Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era

Abstract

Background

Immunotherapy is currently being examined as a treatment modality for glioblastoma. Maintaining an optimal total lymphocyte count (TLC) after radiotherapy (RT) and using temozolomide may be beneficial in optimizing immunotherapy. However, conventional temozolomide-based chemoradiation is known to induce immunosuppressive effects, including lymphopenia. Therefore, this study aimed to identify potential clinical predictors of acute severe lymphopenia (ASL) in patients receiving chemoradiation for glioblastoma.

Methods

We identified patients with glioblastoma treated with RT plus temozolomide from 2006 to 2017. ASL was defined as a TLC of < 500/μL within 3 months after initiating RT. Independent predictors of ASL were determined using logistic regression.

Results

A total of 336 patients were evaluated. Three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) were used in 186 (55.4%) and 150 patients (44.6%), respectively. TLC decreased during RT and remained persistently low during the 1-year follow-up, whereas the levels of other blood cell types recovered. In total, 118 patients (35.1%) developed ASL. During a median follow-up of 19.3 months, patients with ASL showed significantly worse overall survival than did those without ASL (median, 18.2 vs. 22.0 months; P = .028). Multivariable analysis revealed that increased planning target volume (PTV) was independently associated with increased ASL incidence (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00–1.03; P = .042), while IMRT was independently associated with decreased ASL incidence (HR, 0.48; 95% CI, 0.27–0.87; P = .015). A propensity-matched comparison showed that the incidence of ASL was lower with IMRT than with 3D-CRT (20% vs. 37%; P = .005).

Conclusions

IMRT and low PTV were significantly associated with decreased ASL incidence after RT plus temozolomide for glioblastoma. An IMRT-based strategy is necessary to enhance treatment outcomes in the immune-oncology era.

Background

Radiotherapy (RT)-induced lymphopenia (i.e., a reduction in the total lymphocyte count [TLC]) has been reported in various types of tumors, such as glioblastomas, pancreatic cancer, and lung cancer [1,2,3,4,5,6,7]. Although radiation has local effects, RT to peripheral organs can result in irradiation of a substantial proportion of circulating lymphocytes during multifraction treatments [8]. Recently, several studies have demonstrated that partial brain RT can contribute to systemic lymphopenia [5,6,7,8]. RT-induced lymphopenia is associated with poor survival in patients with high-grade gliomas who underwent standard therapy with RT and temozolomide [5, 6].

Despite multimodal treatment involving surgery, RT, and temozolomide, glioblastoma has a poor prognosis and almost all patients with glioblastoma eventually experience disease relapse [9]. Although repeat surgery, re-irradiation, and pharmacological treatment have been performed in the recurrent setting, evidence that any therapeutic intervention has a major effect on survival is lacking [10, 11]. Accordingly, different immunotherapy modalities for glioblastoma are being actively investigated, spurred on by advances in immuno-oncology for other tumor types [

Conclusions

This study revealed that although a large PTV can increase the risk of ASL, IMRT can effectively lower the risk of ASL after the initiation of RT plus temozolomide for treating glioblastoma. Our findings add to the growing evidence on the association between RT and treatment-induced lymphopenia in patients with glioblastoma. Particularly, in cases with a large tumor size or surgical cavity, IMRT-based therapeutic strategies should be actively considered to preserve the TLC. Such strategies could potentially improve treatment outcomes in the immuno-oncology era, and would thus need further study.