Afternoon Chemotherapy Found to Improve Treatment Outcomes in Women With Lymphoma

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Chronochemotherapy aims to time drug delivery when the body is the least vulnerable to harmful effects, while the cancer cells are the most vulnerable.

Among female patients with lymphoma, afternoon treatment with chemotherapy was found to decrease both mortality rate and cancer recurrence, according to new study findings.

Although chemotherapy is highly effective at killing cancer cells, these treatments are also notorious for killing healthy cells in the body. Because of this, minimizing the drug’s damage to patients is crucial to improve the prognosis.

Chronochemotherapy may be one way to minimize this damage. According to researchers, this treatment approach aims to time the delivery of the drug when the body is the least vulnerable to harmful effects, while the cancer cells are the most vulnerable.

Chronochemotherapy exploits the fact that human physiological processes, including cell proliferation and differentiation, are regulated by the circadian clock. However, this is not widely exploited in real-world clinical settings because there is currently no systematic method to find the optimal chemotherapy delivery time.

“Because the time of the internal circadian clock can vary greatly depending on the individuals’ sleep-wake patterns, we are currently developing a technology to estimate the time of the circadian clock from the patient’s sleep pattern,” said Jae Kyoung Kim, a mathematician at the Biomedical Mathematics Group in the Institute for Basic Science, in a press release. “We hope that it can be used to develop an individualized anti-cancer chronotherapy.”

To tackle this problem, investigators from South Korea studied a group of patients with diffuse large B-cell lymphoma (DLBCL), a type of blood cancer caused by the malignant transformation of lymphoid tissue cells. Lymphoma is divided into Hodgkin lymphoma and non-Hodgkin lymphoma, and DLBCL accounts for approximately 30% to 40% of non-Hodgkin lymphoma.

The investigators noticed that patients with DLBCL at Seoul National University Hospital received chemotherapy at 2 different schedules, with some patients receiving treatment at 8:30 am while others received it at 2:30 pm. All patients received the same treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) 4 to 6 times in the morning or afternoon at intervals of approximately 3 weeks.

The researchers analyzed 210 patients to investigate whether there were any differences between morning and afternoon treatment. They found that female patients who received afternoon treatment had a 12.5 times reduced mortality rate (25% vs 2%), whereas cancer recurrence after 60 months decreased by 2.8 times (37% vs 13%). Additionally, adverse effects (AEs) of chemotherapy, such as neutropenia, were more common in female patients who received morning treatment.

Surprisingly, the investigators found no difference in treatment efficiency depending on the treatment schedule in male patients.

In order to understand these sex-based differences, the team analyzed approximately 14,000 blood samples. They found that in women, white blood cell count tends to decrease in the morning and increase in the afternoon, indicating that the bone marrow proliferation rate is higher in the morning than in the afternoon.

According to the study, this indicates that if a female patient receives chemotherapy in the morning when bone marrow is actively producing blood cells, the possibility of AEs becomes greater. These results are consistent with the findings from recent randomized clinical trials that showed female colorectal cancer patients treated with irinotecan in the morning suffered from higher drug toxicities.

Importantly, one confounding variable was the drug dose. Because the female patients treated in the morning suffered from greater AEs, the dose often had to be reduced in these patients. On average, the drug dose was reduced by approximately 10% compared to the dose intensity given to female patients receiving afternoon treatment.

Unlike female patients, the study results found that male patients did not show a significant difference in white blood cell count and bone marrow cell proliferation activity throughout the day, which is why the timing of the treatment had no impact.

“We plan to verify the conclusions of this study again with a large-scale follow-up study that completely controls confounding variables, and to confirm whether chemotherapy has similar effects in other cancers,” said researcher Youngil Koh, MD, MS, PhD, an oncologist at Seoul National University Hospital, in the press release.

REFERENCE

Chemotherapy in the afternoon dramatically improves treatment outcomes in female lymphoma patients. News release. EurekAlert; January 24, 2023. Accessed January 25, 2023. https://www.eurekalert.org/news-releases/977250

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