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PubMed1995

Altretamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cancer chemotherapy.

Altretamine (hexamethylmelamine) is a cytotoxic antineoplastic agent which appears to require metabolic activation. Metabolic intermediates may act as alkylating agents; however, altretamine is not directly cross-resistant with classical alkylating agents. Objective response rates to orally administered altretamine as salvage therapy in patients with advanced ovarian cancer were 0 to 33%, with disease stabilisation in a further 8 to 78% of patients. Response rates appear to be higher in patients who have responded to previous alkylating agent or cisplatin-based therapy. There is some evidence that addition of altretamine to platinum-based combination regimens used for induction therapy of advanced ovarian cancer may improve long term survival, particularly in patients with limited residual disease. Although altretamine displays some activity in small cell lung cancer, it is unlikely to have any clinical role in the management of non-ovarian cancer. Altretamine appears to be relatively well tolerated, with gastrointestinal, neurological and haematological toxicities being the main dose-limiting adverse effects. However, assessment of accurate incidence rates for these effects is complicated by the use of altretamine with cisplatin. On the basis of the emerging body of clinical evidence, altretamine appears to have a limited role in the treatment of persistent or recurrent advanced ovarian cancer, primarily in patients who are potentially platinum sensitive yet intolerant of platinum analogues. Additionally, altretamine may be added to platinum-based regimens for induction therapy of advanced ovarian cancer. At the doses currently recommended, altretamine offers a reasonably well tolerated regimen that can be administered orally and is suitable for use on an outpatient basis.

Altretamine↗
PubMed1991

Altretamine.

Altretamine is a National Cancer Institute-designated group C antineoplastic agent used in the treatment of advanced ovarian cancer. Altretamine is a highly lipid-soluble drug available only for oral administration as a capsule. The drug is activated through metabolic oxidation to intermediate methylol derivatives and formaldehyde. It is unclear which metabolite is the major species responsible for cytotoxicity or the primary mechanism of cytotoxicity. As a single agent in the treatment of ovarian cancer, altretamine demonstrates a response rate similar to other active agents in this disease (21-39 percent). The major utility of altretamine is in combination with other agents such as cyclophosphamide, doxorubicin, fluorouracil, melphalan, and cisplatin. However, few randomized trials have evaluated the contribution of altretamine in these multiagent combinations. Dose-limiting toxicities include gastrointestinal (nausea, vomiting, anorexia), hematologic, and neurotoxic (peripheral neurotoxicity). The therapeutic role of altretamine is limited because of a toxicity profile similar to that of cisplatin, one of the more active agents in ovarian cancer. Its use should be reserved for patients who are not candidates for more standard platinum-based regimens.

Altretamine↗
PubMed1991

Analysis of prognostic factors and survival in patients with ovarian cancer treated with second-line hexamethylmelamine (altretamine).

Hexamethylmelamine (altretamine, HMM) 260 mg/m2/day p.o. for 14 days followed by a 14-day drug-free interval was administered to 52 outpatients with advanced ovarian cancer who had previously been treated with chemotherapy. Prior to HMM, 92% (48/52) of these patients had received cisplatin and cyclophosphamide with or without doxorubicin. Two more patients received other cisplatin-based regimens. At the completion of HMM therapy, 15% (8/52) displayed no evidence of disease (NED). Of these eight patients, five are still alive 32 to 82 months after altretamine therapy (median follow-up of 46 months). At 41 months, one patient died of intercurrent illness with no clinical evidence of recurrence; the other two patients died of their disease at 21 and 31 months following HMM therapy. The median survival of the total group was 11 months: nine months for patients who did not respond to altretamine and 46+ months for patients with NED after altretamine (p less than 0.05). Intermittent oral administration of single-agent altretamine was well tolerated: eight patients reported moderate gastrointestinal symptoms, and only one patient reported severe gastrointestinal symptoms. Moderate neurologic toxicity was reported by five patients. No WBC fell below 2000 mm3 and platelet counts fell below 100,000 mm3 in only three patients; no patient experienced severe hematologic toxicity. In this series of patients, the overall response (15%) was comparable to or better than those reported for more toxic chemotherapeutic regimens. On the basis of these data and those reported by other investigators, HMM warrants consideration as a reasonable option in the management of recurrent or persistent ovarian cancer.

Altretamine↗
PubMed1994

Determination of altretamine in human plasma with high-performance liquid chromatography.

A fast, simple, and sensitive isocratic HPLC method has been developed and validated for the determination of the anticancer drug altretamine in human plasma. Spiked serum samples and clinical plasma samples are extracted with acetonitrile at 4 degrees C and the precipitate removed by filtration. The plasma sample volume required (ca. 0.2 ml) is small and the total analysis time is less than 15 min per sample (including batch-wise pre-treatment). Recovery of altretamine is 99 to 106% for pooled human serum spiked with altretamine in the range 200 ng/ml to 10 mg/ml. In this concentration range, the R.S.D. varies from 1 to 8%. The limit of quantitation is ca. 150 ng/ml for an R.S.D. of 10%. The intra-day R.S.D. for human samples spiked at 5 mg/ml varied between 1.7 and 4%; the inter-day R.S.D. at this concentration was ca. 3%. A preliminary study with one patient receiving 260 mg/m2 by mouth indicated that the peak altretamine concentration was significantly lower after a standard breakfast than in the fasting state.

Altretamine↗
PubMed1997

Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125.

PURPOSE: A phase II study was performed of oral altretamine in 71 patients with ovarian carcinoma who entered clinical complete remission with CA125 levels less than 35 U/mL after initial or second-line chemotherapy, and relapsed more than 6 months later. Response was compared between standard and CA125-based criteria. PATIENTS AND METHODS: Altretamine 260 mg/m2 was given in divided doses daily for 14 days per month. Response was evaluated according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 45 of 66 eligible patients. Response was assessed according to precise CA125 criteria in 51 patients based on either a confirmed > or = 50% or > or = 75% decrease in CA125 levels. RESULTS: A combination of domperidone, dexamethasona, and chlorpromazine at night controlled toxicity in most patients, which was mainly nausea (National Cancer Institute criteria grade 2 or 3 in 27), vomiting (grade 2 or 3 in 19, grade 4 in one), and tiredness (grade 2 or 3 in 15). Responses (complete plus partial) were seen in 18 (40%; 95% confidence interval [CI], 25.4% to 54.6%) of those evaluated according to EORTC criteria and in 20 (39%; 95% CI, 25.5% to 52.9%) of those evaluated according to CA125 level. The overall response rate was 26 of 57 (45.6%) and was related to treatment-free interval: 6 to 12 months, 35%; 12 to 24 months, 52%; and greater than 24 months, 67%. The medium duration of response was 8 months. CONCLUSION: Oral altretamine is a useful agent in patients-who relapse after previously responsive ovarian cancer. Response evaluation by a strict CA125 definition gave a similar estimate of the efficacy of altretamine as EORTC criteria.

Administration, Oral↗
PubMed1995

Clinical pharmacokinetics of altretamine.

Altretamine (hexamethylmelamine) is an antitumour drug with demonstrated antitumour activity in refractory ovarian cancer. Due to its poor water solubility, the drug has been given by the oral route. In all animal species, including humans, altretamine undergoes oxidative N-demethylation with the formation of hydroxymethyl derivatives as intermediates. Hydroxymethylmelamines are believed to be responsible for the cytotoxic and antitumour activity of the drug. The inter-hand intrapatient variability of the bioavailability of altretamine after oral administration represents an important drawback for effective clinical use of this drug. The variability appears to be mostly related to the first-pass effect and therefore may be overcome by intravenous administration of the drug. Although attempts to administer the drug intravenously have not been successful in the past, some investigations on the use of the new parental formulation of altretamine are in progress.

Administration, Oral↗
PubMed1998

Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial.

OBJECTIVES: In an effort to critically examine the antitumor activity of altretamine (hexamethylmelamine) as salvage therapy of platinum-refractory ovarian cancer, the Gynecologic Oncology Group initiated a Phase II trial of the agent administered in this clinical setting. METHODS: Altretamine was administered at a dose of 260 mg/m2 orally for 14 days in a 28-day course. Treatment was continued until disease progression or unacceptable side effects prevented further therapy. A total of 36 patients (median age: 56.5) were treated on this trial, of whom 33 were evaluable for toxicity and 30 for response. All patients had previously received either cisplatin or carboplatin and paclitaxel. RESULTS: The major side effect was emesis (grade 3-4, 7/33, 21%). The objective response rate was 10% (one complete response, two partial responses). CONCLUSION: We conclude that altretamine has limited activity in platinum-refractory ovarian cancer.

Administration, Oral↗
PubMed1989

The bioavailability of three altretamine formulations.

The bioavailability of two altretamine preparations was studied in a randomized cross-over design. The two preparations were compared with a third in a parallel design. Dissolution differences between the preparations were observed, which could give rise to differences in bioavailability caused by the extensive first-pass effect of altretamine. The in vivo data showed a trend to differences in bioavailability.

Adult↗
PubMed1996

Phase II evaluation of altretamine for advanced or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study.

A Phase II trial was conducted by the Gynecologic Oncology Group to determine the activity of altretamine in previously treated patients with squamous cell carcinoma of the cervix. Thirty-two women with advanced or recurrent squamous cell carcinoma of the cervix were entered. The starting dose was 260 mg/m2/day for 21 days every 4 weeks. Twenty-six patients were evaluable for response and 29 were evaluable for toxicity. Among the 26 evaluable patients, 21 had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1-6). Grade 3 or 4 gastrointestinal toxicity, occurring in 17%, was the most common complication (grade 3, 13.8%; grade 4, 3.4%). Grade 3 anemia was slightly less common occurring in 13.8%. Grade 3 peripheral neurotoxicity occurred in 3.4%. There were no objective responses, demonstrating that this agent is useful in previously treated squamous cell carcinoma of the cervix.

Altretamine↗
PubMed1989

Fluorouracil, doxorubicin, cisplatin and altretamine in the treatment of metastatic carcinoma of unknown primary.

Eighty-five patients, median age 55 years, with evolutive metastatic carcinoma of unknown primary (CUP) were included in this study. The treatment combination consisted of fluorouracil (5-FU) (600 mg/m2 in a 30 min infusion) days 1 and 8, doxorubicin (DXR) (30 mg/m2 by i.v. bolus injection) day 1 and cisplatin (CDDP) (80 mg/m2 in a 4-h infusion) day 1. Altretamine (HMM) (150 mg/m2) was administered orally days 2-8, therapy being resumed every 29 days. An objective response was noted in 18/85 patients (21%) with a median duration of response of 7 months. Thirty-three/77 patients (43%) who had tumor-related symptoms were relieved of their troubles. The overall median survival of patients was 7 months; the median survival of responders was 12.5 months. Toxicity occurred in one-third of patients (mainly digestive and hematologic), leading twice to a halt in treatment and to drug dose reduction in 26/77 (33%) evaluable patients. Such a regimen is of limited efficacy, has a non-negligible toxicity and appears of little interest in such a palliative situation.

Adult↗
PubMed1996

Patient compliance with prolonged oral altretamine treatment in relapsed ovarian cancer.

Using an 'intelligent' tablet bottle which, unknown to the patient, electronically records the times of opening, we have assessed the compliance of patients with prescribed oral altretamine for ovarian cancer. During the periods of compliance monitoring the physical and mental state of the patients was also monitored by means of self-assessed diary cards. 11 patients were assessed over 21 monitoring periods, each of 14 days, representing a total of 294 days. The Overall Compliance (OC), which we define as the number of bottle openings in a monitoring period as a percentage of that number expected on the assumption of perfect compliance, had a mean (SD) of 97.4 (6.9)% over the 21 periods. The OC was not related to any of the diary card measures, or to the cycle number (range 1-5) of the treatment. The high level of compliance is encouraging and is in line with our previous reports in patients with lymphoma and with small cell lung cancer.

Administration, Oral↗
PubMed1991

A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) vs. cyclophosphamide, doxorubicin, and cisplatin (CAP) in advanced ovarian cancer.

We retrospectively compared the results of treatment with hexamethylmelamine (HMM), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with advanced ovarian cancer. The treatments were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following 6 months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) and 14/21 (67%) patients had objective responses to H-CAP and CAP respectively (p = 0.001). The pathologic complete response rate as determined by second-look laparotomy was higher in the patients who received H-CAP (35% vs. 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. In limited residual disease patients (maximum tumor diameter less than or equal to 3 cm), the median survival also favored the H-CAP treatment (101 months vs. 21 months, p = 0.002). The median time to progression was greater in patients receiving H-CAP vs. those receiving CAP (67 months vs. 16 months, p = 0.045). Treatment-related toxicity was similar for the two regimens. These findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival for patients with limited residual disease advanced ovarian cancer.

Altretamine↗
PubMed1993

Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis.

BACKGROUND: In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. PURPOSE: This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. METHODS: We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. RESULTS: The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. CONCLUSIONS: Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. IMPLICATIONS: Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.

Altretamine↗