Does Immunotherapy Timing Influence Cancer Survival Rates?

Is Immunotherapy More Effective Earlier in the Day?

A growing body of research is exploring whether the timing of immunotherapy infusions can influence cancer treatment outcomes. A recent meta-analysis that examined data from over a dozen studies suggests that receiving immunotherapy earlier in the day may substantially improve both progression-free survival and overall survival in a variety of cancers, including metastatic melanoma, renal cell carcinoma, esophageal cancer, and non-small cell lung cancer (NSCLC), whether locally advanced or metastatic.

For example, a 2023 study focused on stage IV melanoma found that patients who received more than 75% of their immunotherapy infusions after 2 PM had a median overall survival of only 14.9 months, compared to 38.1 months for those who had earlier infusions. This difference highlights the potential impact of timing on outcomes. Additionally, a recent study involving older patients with locally advanced NSCLC found that those receiving at least half of their durvalumab infusions within 3 hours of sunset had more than a twofold higher risk of distant metastases and worse progression-free survival.

Understanding the Biological Mechanisms Behind Immunotherapy Timing

Why might timing matter so much? The key may lie in the body’s internal circadian rhythm, the internal clock that regulates many biological processes, including immune function. Circadian rhythms control the expression of genes related to immunity, DNA repair, and cell proliferation, and disruption of these rhythms has been linked to an increased risk of cancer. Conversely, optimizing cancer therapies through chronotherapy—administering treatments at specific times of the day when they are most effective—has emerged as a potential strategy for improving outcomes.

Research has shown that lymphocyte (immune cell) levels are highest in the body earlier in the day and drop as the day progresses. Since immunotherapy relies heavily on lymphocytes to target and destroy cancer cells, treatments administered when lymphocyte concentrations are at their peak may be more effective. Studies on metastatic renal cell carcinoma support this hypothesis, showing that T-cell activity was highest in the morning, correlating with improved survival outcomes when immunotherapy was administered earlier in the day.

Study Reference: https://www.esmoopen.com/article/S2059-7029(23)01461-8/fulltext

The Role of Other Cancer Treatments and Timing

While immunotherapy appears to benefit from being administered earlier in the day, the evidence is less consistent for other forms of cancer treatment. For example, research on radiation therapy has shown conflicting results. A study on NSCLC patients receiving chemoradiotherapy found that radiation treatments given later in the day were associated with better tumor control and lower risks of distant metastasis. The researchers hypothesized that radiation given later in the day may result in fewer lymphocytes being killed, leading to better immune system function and greater tumor control.

On the other hand, chemotherapy timing is still a topic of debate. Some studies suggest that administering chemotherapy in the morning may be more beneficial, while others indicate that it doesn’t make a significant difference, with even contradictory findings in certain populations. For example, a study on patients with prostate cancer found that treatments administered in the morning were associated with better outcomes, particularly in White men, but had no overall impact for other racial groups.

Challenges and Future Research Needs

Despite promising findings regarding the timing of immunotherapy, these insights have not yet translated into changes in clinical practice. One major hurdle is the lack of large, multicenter randomized trials to definitively prove the benefits of immunotherapy timing. Logistical concerns, such as coordinating infusion schedules across multiple centers and pharmacies, and funding issues, also complicate the implementation of studies on this topic.

Dr. David Qian, a key researcher on the topic, has encountered difficulties in securing funding for large-scale trials, as pharmaceutical companies may be hesitant to fund studies that could suggest a shift in the timing of treatments. In response to this challenge, Qian and colleagues are planning to conduct a smaller randomized trial at Emory University with over 100 patients diagnosed with metastatic melanoma, aiming to determine whether immunotherapy should be administered in the morning, midday, or later in the day for optimal results.

Even without large-scale clinical trials, some patients are already actively requesting that their immunotherapy infusions be scheduled earlier in the day after learning about the potential benefits. This growing interest may prompt further investigation and eventually influence the wider oncology community’s approach to treatment timing.

Conclusion

While the evidence on the timing of immunotherapy is still emerging, the early studies suggest that receiving immunotherapy earlier in the day may significantly improve survival outcomes for certain cancers. The underlying biological mechanisms, such as the circadian rhythm’s effect on immune function, offer a plausible explanation for these findings. However, more large-scale, randomized clinical trials are needed to fully understand the impact of treatment timing on cancer progression and survival. For now, the timing of immunotherapy remains an area of active research, and it may be a key factor in optimizing cancer treatment in the future. As more data becomes available, it could lead to changes in how therapies are scheduled to provide patients with the best possible outcomes.