Implications of circadian clocks for the rhythmic delivery of cancer therapeutics.

The circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell, circadian physiology, and the suprachiasmatic nuclei--a hypothalamic pacemaker clock that coordinates circadian rhythms. As a result, both the toxicity and efficacy of over 30 anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in cancer patients. Programmable-in-time infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000 cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of oxaliplatin against colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of oxaliplatin and 5-fluorouracil-leucovorin. Here, the relevance of the peak time, with reference to circadian rhythms, of the chemotherapeutic delivery of these cancer medications for achieving best tolerability was investigated in 114 patients with metastatic colorectal cancer and in 45 patients with non-small cell lung cancer. The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5-fluorouracil-leucovorin, at 1 p.m. or 4 p.m. for oxaliplatin, and at 4 p.m. for carboplatin. Sex of patient was an important determinant of drug schedule tolerability. This finding is consistent with recent results from a chronotherapy trial involving 554 patients with metastatic colorectal cancer, where sex also predicted survival outcome from chronotherapy, but not conventional drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring cancer chronotherapeutics to the main rhythmic characteristics of the individual patient. Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of cancer patients through personalized cancer chronotherapeutics.

High-dose oral medroxyprogesterone acetate or tamoxifen as adjuvant hormone therapy for node-negative early-stage breast cancer: randomized trial with 7-year update.

A randomized adjuvant trial compared tamoxifen 20 mg daily for 5 years with high-dose oral medroxyprogesterone acetate (MPA) 1 g orally for 9 months. One hundred ninety-four patients with histologically proven primary node-negative breast carcinoma were enrolled between December 1990 and October 1996, with 98 patients randomized into the tamoxifen arm and 96 into the MPA arm. At a median follow-up of 86 months, 25 relapses and 13 deaths were recorded. The relapse-free survival rate at 7 years in the tamoxifen arm was 93%, versus 81% in the MPA arm (P = 0.02). The difference was observed in patients with stage T2 disease (100% in the tamoxifen group vs. 64% in the MPA group; P = 0.01), in younger and/or premenopausal patients (in patients < 50 years of age, 100% in the tamoxifen arm vs. 81% in the MPA arm [P = 0.02], and in patients > or = 50 years of age, 90% in the tamoxifen arm vs. 82% in the MPA arm [P = 0.16]). Also, the overall survival rate at 7 years was lower in women < 50 years of age (P = 0.04).