Chemotherapy is a commonly used regimen for cancer treatment, but it is also a double-edged sword. While the drugs are highly effective at killing cancer cells, they are also notorious for killing healthy cells in the body. As such, it is necessary to minimize the drug’s damage to the patient’s body in order to improve the prognosis of chemotherapy.
Recently, “chronochemotherapy” has gained a lot of interest in the research community. As the name suggests, the goal is to time the delivery of the drug when the body is least vulnerable to the drug’s harmful effects, while the cancer cells are most vulnerable.
Chronochemotherapy exploits the fact that human physiological processes, including cell proliferation and differentiation, are regulated by an endogenous timer called the circadian clock. However, it is not yet widely exploited in real-world clinical settings because there is currently no systematic method to find the optimal chemotherapy delivery time.
This problem was solved by an interdisciplinary team of researchers from South Korea. They were led by lead researchers KIM Jae Kyoung (a mathematician at the Biomedical Mathematics Group, Institute for Basic Science) and KOH Youngil (an oncologist at Seoul National University Hospital). The researchers studied a group of patients suffering from diffuse large B-cell lymphoma (DLBCL).
The research team noted that DLBCL patients at Seoul National University Hospital received chemotherapy on two different schedules, with some patients receiving morning treatment (8:30 a.m.) while others took the medication in the afternoon (2:30 p.m.). All patients received the same cancer treatment (R-CHOP), which is a combination of targeted therapy and chemotherapy, 4 to 6 times in the morning or afternoon at intervals of approx. 3 weeks.
They analyzed 210 patients to investigate whether there is a difference between morning and afternoon treatment. It found that female patients who received afternoon treatment had a 12.5-fold reduction in mortality (25% to 2%), while cancer recurrence after 60 months was reduced by 2.8-fold (37% to 13%). In addition, chemotherapy side effects such as neutropenia were more common in female patients receiving morning treatment.
Surprisingly, there was no difference in treatment efficacy depending on the treatment plan for male patients.
To understand the cause of gender differences, the research team analyzed ~14,000 blood samples from the Seoul National University Hospital Health Examination Center. It was found that in women, the white blood cell count tends to decrease in the morning and increase in the afternoon. This indicates that bone marrow proliferation is higher in the morning than in the afternoon because there is a ~12 hour lag between bone marrow proliferation and blood cell production.
This means that if a female patient receives chemotherapy in the morning, when the bone marrow is actively producing blood cells, the possibility of unwanted side effects increases. These results are consistent with the results of recent randomized clinical trials showing that female colorectal cancer patients treated with irinotecan in the morning suffered from higher drug toxicity.
A confounding variable was drug dose. Since the morning, female patients suffered from greater unwanted side effects, and often the dose had to be reduced in these patients. On average, the drug dose was reduced by ∼10% compared to the dose intensity given to female patients receiving afternoon treatment.
In contrast to female patients, male patients were found not to show a significant difference in white blood cell count and bone marrow cell proliferation activity during the day, which is why the time of treatment had no effect.
We plan to re-verify the conclusions of this study with a large-scale follow-up study that fully controls for confounding variables and to confirm whether chemotherapy has similar effects in other cancers.”
Professor Koh Young-il
CI KIM Jae Kyung said, “Because the time of the internal circadian clock can vary greatly depending on the individual’s sleep-wake patterns, we are currently developing a technology to estimate the time of the circadian clock based on the patient’s sleep pattern. We hope that it can used to develop an individualized anti-cancer chronotherapy.”
Department of Basic Science
Kim, DW, et al. (2022) Chemotherpay delivery time affects treatment outcomes of female patients with diffuse large B-cell lymphoma. JCI Insights. doi.org/10.1172/jci.insight.164767.