Aligning Anticancer Drug Administration with the Body Clock Could Enhance Survival Rates

It is often said that timing plays a crucial role, and cancer treatment might be no exception. Researchers have discovered that adjusting the timing of immunotherapy drugs administered to cancer patients can enhance survival rates, adding to the evidence that our body’s internal clock affects cancer treatment efficacy.

The activities of cells and tissues within our bodies follow a 24-hour cycle termed the circadian rhythm, which governs everything from hormone release to cell division and repair timing. These rhythms are frequently disrupted in cancer cells, which tend to divide uncontrollably rather than at set intervals.

This has led to efforts aimed at alleviating chemotherapy side effects by targeting quickly dividing cells while the healthy tissue is less active. However, researchers are also exploring whether administering cancer drugs at particular times can enhance their efficacy.

One class of drugs under scrutiny is immune checkpoint inhibitors, which enable immune T cells to more effectively identify and target tumors. “T cells and other immune agents are naturally more active in the morning, making them more responsive,” explains Dr. Celine Ismail Sutton at Easbeatty Gwynedd Hospital in Bangor, England, who was not part of the study. “Administering immune checkpoint inhibitors during this window may bolster antitumor effects and enhance effectiveness.”

Earlier this year, ze fan and colleagues from Central South University in Changsha, China, documented that giving the checkpoint inhibitor pembrolizumab before 11:30 a.m. alongside chemotherapy to patients with advanced non-small cell lung cancer (NSCLC) resulted in a survival rate that nearly doubles compared to those receiving treatment primarily in the afternoon.

To assess whether timing treatments in accordance with circadian rhythms, termed chronotherapy, could benefit patients with rapidly dividing, aggressive small cell lung cancer, the same team analyzed data from 397 individuals treated with the checkpoint inhibitors atezolizumab or durvalumab alongside chemotherapy from 2019 to 2023.

“Patients treated before 3 p.m. exhibited significantly longer progression-free survival and overall survival in comparison to those treated later in the day,” reported team members. Zhang Yongchang, also at Central South University, noted.

After accounting for numerous confounding variables, early treatment appeared to be associated with a 52% reduced risk of cancer progression and a 63% decreased risk of mortality.

Zhang suspects that this effect may manifest in additional tumor types, referencing evidence from studies on renal cell carcinoma and melanoma. Research on NSCLC trials illustrated that morning dosing boosts circulating T cell levels and activation, while later dosing does the opposite. Mouse studies have shown that the behavior of tumor-infiltrating T cells fluctuates throughout the 24-hour cycle and that circadian clocks in adjacent endothelial cells influence when immune cells migrate into tumors.

While larger randomized controlled trials are essential, this investigation “adds further support to a growing number of studies globally that indicate improved outcomes when immunotherapy drugs are administered earlier in the day,” states Pasquale Innominato from the University of Warwick, UK.

But is it feasible for hospitals to implement this? When it comes to modifying treatment schedules, “adjusting infusion times is a straightforward clinical decision that incurs minimal costs,” asserts Zhang.

Nevertheless, treating everyone early in the day isn’t practical. According to Robert Dalman, also at the University of Warwick, each person’s body clock varies. “For instance, the biological time discrepancy between an ‘early bird’ and a ‘night owl’ can span several hours.”

Nonetheless, biomarkers that accurately assess individuals’ chronotypes are currently in development. Once established and validated, chronotherapy could emerge as a “cost-effective, resource-efficient innovation with the capability to significantly enhance treatment outcomes. A simple shift in timing can unveil a new facet of precision medicine,” concludes Ismail Sutton in a recently published perspective on this innovative strategy.