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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.

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PubMed2004

Oral altretamine used as salvage therapy in recurrent ovarian cancer.

BACKGROUND: Altretamine has reported efficacy in the treatment of recurrent ovarian cancer following platinum-based therapy. This report presents the cases of two long-term survivors with recurrent ovarian cancer given oral altretamine. CASES: Two patients diagnosed with stage IIIC ovarian cancer underwent optimal cytoreductive surgery. Both women were subsequently treated with platinum-based chemotherapy. One had persistent cancer documented 2 months post therapy, while the other was disease-free for 22 months before recurring. Both received altretamine in a salvage setting. Each of these women achieved a prolonged response to third-line altretamine therapy, and one of whom was disease-free for 4 years and the other remains disease-free over 7 years following initiation of salvage therapy. CONCLUSION: Outpatient-administered oral altretamine can provide a prolonged disease-free interval with minimal toxicity.

Administration, Oral↗

PubMed2003

Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study.

OBJECTIVE: To evaluate the activity of oral Altretamine in women with epithelial ovarian carcinoma who responded (PR or CR) to first line chemotherapy but relapsed within 6 months. The protocol was later amended to include patients with relapse within 12 months. METHODS: A multicentric phase II trial. The patients had to have measurable disease. No more than one prior chemotherapy regiment was allowed. The patients were treated with 260 mg/m(2)/day of Altretamine in four divided doses for 2 weeks, repeated every 4 weeks. The response was evaluated after every two courses. RESULTS: Thirty-one eligible patients were treated with a median of 3 courses of Altretamine (range 1-12). Hematological toxicity was minimal. Gastrointestinal toxicity was common. Response evaluation was possible for 26 patients. Three patients (9.7% intent-to-treat) achieved a partial response. Eight patients had stable disease, and 15 patients had progressive disease after two treatment courses. The median time to progression was 10 weeks (range, 5-51 weeks). Medial survival was 34 weeks (range, 7-112+). CONCLUSION: Altretamine should not be chosen as standard treatment in patients with platinum-resistant recurrent ovarian cancer. However, Altretamine represents a useful alternative in patients who prefer oral treatment or when socioeconomic considerations are an important issue.

Administration, Oral↗

PubMed2001

A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer.

PURPOSE: The efficacy and pharmacokinetics of paclitaxel when combined with altretamine for ovarian cancer were studied. METHODS: A group of 30 patients, whose only chemotherapy was one or more cisplatin-based non-paclitaxel-containing regimens and whose ovarian cancer failed to respond or had relapsed within 6 months of their last platinum regimen, received paclitaxel as a 3-h intravenous infusion and altretamine given orally in four divided doses daily for 14 days repeated every 28 days. Doses were escalated from paclitaxel/altretamine 135/150 mg/m2 to 250/300 mg/m2 in cohorts of three patients. RESULTS: The dose-limiting toxicities at 250/300 mg/m2 were WHO grade 3 myalgias and arthralgias in two patients and grade 3 lethargy, stomach cramps, peripheral neuropathy and vomiting in single patients. Considering all dose levels in cycle 1, 16 patients had grade 3 or 4 neutropenia but there was only one episode of febrile neutropenia. Other grade 3 toxicities were vomiting in four patients, myalgias in three, peripheral neuropathy in two and lethargy in two. Grade 3 alopecia occurred in 23 patients. Three patients achieved a complete response and 12 achieved a partial response for an overall objective response rate of 50%. Responses occurred at all dose levels of 175/150 mg/m2 and higher. The median freedom from progression was 35 weeks, with a median survival of 55 weeks. Altretamine did not alter the pharmacokinetics of paclitaxel and there were no consistent differences in paclitaxel pharmacokinetic parameters or toxicities between course 1 and 2. No dose-response relationships were evident above paclitaxel/altretamine 175/150 mg/m2. CONCLUSION: Paclitaxel and altretamine can be safely combined and with a high response rate in relapsed ovarian cancer, justifying further studies with this combination.

Administration, Oral↗

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.

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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↗

PubMed2001

Altretamine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group trial.

Thirty patients with advanced renal cell carcinoma were treated on a phase 11 trial with altretamine. Altretamine was administered orally at a dosage of 260 mg/m2 days 1 through 14 with cycles repeated every 28 days. Nausea and vomiting were the most common toxicities. Ten percent (3 of 30) experienced Grade 3 gait abnormalities. None of the thirty evaluable patients achieved a complete or partial response. In summary, altretamine did not show antitumor activity in the treatment of advanced renal cell carcinoma.

Adult↗

PubMedDate not supplied

Long-term follow-up of a phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer in the Southwest Oncology Group.

OBJECTIVE: This report provides follow-up progression-free survival (PFS) and median survival data for women who achieved clinical complete remission (cCR) from stage III ovarian cancer after first-line therapy and were treated with altretamine consolidation therapy. METHODS: Patients who enrolled in the SWOG 9326 study from September 1993 to July 1997 were required to have documented cCR from stage III ovarian cancer following front-line platinum-based therapy. Treatment consisted of 6 months of oral altretamine at 260 mg/m(2)/day for 14 consecutive days of a 28-day cycle. RESULTS: Ninety-seven of 112 enrolled patients were evaluable for efficacy. This report presents median 6.2-year follow-up, dating from study registration. Median PFS was 28 (95% CI: 19-43) months. Median PFS for patients with optimal disease was 45 (95% CI: 27-48) months and for patients with suboptimal disease was 17 (95% CI: 12-26) months. Twenty-six of 61 (43%) patients with optimally debulked lesions and 5 of 36 (14%) patients with suboptimally debulked lesions remained disease free. Median survival of patients with optimally debulked disease has not been reached; median survival of patients with suboptimally debulked disease was 39 (95% CI: 19-51) months. No treatment-related adverse events were reported during the follow-up period. CONCLUSIONS: Consolidation therapy with oral altretamine was generally well tolerated and associated with prolonged progression-free and overall survival in the Phase II setting.

Administration, Oral↗

PubMed2001

Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326).

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.

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↗

PubMed2001

Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer.

BACKGROUND: Management of patients with recurrent epithelial ovarian cancer is difficult. Although several agents are active, responses are short-lived and observed in only a small number of patients. Side effects of these drugs are substantial. There is a need for more effective and less toxic therapies. Altretamine is a well tolerated oral agent with minimal toxicity. There are only a few trials evaluating its efficacy as a single agent in recurrent epithelial ovarian cancer. METHODS: We prospectively studied patients with recurrent epithelial ovarian cancer who were able to take oral medication and had adequate bone marrow, liver and renal functions. All had been previously treated with at least one platinum-based chemotherapy regimen and had either relapsed or failed to achieve an adequate response. RESULTS: Seventeen patients were studied. The commonest histological subtype was serous adenocarcinoma. Seven patients had platinum refractory disease. The mean duration of therapy was 6.1 months. Six patients (35%) achieved complete or partial remission, time to progression was 6.0 months and mean overall survival was 15.1 months. Toxicity was primarily nausea, vomiting and asthenia and was easily manageable. CONCLUSION: Altretamine is an acceptable and apparently less toxic alternative to other cytotoxic drugs used for palliation of patients with recurrent epithelial ovarian cancer.

Administration, Oral↗

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↗

PubMed2000

[Combination chemotherapy with hexamethylamine (Hexalen, Altretamine, Hexastat) and sarcolysine in advanced ovarian carcinoma].

Combination chemotherapy with hexamethylmelamine (hexalen, altretamine, hexastat), 100 mg, thrice a day, per os, 14 days (out of a 28-day course) and sarcolysin, 15 mg, per os, during the first 5 days of the course, was received by 24 patients with primary advanced tumors of the ovaries, prior to or after cytoreductive surgery. Total apparent response to chemotherapy among 19 patients of the study group was 47.2%, clinically significant (plus stabilization)--94.5%, without significant untoward side-effects (vomiting--19%; leukopenia degree II-III--33% and thrombocytopenia--19%). The drug proved an active component of combination therapy for advanced ovarian carcinoma.

Adult↗