Anatomical Association of Dose Distribution With Radiotherapy-Related Lymphopenia in Oropharynx Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Lymphopenia during radiotherapy (RT) may be related to adverse outcome for head and neck cancer and is a theoretical concern for effectiveness of adjuvant immunotherapy. Prevention may be possible via plan adaptation if the relationship between RT dose distribution and incidence of lymphopenia is known. This work utilized image-based data mining to identify anatomical regions associated with development of lymphopenia during RT. <h3>Materials/Methods</h3> 639 oropharyngeal cancer patients treated from 2005-2016 at a single institution with curative intent RT and baseline lymphocytes ≥ 0.5 × 10⁹/L were studied. To control for co-founders and improve data mining sensitivity, two matched groups were defined - patients with and without lymphopenia (defined as Grade 3 or higher based on lymphocytes at nadir during RT < 0.5 × 10⁹/L according to CTCAE v5.0) - matched on target volume, baseline lymphocytes, and prescribed dose (propensity score matching, M = 1:1, caliper = 0.2). Following matching, 309 patients remained, and image-based data mining was used to identify regions where dose correlates with lymphopenia. EQD2 dose matrices (α/β = 10) were mapped onto a reference patient using deformable registration of the planning CT images. L-R mirrored images were included in the cohort to compensate for potential laterality bias. Mean dose distributions for the groups with/without lymphopenia were calculated and regions with significant differences between the mean dose of the two groups detected using permutation testing with 1000 permutations. Multivariable logistic analysis was conducted for the full cohort including mean dose to the identified region, along with age, gender, smoking, performance status, HPV status, stage, histology, target volume, prescribed dose, RT modality, RT duration, baseline lymphocytes, and chemotherapy delivery to generate a predictive model for development of lymphopenia. <h3>Results</h3> 74% of the patients developed lymphopenia ≥ G3 during RT. An association with dose to a discrete anatomical region was found. Of interest, this location corresponds to dense lymphoid tissue, bone marrow reserve, and numerous blood vessels. Following elastic-net least absolute shrinkage and selection operator regression, bootstrapped 100 times, a model including baseline lymphocytes (HR = 0.43, <i>P</i> < 0.001) and mean dose to the identified region (HR = 1.02 Gy⁻¹, <i>P</i> = 0.006) adjusted for age (HR = 0.98, <i>P</i> = 0.09) and target volume (HR = 1.83, <i>P</i> = 0.07) was proposed. The Hosmer-Lemeshow test indicated that the model was a good fit, C-statistics 94%. <h3>Conclusion</h3> In this large oropharynx cohort, RT related lymphopenia ≥ G3 was associated with dose to a discrete anatomical region including structures containing blood, lymphoid tissue, and bone marrow that may offer a mechanistic explanation. While hypothesis generating, this suggests the possibility that treatment related lymphopenia may be mitigated by prioritizing dose reduction to this region. Further confirmatory studies are indicated.