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Altretamine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Cancer Chemotherapy

  • Drug Evaluation
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Summary

Synopsis

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 farther 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 off ers a reasonably well tolerated regimen that can be administered orally and is suitable for use on an outpatient basis.

Pharmacodynamic Properties

Altretamine (hexamethylmelamine) is a sym-triazine cytotoxic agent which is structurally related to the alkylating agents. Its precise mechanism of action is unknown but hydroxymethyl intermediates in the metabolism process are possibly the reactive species, and may act as alkylating agents. However, altretamine is not directly cross-resistant with classical alkylating agents.

In in vitro tests altretamine required metabolic activation to demonstrate cytotoxic activity. Altretamine demonstrated in vivo activity against various human xenograft cancer models, including ovarian and lung cell lines. Its activity compared with other commonly used cytotoxic agents was variable. The cytotoxic activity of altretamine was schedule dependent against Yoshida sarcoma in rats.

Pharmacokinetic Properties

After single dose oral administration of altretamine 120 to 300 mg/m2 to patients with ovarian cancer, variable peak plasma concentrations (Cmax) of 0.2 to 20.8 mg/L occurred 0.5 to 3 hours after administration. In addition, the area under the plasma concentration-time curve (AUC) for altretamine and its metabolites showed a 50-fold interpatient variation, and neither this nor the peak plasma concentration were related to the dose administered. Differences in the rate of drug metabolism, rather than in the extent of drug absorption, would appear to account for this large inter-patient variation in Cmax and AUC.

The presence of ascites did not appear to alter the AUC and elimination half-life of altretamine following a single dose of 115 to 200 mg/m2 in patients with ovarian cancer.

The plasma distribution half-life of altretamine was 42 to 53 minutes. Altretamine concentrations were highest in fatty tissue; tumour drug concentrations were similar to those in plasma, although concentrations of altretamine in metastases were higher than in the primary tumour.

Altretamine undergoes N-demethylation in the liver, forming formaldehyde which is oxidised to carbon dioxide; the remaining triazine ring products are excreted in the urine. The terminal elimination half-life of altretamine varied from 2.3 to 13.7 hours.

Therapeutic Use

Studies conducted to date suggest that patient survival may be improved by the addition of altretamine or the combination of altretamine and doxorubicin to platinum-based regimens used for induction therapy of advanced ovarian cancer, although this remains to be conclusively established. In a retrospective comparison, the addition of altretamine to a regimen of cisplatin, cyclophosphamide and doxorubicin increased median survival from 21 to 47 months. This contrasts with the results of 2 prospective studies which showed no difference in objective response rate or survival between patients receiving altretamine, doxorubicin, cisplatin and cyclophosphamide and those administered cisplatin and cyclophosphamide (≈2.5 months). Nevertheless, at late (median ≈ 8 years) follow-up, mortality findings suggested an overall trend in favour of the 4-drug combination on long term survival: 5-year survival rates with the 2 treatment regimens were 33% and 22%. However, in a substitution study, no significant differences in survival were observed in patients receiving doxorubicin and cyclophosphamide in combination with either altretamine 150 mg/m2/day for 14 days or cisplatin 50 mg/m2 administered on day 1 (23.1 vs 25.5 months).

Subgroup analysis suggests that the addition of altretamine or the combination of altretamine and doxorubicin to cyclophosphamide and cisplatin may confer survival advantages in patients with limited residual disease following debulking surgery.

As salvage treatment in patients with ovarian cancer who had received an alkylating agent or cisplatin-based regimen, altretamine monotherapy at dosages of approximately 250 to 330 mg/m2/day administered continuously, or for 14 to 21 days of a 28-day cycle, produced objective responses in 0 to 37% of patients and disease stabilisation in 8 to 78%. Response rates were higher in patients who had previously responded to cisplatin therapy; altretamine had little activity in patients who showed true platinum resistance (disease progression during platinum therapy).

In salvage combination therapies for advanced ovarian cancer, the addition of altretamine to cisplatin and doxorubicin did not improve response rate or survival. Similarly, the combination of altretamine and melphalan was no more effective than melphalan alone.

In an early study, induction monotherapy with altretamine 8 mg/kg/day continuously produced an objective response rate of 41% and a median response duration of 32 months in patients with ovarian cancer. In this study altretamine was at least as effective as melphalan and more effective than fluorouracil.

Altretamine has demonstrated modest activity in monotherapy of small cell lung cancer, with objective response rates of 24 to 42% and survival of 5 to 7 months in patients with previously untreated disease. Limited activity has also been observed in patients with advanced head and neck cancer, Hodgkin’s disease and multiple myeloma.

Tolerability

The dose-limiting adverse effects of altretamine are gastrointestinal, haematological and neurological, but accurate incidence rates for these effects are not available. In studies where altretamine 260 mg/m2/day was administered as monotherapy for 14 days of a 28-day cycle or at 6 to 8 mg/kg/day for 21 days of a 28-day cycle, 33 to 75% of patients with ovarian cancer experienced nausea and vomiting, and 5 to 31% developed peripheral sensory neuropathy; anaemia occurred in 33 to 37% and leucopenia in 5 to 32% of patients.

Other neurological effects reported include paraesthesia, ataxia, dizziness, vertigo and mood disorders. In addition, seizures, respiratory dyskinesia and acute myelocytic leukaemia have occurred in individual patients. Severe orthostatic hypotension has been reported in a few patients treated concurrently with a monoamine oxidase inhibitor or tricyclic antidepressant and altretamine.

No additional effect of altretamine on the neurotoxicity of cisplatin was detected in a study giving the drugs in combination. Nausea and controllable vomiting occurred in 35% of patients receiving altretamine in combination with doxorubicin and cyclophosphamide, whereas severe vomiting occurred in all patients receiving cisplatin with doxorubicin and cyclophosphamide. The incidence of neurotoxicity and haematological toxicity did not differ between the regimens.

Dosage and Administration

The recommended dosage of altretamine monotherapy for the palliative treatment of patients with persistent or recurrent advanced ovarian cancer is 260 mg/m2/day administered for 14 to 21 consecutive days of a 28-day cycle. Altretamine has been administered in combination with other cytotoxic agents, usually at a dosage of 150 mg/m2/day for 14 days of a 28-day cycle.

Blood counts and a neurological examination should be performed before each cycle of altretamine and the dose adjusted as necessary.

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    C. Rhoda Lee & Diana Faulds

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Various sections of the manuscript reviewed by: G. Bonadonna, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; H.W. Bruckner, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA; J. Dubois, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; P.J. Hoskins, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; I.R. Judson, Institute of Cancer Research, Royal Cancer Hospital, Sutton, England; S. Kohnoe, National Kyushu Cancer Center, Fukuoka, Japan; J.A. Ledermann, Department of Oncology, University College London Medical School, London, England; F.M. Muggia, Department of Medical Oncology, University of Southern California, Los Angeles, California, USA; J.P. Neijt, Department of Internal Medicine, Utrecht University Hospital, Utrecht, The Netherlands; M. Ogawa, Aichi Cancer Center, Nagoya, Japan; J.L. Pater, National Cancer Institute of Canada, Queen’s University, Kingston, Ontario, Canada; G. Rustin, Department of Medical Oncology, Charing Cross Hospital, London, England; C. Sessa, Department of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland; J.T. Thigpen, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA; I. Vergote, Universitaire Zeikenhuizen Leuven, Leuven, Belgium; R.B. Weiss, Walter Reed Army Medical Center, Washington, District of Columbia, USA; P.E. Wiernik, Albert Einstein Cancer Center, New York, New York, USA.

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Lee, C.R., Faulds, D. Altretamine. Drugs 49, 932–953 (1995). https://doi.org/10.2165/00003495-199549060-00007

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