreatment CA-125 and risk of relapse in advanced ovarian cancer.
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PURPOSE: A previous report suggested the nadir serum CA-125 level within the group of patients with ovarian cancer who achieved normalization of CA-125 accurately defined the risk of relapse. Using similar CA-125 subgroups, we sought to determine if the baseline CA-125 level before initiation of maintenance chemotherapy in women achieving a clinically-defined complete response to primary chemotherapy would be of prognostic value. PATIENTS AND METHODS: Patients included in this retrospective analysis had been treated on one of two previously reported trials of maintenance chemotherapy (three v 12-monthly cycles of paclitaxel; oral altretamine), with a baseline CA-125 level of < or = 35 u/mL. Progression-free survival (PFS) from study entry was analyzed by the Cox regression model. RESULTS: The distribution of premaintenance baseline CA-125 levels for the 384 patients was 58%, 34%, and 8% for values of (A) < or = 10 u/mL, (B) 11 to 20 u/mL, and (C) 21 to 35 u/mL, respectively. The baseline CA-125 was highly statistically significant, either as a categoric variable (P < .001) or as a continuous variable (P < .0001). Median PFS was 24 months, 17 months, and 7 months for groups (A), (B), and (C), respectively. There was no evidence the CA-125 effect differed by trial or treatment in an interaction analysis (P = .70). CONCLUSION: The baseline CA-125 level before initiation of maintenance chemotherapy strongly predicts the risk of subsequent relapse. Patients with premaintenance baseline CA-125 values < or = 10 u/mL have a superior PFS compared with higher levels in the normal CA-125 range. (+info)
Relationship between frailty and cognitive decline in older Mexican Americans.
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Subrenal capsule assay in selection of chemotherapy after operation for recurrent ovarian cancer.
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Forty-six patients with recurrent ovarian cancer were reoperated, and cancer samples for the subrenal capsule assay (SRCA) were collected from 23 of them, whereas this test was not done in the remaining 23 control patients. The SRCA was evaluable in 22 cases (96%). Taken together, no significant difference appeared in the 3 years' survival figures between the groups: seven of 22 patients (32%) with the evaluable SRCA and six of 23 control patients (26%) were alive. However, a further analysis of the data revealed that the SRCA guided the selection of chemotherapy only in 15 patients, whereas tumour samples were resistant to all cytostatics tested in six cases and toxic side-effects limited the clinical application of the test results in the remaining one case. Four of the 11 patients (36%) whose further chemotherapy was strictly chosen based on the SRCA and seven of the 24 patients (29%) whose treatment was based on physician's choice survived at least 3 years. Our conclusion is that the SRCA is of limited value in the selection of second-line chemotherapy in recurrent ovarian cancer. (+info)
Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience.
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Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed. (+info)
Hexamethylmelamine as consolidation treatment for patients with advanced epithelial ovarian cancer in complete response after first-line chemotherapy.
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Prognostic factors in advanced epithelial ovarian cancer. (Gruppo Interregionale Cooperativo di Oncologia Ginecologica (GICOG)).
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The data on 914 patients enrolled in four randomised trials in advanced ovarian cancer, consecutively conducted by the same cooperative group between 1978 and 1986, were analysed with the aims of: (1) determining the impact of selected prognostic variables on survival; (2) finding, from the interaction of favourable prognostic factors and treatment, an approximate estimate of the magnitude of the survival advantage associated with the use of platinum-based combination chemotherapy. The overall 3-year survival in this series of patients is twice that reported historically (22%; 95% CL 18.7-25.4). The proportional hazard regression model was used to perform the analysis on survival. Residual tumour size, age, FIGO stage and cell type were all independent determinants of survival. Differences in survival from the various prognostic groups were impressive with 5-year survival rates ranging from 7 to 62%. However, these differences were not qualitative (i.e. the kinetics of survival were similar for the best and the worst groups) suggesting that current prognostic factors are of little use for selecting 'biologically' different sub-populations. Platinum-based regimens were associated to an overall prolonged median survival, but this benefit was not observable in the subgroup with most favourable prognosis (less than 2 cm residual tumour size). The implications of these observations for clinical research and ovarian cancer patients care are discussed. (+info)