More is not better when it comes to radiation therapy in patients with stage III non-small cell lung cancer (NSCLC), according to a large phase 3 clinical trial. In fact, researchers found that patients treated with higher doses of radiation had shorter overall survival (OS) than those treated with lower doses. The bottom line is: Radiation may negatively affect the immune system, especially when delivered to highly perfused areas, such as the lungs.
The importance of the body’s own immune system in battling cancer cannot be overstated, and was the cornerstone for the fairly recent development of immunotherapy as an effective treatment for many types of cancer. Yet, in addition to immunotherapy, the effects of other cancer treatments—such as radiation therapy—on the body’s immune system also merit further consideration.
“Over the past decade, it has become increasingly apparent that the host immune system can work in conjunction with chemotherapy and radiation therapy to improve local tumor cell killing both during and after treatment,” wrote the researchers, led by senior author Sameer K. Nath, MD, investigator, University of Colorado Cancer Center, and assistant professor, Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO.
“Radiation therapy may also contribute to immune activation through noncanonical cytokine signaling cascades or tumor antigen release, leading to tumor regression outside of the radiation fields (known as the abscopal effect). Consequently, impairment of immune function may diminish the efficacy of chemoradiation and therefore survival. This may be of even greater importance in patients receiving immunotherapy, where radiation-induced lymphopenia before immunotherapy may decrease the efficacy of therapy,” they added.
In their study, Dr. Nath and fellow researchers retrospectively analyzed data from 117 patients with stage III NSCLC who had been treated with definitive fractionated radiation (median dose: 60 Gy; 60% received intensity modulated radiation therapy; 92% underwent concurrent platinum-based chemotherapy).
To determine the effects of the estimated dose of radiation to immune cells (EDRIC) on cancer-specific outcomes, they calculated EDRIC as a function of the number of radiation fractions used, and—based on a previously developed model—mean doses to the heart, lungs, and remaining body.
After a median follow-up of 16 months, 5-year OS was 11.2% (median: 17.3 months).
Upon multivariate analysis, Dr. Nath and colleagues found that EDRIC was independently associated with OS (HR: 1.17; P = 0.03), as well as local progression-free survival (LPFS; HR: 1.17; P = 0.02) and disease-free survival (DFS; HR: 1.15; P = 0.04).
Median EDRIC was 6.1 Gy. In patients with high EDRIC (above 7.3 Gy), median OS was 14.3 months, compared with 28.2 months in those with low EDRIC (less than 5.1 Gy). Higher EDRIC was also associated with a greater risk of grade 3 or higher lymphopenia (P = 0.004).
Dr. Nath et al also found that the myelosuppressive effects of EDRIC were additive to chemotherapy. Indeed, in these patients, EDRIC significantly predicted who would manifest decreased immune cell counts, even after adjusting for different regimens and sequencing of chemotherapy. This was true despite the fact that 97% of patients received cytotoxic chemotherapy.
“We have shown that a higher EDRIC is associated with diminished lymphocyte and neutrophil counts in addition to poorer LPFS, DFS, and OS. These findings are important because with the advent of modern radiation therapy techniques, EDRIC is a quantifiable and potentially modifiable risk factor. Tailoring radiation therapy to minimize damage to the host immune system may help optimize the efficacy of therapy in the future,” wrote Dr. Nath and colleagues.
Indeed, added Dr. Nath, tailoring an approach to immune-sparing radiation therapy may be particularly beneficial in patients who undergo radiation therapy of the chest. Specifically, radiation that is delivered to the lungs affects not only the lungs, but the blood that passes through the lungs and the heart as well. This can have a negative effect on the immune components in the blood.
“As you give each fraction of radiation to the chest, there's a certain volume of blood that's in the field. Many of the lymphocytes in that field will be killed and as you repeat each treatment, you keep hitting a different volume of blood, and overall end up depleting that circulating pool. If we reduce number of radiation fractions or give the dose over a shorter time period, we would be hitting less blood, overall,” he said.
Their results may help shed light on the benefits of delivering more focused forms of radiation to circumvent extremely perfused areas that are identifiable with functional lung imaging, for example, to spare circulating immune cells.
“These results may also have implications for other patients undergoing fractionated radiation therapy with chemotherapy in close proximity to highly vascular tissues as well as for those receiving consolidative immunotherapy. Additional research exploring the feasibility of achieving lower EDRIC values while maintaining adequate tumor coverage is warranted,” they concluded.