A Blog Around The Clock

Oversimplified, but much believed idea: Many cancer drugs target cells during cell division. Healthy cells divide at a particular time of day (exact timing may differ between cell types). Cancer cells are not under the control of the circadian clock so they divide at all times of the day (and they divide more often anyway). Thus, incorrect timing of chemotherapy – given during the time most healthy cells divide as well as some cancer cells – will kill more healthy than cancerous cells, leading to early termination of treatment and worse prognosis. Correct timing – during the time when healthy cells are not dividing, but cancer cells are – will preferentially kill cancer cells, leading to a better outcome. That is the theory. Here is one example of a study testing this idea:
Chronomodulated Therapy for Colorectal Cancer Produces Promising Results in Men:

Among patients with metastatic colorectal cancer, administration of the chemotherapy drugs Eloxatin® (oxaliplatin), 5-fluorouracil, and leucovorin on a schedule that is adjusted to circadian rhythms (chronomodulated) appears to improve outcomes in men but not in women.
—————————snip—————————–
In an attempt to improve outcomes among patients treated with chemotherapy, researchers in Europe recently studied the effects of varying the delivery chemotherapy according to a patient’s circadian rhythm (the body’s 24-hour cycle). The idea behind this approach is that there may be certain points in the circadian rhythm when chemotherapy drugs will have the greatest effect with the least toxicity. Varying delivery of treatment according to the circadian rhythm is referred to as chronomodulated therapy.
—————————snip—————————–
* Overall, survival was similar in the two treatment groups: Among patients treated with FOLFOX2, 36.9% of patients survived for two years or longer. Among patients treated with chronoFLO4, 37% of patients survived for two years or longer.
* The frequency of serious side effects was similar in the two treatment groups, but the types of side effects varied. Patients treated with FOLFOX2 were more likely to experience low white blood cell counts (neutropenia), and patients treated with chronoFLO4 were more likely to experience problems such as diarrhea.
* The effect of chronoFLO4 differed by sex. Among men, those treated with chronoFLO4 had a 25% reduction in risk of death compared to those treated with FOLFOX2. Among women, those treated with chronoFLO4 had a 38% increase in risk of death compared to those treated with FOLFOX2. The reasons for this difference between men and women are uncertain.

I really need to get back in the saddle and continue studying sex differences in circadian function….

A number of media outlets are reporting on the new Duke University study on the effects of time-of-day on the outcome of surgery:

Patients who undergo surgery late in the afternoon are more likely to experience unexpected adverse events related to their anesthesia than are patients whose operations begin in the morning, a new analysis by Duke University Medical Center researchers suggests.
——————-snip———————–
In addition to spotting problems related to anesthesia, Wright and her colleagues also found that surgery patients experienced a significant increase in “administrative delays” during late afternoon, which might contribute to the increase in adverse events that occur during this time. The delays included waiting for laboratory test results, doctors running late, transporters not being available to move patients and rooms not being ready on time.
——————-snip———————–
Based on their findings, Wright and her colleagues suggest a number of factors that might contribute to variations in health outcomes. These factors include fatigue among health care providers, swings in the circadian rhythms that influence a person’s natural ups and downs over the course of a day, and institutional work schedules.
——————-snip———————–
Wright said that many factors, involving both patients and hospitals, may contribute to increased rates of adverse events late in the afternoon. For example, patients may be more susceptible to either pain or post operative nausea and vomiting in the late afternoon. We don’t know if issues such as not having eaten all day or spending a stressful day waiting in the hospital may have an influence on this, Wright said.
Late afternoon also is a time when changes in the teams that administer anesthesia during surgery coincide with natural circadian rhythm lows, Wright said. The circadian rhythm serves as the body’s internal clock that regulates sleep, brain wave activity and other bodily functions. Circadian lows occurring around 3 p.m. to 5 p.m. and again at 3 a.m. to 5 a.m may affect human performance of complex tasks such as those required in anesthesia care. Changes in anesthesia care teams usually occur around 7 am and again between 4 pm and 6 pm. End of day fatigue, a circadian low point, and changes in care team are all occurring around 3 pm to 6 pm and may be interacting in a way that affects patient care, she said.

This was know before, but the size and scope of this study is remarkable.