Modeling Potential Lymphocyte-Sparing Effect of Involved-Field Radiotherapy in Rectal Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphopenia (RIL) is associated with worse disease-free and overall survival in solid tumors including rectal cancer, as well as lower response rates to checkpoint inhibitors. Large elective nodal volumes, as are utilized in whole-pelvis radiotherapy (WPRT) for rectal cancer, are associated with high RIL risk, while involved-field radiotherapy (IFRT) reduces planning target volume (PTV) size, potentially sparing circulating lymphocytes. In rectal cancer, effective use of IFRT may be facilitated by advances in imaging and high response rates to doublet/triplet chemotherapy regimens such as FOLFOX and FOLFIRINOX. We investigated the potential for IFRT to spare circulating lymphocytes in rectal cancer patients by comparing predicted absolute lymphocyte count (ALC) depletion rates associated with WPRT vs. IFRT. <h3>Materials/Methods</h3> Seventy-five rectal cancer patients who underwent chemoradiotherapy (CRT) were selected. Two different CTVs were contoured in all patients, CTV_(WP) containing traditional at-risk RTOG nodal volumes and CTV_(IF) incorporating primary tumor with a 1-2cm margin, entire mesorectum including a 1cm anterior margin, and any grossly enlarged lymph nodes with a 1cm margin. Two different PTVs, PTV_(WP) & PTV_(IF), were generated using a 0.8-cm isotropic expansion. Wilcoxon signed-rank test was used to compare the two different PTV volumes. Median PTV volume from each data set was used to compute the probability of ALC depletion resulting from PTV_(WP) & PTV_(IF). The equation used to calculate the ALC decay constant k_ALC was: k_ALC = 0.058 + (0.056 * PTV volume/total blood volume) * (dose per fraction)². The computed k_ALC was then used to calculate predicted end-treatment ALC for each field design. Predicted rate of CTCAE v5.0 Grade 3-4 lymphopenia was also computed for these cohorts. <h3>Results</h3> Of the 75 patients, 45 had node positive disease, and 6 patients had pelvic sidewall lymph node/s. 59 patients had T3 disease. Median PTV volume was 1330 cc (IQR: 1200,1534) for PTV_(WP) and 802 cc (IQR: 697,969.8) for PTV_(IF) (ΔPTV 41%, p<0.0001). In summary, PTV_(IF) was 41% smaller than the PTV_(WP). Assuming a baseline ALC of 1800 cells/μL, the predicted median ALC at the end of RT was 360.2cells/μL for PTV_(WP), and 483.0cells/μL for PTV_(IF)(p<0.0001). Grade 3 lymphopenia was predicted in all patients in the PTV_(WP) cohort, whereas it was predicted for only 60% if PTV_(IF) were to be used. <h3>Conclusion</h3> In rectal cancer patients undergoing neoadjuvant CRT, involved-field RT results in a significantly lower median PTV volume when compared to whole-pelvis RT (ΔPTV 41%). This in turn led to improved predicted lymphocyte-sparing and 40% absolute reduction in the risk of predicted grade 3 lymphopenia. These results will be validated in a larger cohort and will help design a prospective study investigating lymphocyte-sparing radiotherapy for rectal cancer patients.