Combined radiotherapy and immunotherapy in urothelial bladder cancer: harnessing the full potential of the anti-tumor immune response

Abstract

Purpose Radiotherapy (RT), as part of trimodal therapy, is an attractive alternative treatment in patients with urothelial muscle-invasive bladder cancer (MIBC). There is accumulating evidence suggesting the immunomodulatory effects of RT and its potential synergy when combined with immunotherapy. The aim of this review was to report on the most recent advances on this combination, including the mechanisms of RT immunomodulation, practical approach to combining RT and immunotherapy, and ongoing clinical trials in bladder cancer. Methods Using the PubMed database, we identified articles published between March 2004 and April 2020 on the combination of RT with immunotherapy in localized or metastatic MIBC. A search of the Clinicaltrials.gov and Clinicaltrialsregister. eu/ retrieved ongoing clinical trials on the topic as well. Results Combination of RT with immunotherapy leads to immunogenic cell death and an increase in immune markers thus leading to improved tumor control. For localized MIBC, there are safety concerns related to the use of concurrent immunotherapy with hypofractionated RT, thus neoadjuvant or adjuvant immunotherapy is preferred. In the metastatic setting, the combination of multi-site RT with SBRT-like doses (≥ 6 Gy per fraction) and concurrent immunotherapy seems most efficacious at harnessing the abscopal effect. At least 25 clinical trials combining immunotherapy and RT in MIBC are currently ongoing and will answer pending questions on safety, efficacy, and practical considerations on RT scheduling, fractionation, and targets volumes. Conclusion RT has the potential to synergize with immunotherapy to improve oncological outcomes in patient with localized or metastatic MIBC. Clinical trials results are eagerly awaited.

Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma

“…Dovedi et al reported that mice treated with anti–PD-L1 treatment and concurrent irradiation had longer survivals compared to those treated with anti–PD-L1 treatment seven days after irradiation in vivo [ 28 ]. However, the concurrent use strategy may not be clinically feasible because previous clinical trials were discontinued due to unacceptably high rates of severe adverse events following the concurrent use of hypofractionated radiotherapy and anti–PD-1/PD-L1 treatment in UC patients [ 29 , 30 ]. Meanwhile, recent findings from clinical data, including ours, showed that a history of radiotherapy was significantly associated with favorable prognosis after pembrolizumab therapy in patients with advanced UC [ 31 ] and non-small cell lung cancer [ 32 ], in which a history of radiotherapy was not associated with higher rates of adverse events.…”

Radiation therapy for nonmetastatic medically inoperable upper-tract urothelial carcinoma

“…Immunotherapy targeting the PD-1/PD-L1 pathway has had good effects in treating urothelial tumors (27). It has been reported that radiotherapy has the potential to synergize with immunotherapy to improve oncological outcomes in patients with urothelial muscle-invasive bladder cancer (28). PD-L1 expression on tumor cells independently predicted shorter CSS in UTUC (29).…”

MR-Guided Adaptive Radiotherapy for Bladder Cancer

“…Given this volume is up to 45% smaller than an anatomically defined bladder GTV, it opens the possibility of further normal tissue sparing (131). As the volume of radiation influences the immunogenic potential of the tumor microenvironment, defining alternative meaningful target sub-volumes particularly with systemic immunotherapy warrants further evaluation (132,133).…”