Giving chemotherapy in the morning resulted in worse survival and worse toxicity in comparison with giving the same drugs in the afternoon, say researchers. However, these differences were only among women patients, and men.

The study involved 210 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

Among the women who received the chemo regimen in the morning, progression-free survival (PFS) was reduced by 64% and overall survival was reduced by 86% in comparison with women who received their chemotherapy in the afternoon.

Among the women who were treated in the morning, there were also greater reductions in dose intensity, which was largely attributed to a greater incidence of infection and febrile neutropenia.

The results were published online on Decemeber 13 in JCI Insight.

“Female patients should, if possible, avoid receiving R-CHOP in the morning for optimal chemotherapy delivery with maximum response,” the authors conclude.

“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 senior author Koh Young-il, MD, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea, in a statement.

“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 from the patient’s sleep pattern,” added co-author Kim Jae Kyoung, PhD, Institute for Basic Science, Daejeon, South Korea.

“We hope that it can be used to develop an individualized anti-cancer chronotherapy.”

The authors note that they”found solid evidence of naturally occurring diurnal leukopenia/neutropenia, which may be the culprit leading to the sex moderation of the chronotherapeutic effect.

“Taking our findings into context, rather than uniformly increasing the chemotherapy dose for all, chronomodulated R-CHOP delivery for women may guide us toward effective yet safe dose intensification,” they continue.

The team also notes that there may be a “potential chronotherapeutic impact” on immunotherapy, as recent data have suggested that for patients with melanoma and non–small cell lung cancer, survival outcomes improve with timed immune checkpoint inhibitor therapy.

Study Details

In their study, to analyze survival data, the authors focused on 210 patients with DLBCL who underwent standard R-CHOP with prophylactic pegylated granulocyte colony-stimulating factor at two hospitals between January 2015 and August 2017.

The chemotherapy centers at the hospitals were open twice a day. Patients who received treatment predominantly at 8:30 AM were classified as the morning group, while those who underwent therapy predominantly at 2:30 PM were classified as the afternoon group.

The morning group comprised 49 men and 51 women, and the afternoon group comprised 74 men and 36 women.

These patients with DLBCL were compared with a control population of 18,125 disease-free individuals who underwent routine health checkups between January 2016 and December 2019. The routine checkups provided data on normal diurnal variations of hematologic laboratory findings.

The median overall survival was 86 months, while the median PFS was not reached.

Among the women in the morning group, PFS was significantly shorter than among those in the afternoon group, at a rate of progression of 33.3%, vs 13.9% (hazard ratio [HR], 0.357; P = .033). There was no difference between the male morning and afternoon groups.

The results also showed that women in the morning group experienced more deaths than those in the afternoon group, at 19.6% vs 2.8%. This led to a significantly shorter 3-year overall survival, at 69.2% vs 88.6% (HR, 0.141; P = .032).

Factors associated with poorer overall survival were adminstereing chemotherapy in the morning (P = .043), older age (P = .013), and stage III–IV disease (P = .015).

The researchers highlight that overall survival was “not affected by the chemotherapy delivery time for male patients.”

To analyze the effect of chemotherapy timing on adverse events, the team focused on 129 DLBCL patients, including 22 men and 24 women in the morning group and 24 men and 41 women in the afternoon group.

While there were no significant differences in baseline hematologic parameters between the groups, women in the morning group experienced more dose delays than women in the afternoon group, at 33.3% vs 9.8% (P = .042).

The relative dose intensity was also lower among women treated in the morning, with significantly more receiving <80% of the planned dose intensity than those who received their chemotherapy in the afternoon (P = .032).

Among women treated in the morning, the intensity of doses was reduced with respect to cyclophosphamide (10%; P = .002), doxorubicin (8%; P = .002), and rituximab (7%; P = .003).

The results also showed that among the women treated in the morning, there was a numerically higher incidence of febrile neutropenia in comparison with those treated in the afternoon, at 20.8% vs 9.8%, as well as a significantly higher rate of viral infections, at 16.7% vs 2.4% (P = .038).

Again, no such differences were seen in male patients.

Among women, there were greater diurnal variations in whole blood and absolute neutrophil counts than among men. The lowest counts were seen in women in the morning group.

Speculating on the possible reasons why women might more often be treated in the morning than men, the authors suggest that it “might be associated with social factors, such as men being more economically active than women in South Korea.

“Due to morning work schedules, economically active populations often prefer afternoon or evening sessions, leading to an allocation of more female patients to the morning session than to the afternoon session.

“Better designed prospective trials should ensue to address these unresolved issues,” they add.

The study was supported by a National Research Foundation of Korea grant funded by the Korean government (the Ministry of Science, the ICT, and Future Planning), the Institute for Basic Science, and a Human Frontiers Science Program Organization grant. The authors have disclosed no relevant financial relationships.

JCI Insight. Published online December 13, 2023. Full text

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