The Toxicity of Low-Dose Whole Abdomen Radiotherapy in Advanced Gynecologic Malignancies Receiving Stereotactic Body Radiotherapy and Immunotherapy

Abstract

<h3>Purpose/Objective(s)</h3> The objective of this retrospective study was to evaluate the safety of low-dose whole abdomen radiotherapy (LD-WART) in patients with gynecologic malignancies receiving stereotactic body radiotherapy (SBRT) and immunotherapy (IO). We hypothesized that LD-WART volume would not be associated with increased adverse events (AEs). <h3>Materials/Methods</h3> Study design was a pooled secondary analysis of two prospective phase I trials, in which patients with advanced solid malignancies were treated with multi-site SBRT (≤4 sites) with IO. The study cohort (N = 22) was limited to patients with a gynecologic primary (ovarian or uterine) that received SBRT to ≥1 abdomino-pelvic site. IO was administered either concurrently (N = 8) or sequentially (i.e., within 7 days of SBRT, N = 14). IO regimens included pembrolizumab (N = 14), nivolumab plus urelumab (N = 6), and nivolumab plus cabiralizumab (N = 2). Whole abdominal cavities (with inclusion of the pelvis) were contoured for all patients. The kidneys and a 1cm isocentric contraction of the liver were excluded. Based on recent literature supporting immune reprogramming of the tumor microenvironment with doses of 0.5 to 2 Gy, the V0.5Gy (%), V1Gy (%), and V2Gy (%) for the whole abdomen were recorded. Time to CTCAE v4.0 grade 2-4 AEs and overall survival (OS) were defined as the time from start of SBRT to either toxicity or death, respectively. Toxicity was analyzed using the cumulative incidence function with death as a competing risk. Correlation between dose metrics and toxicity were analyzed using the Fine-Gray subdistribution hazard model, including the primary site and number of irradiated abdomino-pelvic sites as covariates. <h3>Results</h3> 22 patients met criteria for inclusion (73% ovarian, 27% endometrial). Median OS was 13.3 months. The median whole abdomen V0.5Gy, V1Gy, and V2Gy was 42% (range, 12% - 97.5%), 32% (range, 8% - 86%), and 26% (range, 6% - 77%), respectively. At 12 months (with 12 of 22 patients evaluable), the cumulative incidence of grade 3+ AEs was 9%, 9%, and 0% when whole abdomen V0.5Gy, V1Gy, and V2Gy exceeded the cohort median, in contrast to 18%, 18%, and 27%, respectively, when less than the cohort median. As a continuous variable in the multivariable Fine-Gray model, grade 3+ AEs were not increased with increasing whole abdomen V0.5Gy (subdistribution hazard ratio [SHR] 0.96, <i>P</i> = 0.26), V1Gy (SHR 0.95, <i>P</i> = 0.11), and V2Gy (SHR 0.95, <i>P</i> = 0.14). Similarly, the grade 2+ AEs were not increased with increasing whole abdomen V0.5Gy (SHR 0.98, <i>P</i> = 0.12), V1Gy (SHR 0.97, <i>P</i> = 0.08), and V2Gy (SHR 0.98, <i>P</i> = 0.17). There were no grade 2+ hepatic or renal AEs. <h3>Conclusion</h3> In this pooled analysis of two phase I trials, increasing LD-WART volume receiving 0.5-2 Gy was not associated with increased toxicity in the setting of SBRT and immunotherapy. These data support the potential safety of a future pilot study being explored by our institution for advanced gynecologic malignancies combining low-dose whole abdominal irradiation, SBRT to gross tumor sites, and IO.