Discussion
RS, tumor, tumors
TUMOR, METASTASIS, DNA DAMAGE, SOLID TUMORS, RECRUITMENT, REGRESSION, TUMORS
We previously reported the safety and efficacy of SBRT+P in patients with advanced solid tumors in a phase I clinical trial (We have provided hypothesis-generating data that clinical response in patients with advanced solid tumors may be obtained by irradiating a metastasis with only partial coverage by the prescription dose (partial-Rx) when radiotherapy is combined with immune-checkpoint blockade. On a dosimetric level, previous studies have established that the minimum SBRT monotherapy dose required for local control of advanced solid tumors is 36 Gy in 3 fractions (Additional within-patient comparisons showed that the majority (84%) of patients demonstrated convergent responses, meaning partial-Rx and complete-Rx tumors responded similarly within the same patient. Although Despite the data suggesting similar LF for partial-Rx and complete-Rx tumors, this study was not designed to establish noninferiority of partial-Rx and complete-Rx treatments. Randomized data is needed to establish noninferior LF of partial-Rx and complete-Rx treatments in the context of immunotherapy. For example, a clinical trial could be conducted randomizing patients with metastatic, advanced, solid tumors receiving immunotherapy and SBRT versus no SBRT followed by a second randomization for the patients receiving SBRT as partial-Rx approach versus complete-Rx treatment. Ideally, the trial would be restricted to 1 or only a few primary histologies. This hypothetical trial could establish both the efficacy of adding SBRT to immunotherapy and of partial-Rx treatment in the setting of immunotherapy.Proposed mechanisms of local response in large tumors observed with the use of SBRT+P, irrespective of PD-L1 status, include a local immune response to radiation. Several groups have found that SBRT is able to induce both innate and adaptive immune pathways, while downregulating genes involved in cell cycle and DNA damage repair pathways (To our knowledge, this is the first study to report that the magnitude of irradiated tumor response to SBRT+P is associated with OS, with responders to SBRT+P demonstrating improved OS compared with nonresponders. These findings were independently supported on multivariable analysis when controlling for other clinical factors. Two hypotheses for this improvement in OS might be cytoreduction in symptomatic tumor burden and/or T cell reinvigoration (Our findings provide a rationale to prioritize sparing radiation dose to adjacent OARs while providing maximum tumor dose (The development of noninvasive biomarkers of treatment response and resistance is an unmet need in oncology and here we propose both the RS and circulating IL-8 levels as potential predictors of outcome. The ability to identify tumors with a T cell–inflamed microenvironment using the RS may allow for improved patient outcomes, treatment modality, and, potentially, even tumor-specific treatment selection for SBRT. IL-8 (CXCL8), which binds to CXCR1/2 receptors promoting neutrophil recruitment and activation (There are limitations to our current investigation. Several patients were excluded from the analysis because they either died before receiving SBRT+P or died before a radiologic assessment, rendering them nonevaluable. The exclusion of these patients may lead to bias, although the landmark analysis was intended to account for this. To address the high mortality rate, we used competing-risks regression to account for the fact that many patients died before developing a LF. There are many plausible explanations for the lack of an observed significant difference in LF between partial-Rx and complete-Rx tumors, one of which being a synergistic relationship between pembrolizumab and SBRT, however, an additive relationship is also possible. The heterogeneous nature of the cohort with various tumor histologies, locations, and volumes, as well as overall PD-L1 data, may introduce bias. We are not able to make claims for a specific tumor type, but future studies are warranted for individual tumor types and perhaps as an earlier line of therapy. The RS is dependent on imaging parameters (In conclusion, these findings demonstrate the safety and feasibility of SBRT and PD-1 immunotherapy in patients with large, advanced, solid tumors. We observe that partial-Rx has comparable LF to complete-Rx in our cohort of patients with large, advanced, solid tumors. Moreover, posttreatment tumor response to SBRT+P is associated with survival, and pretreatment RSs as well as elevated IL-8 deserve further study as predictive biomarkers. A randomized trial is warranted utilizing multi-site SBRT, including partial tumor irradiation, in the setting of immune-checkpoint blockade.