The Immune System: A New Organ at Risk in Lung Cancer Radiation Therapy?

IN REFERENCE TO: Ladbury CJ, Rusthoven CG, Camidge DR, Kavanagh BD, Nath SK. Impact of radiation dose to the host immune system on tumor control and survival for stage III non–small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 2019;105(2):346-355.

The immune system plays critical roles in the pathogenesis, surveillance, progression, and treatment of solid tumors. The ability to evade immune-mediated destruction has been described as a shared trait across multiple tumor types.¹ Host–tumor immunologic interactions are complex, and ionizing radiation has demonstrated both immune-stimulatory and immunosuppressive effects. Despite its apparent significance and sensitivity to radiation, the immune system has not been routinely considered an organ at risk in radiotherapy planning. Estimating radiation dose to circulating immune cells for clinical implementation is inherently challenging. Yovino et al. developed a method for modeling radiation exposure to the circulating blood pool based on assumptions about the behavior of blood flow, the lymphocytes it carries, and a known irradiated volume.² Jin et al.³ subsequently developed a conceptual framework for the immune compartment as an organ at risk by estimating radiation exposure to the circulating blood pool. Effective dose to the immune cells (EDIC) accounts for kinetics of cardiac output and differences in blood flow and radiation exposure among tissues, and it has been simplified into a formula in which EDIC is a function of mean heart dose, mean lung dose, and integral dose. Its prognostic value was evaluated in the locally advanced NSCLC setting; a secondary analysis of RTOG 0617 found EDIC highly prognostic for decreased OS and local PFS.

Investigators from the University of Colorado adapted the original EDIC model, substituting integral dose with mean body dose—termed “EDRIC” (estimated dose of radiation to immune cells)—and evaluated its effects on survival in an institutional cohort of 117 patients with stage III NSCLC.⁴ The majority were treated with definitive radiation therapy at a median dose of 60 Gy, with either concurrent (91.5%) or sequential (5.1%) chemotherapy; none received immunotherapy. Higher EDRIC was an independent predictor of increased all-cause mortality. Notably, it was statistically significant in a multivariable model in which other variables, including the individual EDRIC components, prescription dose, and other dosimetric endpoints, were not significant. Actuarial survival varied substantially by EDRIC quartiles: median OS was 28.2 months (EDRIC < 5.1 Gy; lowest quartile) versus 14.3 months (EDRIC > 7.3 Gy; highest quartile). In a similar fashion, EDRIC was an independent predictor of disease-free survival and local PFS. To provide biologic validation for EDRIC, the authors examined the relationship between EDRIC and treatment-related myelosuppression. Absolute lymphocyte and neutrophil counts captured during treatment were used as corroborating physiologic endpoints. Higher EDRIC predicted grade 3 or higher lymphopenia, neutropenia, and leukopenia, after adjusting for chemotherapy use and its timing in relation to radiation therapy.

Together, these results suggest that dose to the immune compartment, as modeled by radiation exposure to the circulating peripheral blood and supported by a dose-dependent relationship with treatment-related myelosuppression, is a novel prognostic biomarker for death and disease control in NSCLC. Interestingly, total radiation prescription dose and EDRIC component doses (i.e., mean lung, mean heart, and integral doses) were not significant for survival when EDRIC was also present in the multivariable model. This mirrors Jin et al.’s earlier results from the RTOG 0617 secondary analysis. This study adds to the growing literature describing the clinical effects of radiation on the immune system. The same EDIC model has also been applied to early-stage (T1-2N0) NSCLC treated with stereotactic body radiation therapy and esophageal cancer treated with chemoradiation, both with comparable results with respect to its impact on survival.^5,6 Framed in this context, these findings provide a new way of interpreting studies that have identified individual-organ dosimetric endpoints—that is, heart and lung doses—as being prognostic in lung cancer.⁷ It may also shed light on the unexpected increased risk of death in the high-dose chemoradiation arm of RTOG 0617, and perhaps also on why even low-dose parameters, such as volume of the heart receiving 5 Gy, were independent predictors of survival.⁸ Notably, this study predates the widespread adoption of consolidative immunotherapy in stage III NSCLC. Exposure to the immune compartment will arguably be more important with inclusion of standard-of-care durvalumab, given that lymphocytes are the primary effectors of immune-mediated tumor kill. Retrospective data from the advanced metastatic setting support this hypothesis; two studies have identified radiation-induced and pre-immunotherapy lymphopenia as independent predictors of OS.^9,10 Given increasing interest and utilization of immunotherapy in early-stage, resectable and also unresectable NSCLC (PACIFIC-4, SWOG/NRG S1914, and NRG-LU004), understanding the effects of radiation exposure to the modeled immune system will be critical to radiotherapy’s role in these new paradigms.

Lastly, these results may have larger implications for radiation treatment planning and the choice of treatment modality. As a modifiable risk factor, reducing EDIC argues for highly conformal radiation plans, with an emphasis on containing exposure to the low- and moderate-dose regions. Here, the low-dose bath that is characteristic of multiple overlapping beams in intensity-modulated radiation therapy plans is perhaps less than ideal. Proton therapy, however, has unique physical properties that would be particularly well-suited to this scenario. The depth–dose curve’s sharp peak and subsequent falloff at end of range allows proton therapy to achieve a degree of conformality and tissue sparing beyond what is possible with photon-based irradiation. Attendant dosimetric advantages of proton therapy have been well-documented in lung cancer, with current-generation proton delivery technology—that is, pencil-beam scanning—showing additional benefits over traditional passive-scatter delivery.^11,12 Its ability to substantially reduce the risk of severe lymphopenia has also been shown.^13,14 Limiting dose to the immune system organ at risk may provide a novel and compelling motivation for the use of proton therapy. Whether physical advantages of proton therapy will be translated into meaningful clinical outcomes is the subject of multiple ongoing randomized trials. Results from NRG RTOG 1308 and NRG-GI006, which are randomly assigning patients with locally advanced NSCLC and esophageal cancer, respectively, between photon and proton radiation therapy, are eagerly awaited.

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