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Cancer patients may exhibit normal or altered circadian rhythms in tumor and healthy tissues. Four rhythms known to reflect circadian clock function were studied in 18 patients with metastatic colorectal cancer and good performance status. Rest-activity was monitored by wrist actigraphy for 72 h before treatment, and its circadian rhythm was estimated by an autocorrelation coefficient at 24h and a dichotomy index that compared the activity level when in and out of bed. Blood samples (9-11 time points, 3-6 h apart) were drawn on day 1 and day 4 of the first course of chronochemotherapy (5-fluorouracil: 800 mg/m2/day; folinic acid: 300 mg/m2/day; oxaliplatin: 25 mg/m2/day). Group 24h rhythms were validated statistically for plasma concentrations of melatonin, 6-alpha-sulfatoxymelatonin, and cortisol and for lymphocyte counts. Significant individual 24h rhythms were displayed in melatonin by 15 patients, cortisol by seven patients, lymphocytes by five patients, and prominent circadian rhythms in activity were displayed by 10 patients; only one patient exhibited significant rhythms in all the variables. The results suggest the rhythms of melatonin, cortisol, lymphocytes, and rest/activity reflect different components of the circadian system, which may be altered differently during cancer processes. Such 24h rhythm alterations appeared to be independent of conventional clinical factors.

Summary Few data are available on the circadian rhythmicity in cancer patients. Since monitoring the disease usually implies the follow-up of blood concentrations of a number of biological variables, it would be of value to examine the profile of the circadian variations of serum cortisol and tumour marker antigens. This we did in 33 cancer patients (13 breast cancer patients and 20 ovarian cancer patients). The profiles of serum cortisol were documented, since this hormone is considered as a strong marker of circadian rhythms. This study shows that 8 out of 13 breast cancer patients and 15 out of 20 ovarian cancer patients had deeply altered cortisol circadian patterns. The modifications were either high levels along the 24 h scale and/or erratic peaks and troughs and/or flattened profiles. Within 24 h, variations of tumour marker antigens as large as 70% were observed but no typical individual circadian patterns could be found. No relationship between cortisol subgroups and concentration of tumour marker antigens at 8 h could be observed (Kolmogorov-Smirnov's test). The question thus arises as to the origin of these alterations, and whether they are related to a cause or a consequence of the disease, and their possible incidence upon therapeutic designs.

In a study of the internal desynchronization of circadian rhythms in 12 shift workers, 4 of them, aged 25-34 years, agreed to be sampled every 2 h during their night shift (0000 hours to 0800 hours). They were oil refinery operators with a fast rotating shift system (every 3-4 days). We found marked changes in the secretory profiles of melatonin, prolactin and testosterone. Melatonin had higher peak-values resulting in a four-times higher amplitude than in controls. With respect to prolactin and testosterone, peak and trough times were erratic and the serum concentrations were significantly decreased in shift workers. Serum cortisol presented a decreased rhythm amplitude together with higher concentrations at 0000 hours in shift workers. This study clearly shows that fast rotating shift-work modifies peak or trough values and rhythm amplitudes of melatonin, prolactin, testosterone and cortisol without any apparent phase shift of these hormones. Whether the large rhythm amplitude of melatonin may be considered as a marker of tolerance to shift work, as reported for body temperature and hand grip strength, since it would help the subjects to maintain their internal synchronization, needs further investigation.

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Circadian changes in plasma levels of melatonin, prolactin, LH and FSH were studied in four groups: seven healthy young men, six elderly men, six elderly women and six elderly demented patients (two men and four women). The daily activities of the subjects were synchronous and blood samples were taken every 4 h. The 24-h mean concentrations of prolactin in plasma were the same in all groups, whereas those of LH and FSh were twice as high in the elderly as in the young men and eight and 23 times higher respectively in the elderly women. The 24-h mean plasma levels of melatonin in the elderly were half those in the young, but were not influenced by the sex or mental condition of the subjects. A statistically significant circadian rhythm for melatonin was defined in the four groups, for prolactin in all groups except the elderly men and for LH only in the demented patients and in the young men. No circadian rhythm could be detected for FSH in any of the four groups. The acrophases of melatonin and prolactin ranged between 02.30 and 04.00 h, those of LH (when a rhythm was validated) clustered around 01.00 h. The circadian rhythms of plasma levels of melatonin, prolactin and LH are not modified in old age nor in dementia. A positive correlation has been demonstrated in young men between melatonin and LH and between melatonin and prolactin, but no such correlation could be found in the elderly.

Circulating blood cell counts, serum cortisol, proteins, alkaline phosphatase, carcinoembryonic antigen and CA15.3 displayed significant circadian rhythms in a group of 13 women with metastatic breast cancer. Statistical significance (P < 0.05) was assessed with both analysis of variance and cosinor analysis. All patients had been previously treated with chemo-and/or radiotherapy and/or antiestrogens. All patients had been treatment-free for 1 month prior to the study. Each patient had blood drawn every 4 h for 48 h. Circadian rhythms were examined as a function of performance status, graded according to the World Health Organization, liver involvement and number of metastatic sites. Group circadian rhythms in serum cortisol or proteins were abolished in patients with liver metastases, and were altered in cases of poor performance status. Circulating leukocytes, neutrophils or platelets did not exhibit synchronized circadian rhythmicity in patients with poor performance status or liver metastases. The number of metastatic organs had a minor influence on circadian rhythmicity. These results suggest that rhythm alteration may be associated with both poor performance status and liver metastases in patients with advanced breast cancer. Such alteration of the normal circadian time structure may favor and/or result from cancer spread.