The circadian timing of surgery, anticancer drugs,
radiation therapy, and
biologic agents can result in improved toxicity profiles,
tumor control, and host survival. Optimally timed
cancer chemotherapy with
doxorubicin or
pirarubicin (06:00h) and
cisplatin (18:00h) enhanced the control of advanced
ovarian cancer while minimizing side effects, and increased the response rate in metastatic
endometrial cancer.
Therapy of metastatic
bladder cancer with
doxorubicin-
cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed
therapy is also effective in the adjuvant setting, decreasing the expected frequency of
metastasis from locally advanced
bladder cancer. Circadian
fluorodeoxyuridine (
FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic
renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when
FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic
renal cell cancer, patients were randomized to a flat or a circadian-modified
FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group.
Hormone refractory metastatic
prostate cancer has been treated with circadian-timed
FUDR chemotherapy; however, without objective response.
Biological agents such as
interferon-alpha and
IL-2 have shown low but effective disease control in metastatic
renal cell cancer, however, with much toxicity. Each of these
cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of
anthracycline,
platinum, and fluoropyrimidine-based
drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and
genitourinary cancers.