Utilizing chronochemotherapy—a method aimed at delivering chemotherapy at a time when the body is least vulnerable to its harmful effects and when the cancer cells are at their most vulnerable—may improve the outcomes of some patients with diffuse large B-cell lymphoma (DLBCL), according to a novel study published by Kim et al in the Journal of Clinical Investigation Insight.

Background

DLBCL accounts for 30% to 40% of all cases of non-Hodgkin lymphoma.

Although chemotherapy has been found to be highly effective at killing cancer cells, the treatment is also notorious for killing healthy cells. As such, minimizing the drug’s damage to the patient’s body is necessary to improve the prognosis during chemotherapy.

Recently, chronochemotherapy has been gaining interest in the research community. This novel method is designed to exploit the fact that human physiologic processes—including cell proliferation and differentiation—are regulated by the circadian rhythm. However, chronochemotherapy is not yet widely adopted in real-world clinical settings because there are currently no systematic methods to identify the optimal chemotherapy delivery time.

Study Methods and Results

The investigators compared the treatment effectiveness for 210 patients with DLBCL at Seoul National University Hospital who received chemotherapy at two different times: 8:30 AM or 2:30 PM. All patients received the same cancer treatment—a regimen of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone—four to six times in the morning or afternoon at intervals of about 3 weeks.

After conducting their analysis, the investigators found that female patients who received afternoon treatment had a 12.5-fold lower mortality rate compared with those who received morning treatment (25% vs 2%). Female patients who received afternoon treatment also saw a reduction in the rate of 5-year cancer recurrence of 37% vs 13% among patients who received morning treatment. In addition, chemotherapy side effects such as neutropenia were more common in female patients who received morning treatment.

Surprisingly, no differences were observed between the treatment efficiency of chemotherapy administered in the morning or the afternoon among male patients.

To understand the cause of the differences between the sexes, the investigators further analyzed about 14,000 blood samples from the Seoul National University Hospital Health Examination Center. They found that among female patients, white blood cell counts tended to decrease in the morning and increase in the afternoon, indicating that the bone marrow proliferation rate was higher in the morning than in the afternoon as a result of the 12-hour delay between the proliferation and blood cell production.

Conclusions

The investigators hypothesized that female patients who receive chemotherapy in the morning—when bone marrow is actively producing blood cells—may have an increased risk of experiencing adverse side effects. The results were consistent with the findings from recent randomized clinical trials that demonstrated that female patients with colorectal cancer treated with irinotecan in the morning suffered from higher drug toxicities.

A variable that confounded the investigators was the drug dosage. Since female patients who received chemotherapy in the morning suffered from greater adverse side effects, oftentimes, the dosage had to be reduced in these patients. On average, the drug dosage was 10% lower than the dosage given to female patients receiving the afternoon treatment.

Unlike female patients, it was found that male patients did not show a significant difference in white blood cell counts and bone marrow cell proliferation activity throughout the day—which may have explained why the treatment timing had no impact on male patients.

“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,” explained principal co-investigator Youngil Koh, MD, PhD, Assistant Professor of Internal Medicine at the Seoul National University College of Medicine, and an oncologist at the Seoul National University Hospital.

“Because the time of the internal circadian [rhythm] can vary greatly depending on the individual's sleep-wake patterns, we are currently developing a technology to estimate the time of the circadian [rhythm] from the patient’s sleep pattern. We hope that it can be used to develop an individualized anticancer chronotherapy,” concluded principal co-investigator Jae Kyoung Kim, PhD, Associate Professor in the Department of Mathematical Sciences, as well as a mathematician and chief investigator at Biomedical Mathematics Group at the Institute for Basic Science.

Disclosures: For full disclosures of the study authors, visit insight.jci.org.