Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial.

BACKGROUND: Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. METHODS: Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. FINDINGS: With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% CI 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% CI -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% CI 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% CI -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. INTERPRETATION: Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemo therapy for ovarian cancer.

Circadian time dependence of murine tolerance for the alkylating agent peptichemio.

Since the extent of host toxicity of cytostatics is considerably affected by dosing time, a chronopharmacologic approach was undertaken for optimizing the therapeutic index of the alkylating agent, peptichemio (PTC). In 4 studies involving a total of 463 male B6D2F1 mice, a highly statistically significant circadian rhythm characterized murine tolerance for PTC (8 or 10 mg/kg/day i.v. X 3 days). Six circadian stages were explored (3, 7, 11, 15, 19 and 23 Hours After Light Onset--HALO). Day-40 survival rate varied between 20% (PTC at 3 HALO) and 55% (PTC at 15 HALO) (chi 2 = 16.7; P less than 0.01). In each study, body weight loss was maximal in mice injected with PTC at 3 HALO and minimal in those treated at 15 HALO (P less than 0.01). In a further study involving 96 male B6D2F1 mice, the toxicity of PTC on several target tissues (bone marrow, spleen, small bowel, colon, liver, kidney and lungs) was investigated by histology and leukocyte count as a function of drug dosing time. A circadian rhythm in the susceptibility of the bone marrow, the spleen and the intestinal tract was demonstrated. Optimal murine tolerance for PTC resulted from dosing it at 15 HALO, e.g. in the first half of the activity span.

A phase II study of peptichemio in advanced breast cancer.

A phase II trial of Peptichemio (PTC) was conducted on 56 patients with advanced breast cancer that had been resistant to treatment with cyclophosphamide. The overall response rate was 32%, with one complete remission, seven partial remissions, and ten instances of improved disease status. Soft tissue and bone lesions were the primary sites of response. The median duration of response was 11 weeks, with a range of 6--30 weeks. Major toxicities were myelosuppression, affecting predominantly the platelets, and sclerosing phlebitis. Myelosuppression was cumulative and thrombocytopenic bleeding was a likely contributing factor in the death of 2 patients. This trial showed that PTC is another alkylating agent with definite activity in the treatment of breast cancer. More importantly, it showed that cross-resistance with cyclophosphamide does not exist, at least in breast carcinoma.

Phase I trial with peptichemio.

Thirty-two patients with tumor progression, even after conventional cytostatic drug treatment, were treated with peptichemio, with increasing doses for groups of 4 patients. The maximum tolerated dose (with minimum hematological toxicity and without any other evident toxicity) with repeated administrations, was 1.2 mg/kg twice weekly. The recommended doses for phase II trials are, as shown by the detailed analysis of the results, 0.9 mg/kg, twice weekly and administered alone, and 1.3 mg/kg, once weekly combined with other cytostatic drugs, in 500 ml of infusion fluid, with 25 mg of heparin and 25 mg of hydrocortisone to minimize the freqent risk of local phlebosclerosis.