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PubMed1984

Combination chemotherapy and immune capacity in advanced ovarian carcinoma.

The effects of chemotherapy with either Chap-5 (a drug regimen consisting of adriamycin, cis-dichlorodiammine platinum (II), hexamethylmelamine and cyclophosphamide) or Hexa CAF (a drug regimen consisting of methotrexate, 5-fluorouracil, hexamethylmelamine and cyclophosphamide) on the immunocompetence of 22 patients with advanced ovarian carcinoma were studied. Both primary and secondary humoral and cellular immune responses in vivo were studied. In addition, the numbers of granulocytes, lymphocytes and monocytes in peripheral blood were determined, as well as the levels of immunoglobulins and complement proteins. Furthermore, the proliferative capacity of lymphocytes, cytotoxic T-cell function, and K- and NK-cell activities were measured. The results indicate a depression of the primary humoral immune response in vivo in patients receiving Chap-5. Furthermore, a decrease of several parameters in vitro was observed. However, these alterations were only moderate and rapidly reversible.

Adult↗
PubMed1987

Cyclophosphamide, hexamethylmelamine, adriamycin and cisplatin combination chemotherapy in mixed mesodermal sarcoma of the female genital tract.

Clinically mixed mesodermal sarcoma is a different entity among the other subtypes of soft tissue sarcomas. Although adriamycin is considered to be the most active single agent in the treatment of adult soft tissue sarcomas, the drug has only limited activity in mixed mesodermal sarcomas. On the other hand, cisplatin is inactive in soft tissue sarcomas, but was reported to be active in mixed mesodermal sarcomas. Therefore combinations including both adriamycin and cisplatin appear attractive for testing in the treatment of mixed mesodermal sarcomas. We have performed a pilot study with two combinations in mixed mesodermal sarcomas of the female genital tract. Two patients treated with adriamycin and cisplatin showed rapid progression. Of 7 patients treated with cyclophosphamide, hexamethylmelamine, adriamycin and cisplatin (CHAP-5), 6 had measurable disease, of whom 5 yielded a response (2 complete responses for 19+ and 40 months and 3 partial responses for 4, 7 and 8 months). The patient with non-measurable disease had a progression-free survival of 27 months. The median survival for all CHAP-5-treated patients was 20 months. This regimen is recommended for further phase II studies.

Aged↗
PubMed1989

Schedule and dosage modification of a cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin combination chemotherapy regimen for refractory ovarian cancer.

A cyclophosphamide, hexamethylmelamine, doxorubicin and cisplatin (CHAP II) regimen produced median survival of 15 and 17 months. All patients had prior chemotherapy, 26 with cisplatin in the former group, and 27 without cisplatin in the latter group. Treatment employed both a novel sequential schedule of cisplatin (usually in the evening) 24 h before cyclophosphamide-doxorubicin and novel stepwise escalation, first of doxorubicin, then of hexamethylmelamine until either nadir white blood counts fell to 1000-1500/mm3 or platelets to 75,000-100,000/mm3. Compared to prior Mount Sinai experience: (i) survival was significantly improved; (ii) with and without prior cisplatin, response rates approached a significant improvement, 12% and 29% complete and 24% and 35% partial. Five of seven additional patients with progression during unmaintained remission also responded, two with pathologically complete remissions. Findings suggest: (i) the importance of maximum dose intensity in ovarian cancer treatment; (ii) the responsiveness of patients failing first line treatment to dose intensive treatment; (iii) the possible importance of schedule, and sequential or circadian timing of cisplatin, and other drugs; (iv) and testing revised clinical criteria of resistance to drugs.

Altretamine↗
PubMed1991

Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer.

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

Altretamine↗
PubMed1984

The curative action of hexamethylmelamine on intramuscularly or intracerebrally implanted Yoshida sarcoma.

Curative effects of hexamethylmelamine (HMM, NSC 13875) against intramuscularly or intracerebrally implanted Yoshida sarcoma depend on the schedules. A twice daily oral administration over a 2-week period showed a significant chemotherapeutic advantage over a single daily administration. The observed curative effect depends on the tumour site and on its mass. The Yoshida sarcoma seems to be one of the most suitable test models for HMM or related derivatives.

Altretamine↗
PubMed1984

Predictive testing with the subrenal capsule assay.

Measurement of drug activity as an oncolytic effect, use of the control only to monitor the quality of tissue implanted, and the rapid clearance of necrotic tissue from the subcapsular site, as significant factors incorporated into the design of the assay, have permitted use of a simple tumor size parameter for evaluating drug activity. The simplicity and economy of such a parameter, the predictability and reproducibility of the 6-day assay observed thus far, and evidence that the assay does measure a biological property of the tumor apart from host response, have warranted the continued use of the 6-day time frame and the normal immunocompetent CDF1 mouse as xenograft host. These studies have demonstrated the feasibility of using human tumor explants obtained from a variety of solid human malignancies in a straightforward, short term, in vivo predictive assay system. Preliminary correlations between in vivo (assay) tumor sensitivity and clinical response have given reasonable concurrence. This crucial point will require further study, with larger numbers of patients, under more rigid conditions. Final validation of this, and other, predictive assays will require a prospective, randomized study in large numbers of patients. Our present prospective study is being continued, therefore, with expansion to a multi-institutional design over a broader geographic area.

Altretamine↗
PubMed1986

Hexamethylmelamine: a critical review of an active drug.

Hexamethylmelamine is an s-triazine that began clinical trials during the 1960s based on its level of antitumor activity in murine tumor models. Phase I studies were performed using an oral formulation given in divided doses for varying numbers of days. The most frequently reported toxicities included nausea, vomiting, abdominal cramps, anorexia, weight loss and malaise. Less frequently reported toxicities were anemia, thrombocytopenia, leucopenia and peripheral neuropathy. Clinical antitumor activity was noted in the phase I studies in a variety of tumor types. Since then a large number of studies have been performed using hexamethylmelamine as a single agent and in a variety of combinations. Unfortunately, almost none of these studies sought to define the utility of this drug relative to other treatments for the diseases in which it showed activity, or to define the contribution of this drug to the activity of any given combination. Thus its role in the treatment of patients with malignancies remains undefined.

Altretamine↗
PubMed1988

Carboplatin in combination therapy for ovarian cancer.

Cisplatin today is a cornerstone of combination chemotherapy for ovarian cancer. Carboplatin seems equal to cisplatin in antitumour activity, but has a different toxicity profile. After a feasibility study, a randomized phase III study in ovarian cancer stage II, III, and IV was undertaken, comparing carboplatin with cisplatin in combination with cyclophosphamide, doxorubicin and hexamethylmelamine. Preliminary analysis of this study reveals no statistically significant difference in response rate. Notwithstanding equal haematological toxicity, the other side effects evoked by carboplatin in combination treatment are much milder than those evoked by cisplatin. Further analysis will be necessary to draw definite conclusions about the results obtained.

Adult↗
PubMed1991

Hexamethylmelamine: pharmacology and mechanism of action.

Several conclusions can be drawn from a review of HMM preclinical and clinical pharmacology data. The drug is extensively metabolized by animals and by man. The drug is well absorbed following oral administration to animals, but oral bioavailability is low due to first pass metabolism. Based on limited human data and more complete animal data, absorption of HMM following oral administration may be quite high in man. We do not yet know the oral bioavailability of HMM in patients, but again based primarily on animal studies, oral bioavailability is most likely low and variable due to extensive first pass metabolism. Systemic exposure to HMM and demethylated metabolites following oral administration varies greatly from patient to patient and is sometimes quite low. Most patients are, however, exposed to a substantial fraction of the administered dose when determined by urinary recovery of the total dose (based on parent drug and metabolites or total radioactivity) or by the total plasma AUC of parent drug and all metabolites. Systemic exposure to HMM following intravenous administration is clearly greater and less variable than following oral administration. An unresolved question is whether the highly variable and often low systemic exposure after oral administration compromise antitumor activity when compared to intravenous administration. A key issue is whether or not one accepts the hypothesis that metabolism is a prerequisite for antitumor activity. The metabolic activation studies do not rule out other mechanisms of HMM antitumor activity. Modest activity of HMM was observed after prolonged exposure to cells which did not metabolize the drug. However, most of the accumulated data are consistent with the metabolic activation hypothesis. Certainly HMM has clinical activity when administered by mouth. If metabolism is required, then exposure to the total dose (parent drug and metabolites) could be of significance even when exposure to HMM is low, since every demethylated metabolite must have come ultimately from the initial HMM demethylation. We do not know whether the initial metabolic reaction (occurring in the liver rather than in the tumor) provides sufficient exposure of tumor to reactive species. Specifically, does the variable HMM plasma AUC seen after oral administration lead to variable delivery of potentially reactive species to tumor (by rapid breakdown and/or further metabolism of MPMM before it leaves the gut and/or liver) or are quantities of MPMM delivered to tumor comparable to those delivered following intravenous administration. The issue of rate of MPMM formation compared to rate of breakdown and ultimate delivery to tumor has been noted by Judson and Rutty.(ABSTRACT TRUNCATED AT 400 WORDS)

Altretamine↗
PubMed1991

Hexamethylmelamine for the treatment of ovarian cancer--the Mount Sinai experience.

Two regimens were tested, CHAP I and CHAP II, the latter, a hexamethylmelamine dosage-intensive regimen, first as second line (salvage) therapy and then as primary therapy. Both produced the most successful results achieved in the Mount Sinai series up to the time of their introduction, when compared to their predecessor regimens: CAP, AP and P. In an overall interim comparison, CHAP II was significantly superior to historical AP and CAP as primary therapy, as was CHAP I vs. AP in several important subgroups compared as part of a randomized trial. CHAP II overall progression-free survival was improved in spite of added new sensitive test methods. Salvage therapy also improved markedly with the addition of intensive hexamethylmelamine. Several biological and treatment characteristics strongly influenced outcome, especially young age and adding hexamethylmelamine. Other possible factors included: poor tumor grade, poor performance status, and extent of surgical debulking, even to intermediate residual, 2-6 cm size [CHAP II only]; extensive (optimum) surgery [CHAP I only]. The hexamethylmelamine-containing regimens interact favorably with some of these factors, better than did the preceding regimens. Five-year follow-up analyses weakened slightly for extensive surgery, intermediate size and poorly differentiated tumors. It confirmed and strengthened several findings favoring CHAP I & II, the hexamethylmelamine-containing regimens.

Altretamine↗
PubMed1991

The role of hexamethylmelamine in the management of ovarian cancer.

Hexamethylmelamine has been recognized as having useful single-agent activity for the treatment of ovarian cancer for the past 25 years, with some patients surviving disease-free for periods in excess of 12 years. Data from recently analysed and mature trials demonstrate that the addition of hexamethylmelamine to first-line combination chemotherapy results in significant improvements in survival compared to what is achieved with regimens of cisplatin and cyclophosphamide with or without doxorubicin.

Altretamine↗
PubMed1991

Hexamethylmelamine: activity in lymphoma and other tumors.

Hexamethylmelamine, an orally administered substituted melamine, has single agent activity in lymphoma (39% PR + CR), cervical cancer (28% PR), transitional carcinoma of the bladder (27% PR + CR), and Bilharzial bladder cancer (38% PR). Toxicity is mild and reversible and is manifested by myelosuppression, neurotoxicity and gastrointestinal toxicity. The potential role of hexamethylmelamine in combination chemotherapy in the diseases in which it has single agent activity is largely unexplored and should be investigated in clinical trials.

Altretamine↗