Comparative metabolism of 2-[bis(2-chloroethyl)amino]tetrahydro-2-H-1,3,2-oxazaphosphorine-2-oxide (cyclophosphamide) and its enantiomers in humans.

The comparative metabolism of the enantiomers of cyclo phosphamide and of the racemate has been studied in humans. Four patients were each given, sequentially, the racemate, the (+)-enantiomer, and its (-)-antipode. The plasma levels of parent drug and the urinary output (24 hr) of unchanged drug and of two enzymatically produced metabolites, 4-ketocyclophosphamide and carboxyphosphamide, were determined using mass spectrometry-stable isotope dilution. There was no significant difference between the three forms of cyclophosphamide with respect to plasma half-life (beta phase) or in the urinary outputs of the drug or of carboxyphosphamide. The output of 4-ketocyclophosphamide after administration of (+)-cyclophosphamide was significantly greater than that produced from the racemate. Cyclophosphamide recovered from the urine of patients given the racemate was either racemic or only slightly enriched in the (-)-enantiomer. The two enantiomers were almost equally bound to plasma protein. Based on these metabolic studies alone, there is little reason to predict that the enantiomers will differ from each other or from the racemate in their therapeutic effects in humans, but there are other factors, e.g., stereoselective uptake of the intermediary 4-hydroxylated metabolites by neoplastic cells, which could elicit such differences.

Metabolism of high doses of cyclophosphamide.

The excretion of cyclophosphamide and the enzymatically derived metabolites 4-ketocyclophosphamide and carboxyphosphamide has been measured in four patients after the administration of cyclophosphamide (5 g). At this dose the enzymes responsible for the biotransformation and detoxification of cyclophosphamide are not saturated. In two patients the metabolite profile was unaffected by a previous high dose of cyclophosphamide and in one patient a small primary dose did not alter metabolism.

A randomised trial of tamoxifen versus tamoxifen with aminoglutethimide in post-menopausal women with advanced breast cancer.

Sixty-six post-menopausal women with metastatic breast cancer were randomised to receive tamoxifen or tamoxifen with aminoglutethimide. The women in the tamoxifen group were virtually free of toxicity, whilst 45% of patients in the aminoglutethimide group had toxicity and 13% discontinued the drug because of this. Responses were seen in 19% of patients receiving tamoxifen alone and 23% of those receiving both drugs. There is no indication that the increased toxicity seen with the addition of aminoglutethimide to tamoxifen in this situation is justified by an increased response rate.

Adriamycin, vincristine and mitomycin C as first and second line therapy for advanced breast carcinoma.

Forty-three patients with advanced breast cancer were treated with adriamycin, vincristine and mitomycin C at 6 week intervals. Adriamycin 40 mg m-2 and vincristine 1 mg m-2 were given on days 1 and 22: patients treated early in the study received 10 mg m-2 mitomycin C, but in view of repeated treatment delays the dose was reduced to 6 mg m-2. Thirty-two women had received prior hormone therapy and 24 previous chemotherapy. Responses were seen in 15 of 38 evaluable patients (40%) with a further 9 (24%) achieving disease stabilization. Median duration of response was 10 months and of disease stabilization was 5 months. Overall median survival for the whole group was 8 months, but 16 months for the 15 responding patients, five of whom survived beyond 2 yr. Responses were seen more frequently in patients who had received no prior chemotherapy. Myelosuppression may have contributed to three of the five early deaths in the non-pretreated group. Other significant side effects were alopecia, gastrointestinal toxicity and malaise.

Cancer chemotherapy--what have we achieved?

The outcome of referral to a medical oncology unit in a university teaching hospital has been determined for the first 500 patients seen in 1978. Their median age was 58 years, and half had been referred within 6 weeks of diagnosis. 316 had already received some form of treatment. Compared with the overall figures for New South Wales, there was an excess of lung cancer, breast cancer, head and neck cancer, ovarian carcinoma, and testicular cancer, but a smaller proportion of gastrointestinal cancers. No treatment was recommended for one-third. Of the 334 treated, 247 received cytotoxic drugs. By Aug. 1, 1979, 56% from the treated group and 52% of the untreated group had died, the median survival times for the two groups being 45 and 35 weeks, respectively. But, of the 50 who received "curative" or "adjuvant" chemotherapy, only 17 had died by Aug. 1, 1979. Serious complications of treatment occurred in 22 (8.8%) patients. The cytotoxic drugs used by the unit between January, 1978, and August, 1979, cost A$212 000 (9.3% of the hospital's total pharmacy budget for the period). The findings suggest that the widespread use of cancer chemotherapy is not justified outside well conducted clinical trials or specialist cancer centres.

Long term results of cyclophosphamide, adriamycin and platinum chemotherapy in advanced epithelial ovarian cancer.

Between January 1980 and December 1983, 57 consecutive patients with advanced epithelial ovarian cancer (FIGO Stage IIc n = 5; III n = 45; IV n = 7) were treated with 6 cycles of cyclophosphamide 600 mg/m2, adriamycin 30-45 mg/m2 and platinum 50 mg/m2 (CAP) at 3 weekly intervals. Pathological complete remission (CR) was documented in 10 (18%) and 4 with no residual disease after primary cytoreductive surgery were free from progression (FFP). There were 19 partial remissions (PR) giving a 51% overall response rate. The median duration of CR was 33 months from second look surgery. Median survival (MS) for all patients was 22 months. Multivariate analysis indicated that response to chemotherapy was the most important prognostic factor, with MS for CR of 53 months, PR 23 months and stable or progressive disease 11 months (p = 0.001). Most CR (8 of 10) occurred in patients with minimal residual disease (no single lesion greater than 2.0 cm), but extent of disease, though significant in univariate analysis of prognostic factors was not an independent predictor of survival. Six patients (11%) are alive and tumour free with a minimum follow-up of 7 years. All had FIGO Stage III disease at presentation and four had no residual tumour after primary surgery.

Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer.

Fifty-two patients with progressive advanced breast cancer were treated with the novel antifolate CB 3717 (N10-propargyl-5,8-dideazofolic acid) which inhibits thymidylate synthetase. Forty-six patients were pretreated with hormones, 43 with cytotoxic chemotherapy and 39 patients with both treatments. Eight of 48 patients (16.6%) evaluable for response had partial responses (confidence limits 7.4-30.2%, 95% confidence level) following CB 3717 administration. Liver function abnormalities, reversible in most cases, were the most commonest toxicities and were frequently accompanied by malaise. Severe renal failure occurred in eight patients, five of whom had had partial responses to CB 3717. This study shows the importance of thymidylate synthetase as a target for therapy but the clinical value of CB 3717 is limited by its hepatic and renal toxicities.

The treatment of advanced bladder cancer with methotrexate and cis-platinum--a pharmacokinetic study.

As part of a phase III study in advanced bladder cancer, 5 patients received methotrexate (MTX) 50 mg/m2 as a single agent every 2 weeks, and with every alternate dose of MTX (i.e. every 4 weeks) cis-platinum (CDDP) 50 mg/m2 was given simultaneously, together with saline hydration and diuresis. The clearance of MTX was measured in a total of 12 courses by serial serum sampling for up to 72 hr following injection. In 4 patients (with a mean pretreatment creatinine clearance of 97 ml/min) there was no significant difference between the clearance of MTX when given alone [mean t1/2 (beta) 3.2 hr] and when given 2 weeks later with concurrent CDDP [mean t1/2 (beta) 2.9 hr]. In 1 patient with a pretreatment creatinine clearance of 52 ml/min the clearance of MTX when given alone (without hydration) was significantly delayed compared with the clearance of MTX when given 2 weeks later concurrently with CDDP and saline hydration [t1/2 (beta) 19 and 4.5 hr respectively]. Of the 5 patients so far treated with MTX-CDDP, 2 have had a partial objective response and 3 have had stable disease (including 2 with a marked subjective response). These data indicate that in patients with satisfactory renal function, low-dose MTX and CDDP may be given concurrently without risk of enhanced drug toxicity.

Treatment of advanced ovarian cancer with combination chemotherapy using cyclophosphamide, adriamycin and cis-platinum.

Fifty-four patients with advanced ovarian cancer have been treated with combination chemotherapy using cyclophosphamide, adriamycin and cis-platinum. The toxicity of the regimen was manageable but few patients were prepared to tolerate more than 6 months of treatment. Those in complete clinical remission at that time were offered second-look laparotomy and if apparently free of disease, therapy was discontinued. Forty-seven patients could be assessed of whom 33 had had no previous therapy. Twenty-two of these were clinically free of disease after completion of chemotherapy of whom 12 had no detectable disease at second-look laparotomy. Of 14 patients who had failed previous therapy only one remains clinically free of disease. The results in the untreated patients demonstrate the primary importance of bulk reduction at initial laparotomy. The use of the regimen in patients who have failed on previous treatment or in patients with bulk disease seems to be palliative and the toxicity should be assessed in this context.

Marrow autotransplantation accelerates haematological recovery in patients with malignant melanoma treated with high-dose melphalan.

In a Phase I study, melphalan 140 mg/m2 was administered to 8 patients with disseminated malignant melanoma. Marrow was removed from the patients immediately before melphalan administration and returned i.v. 8 h later. Studies on marrow culture and melphalan pharmacokinetics predicted that this was a safe time to administer non-cryopreserved marrow. Four patients received lower doses of i.v. melphalan without autologous marrow. In the group receiving autologous marrow the time for recovery of peripheral-blood granulocytes to 800/mm2 or greater was significantly less (P = 0.01) than in those not receiving marrow. In 7 patients the tumour showed evidence of response to the drug and there was 1 complete remission. This treatment deserves investigation in patients with tumours more sensitive to drugs than melanoma.