Radiotherapy and immunotherapy cooperate to generate antitumor immune responses for therapeutic gain.

The adjuvant treatment of resected head and neck squamous cell carcinoma (HNSCC) is guided by the European Organisation for Research and Treatment of Cancer (EORTC) 22931 and Radiation Therapy Oncology Group (RTOG) 95-01 randomized clinical trials.^1,2 Both trials randomized patients with at least 1 adverse prognostic factor after definitive surgery to adjuvant radiotherapy (RT) or cisplatin-based chemoradiotherapy (CRT), and both demonstrated a progression-free survival (PFS) benefit with CRT. The specific adverse risk features qualifying patients for each trial were variable, but an exploratory combined analysis³ suggested that extracapsular extension (ECE) and positive surgical margins were the most significant prognostic factors, and patients with 1 of these 2 features derived benefit from CRT.

In locally advanced oral cavity squamous cell carcinomas (OCSCCs), surgery followed by postoperative radiotherapy with or without chemotherapy (S+PORT) has been the preferred treatment because of improved reconstruction techniques and the poor outcomes of locally advanced OCSCCs treated with definitive radiotherapy.^1-5 Quiz Ref ID Nevertheless, the morbidities associated surgical resection followed by radiotherapy or chemoradiotherapy (CRT) include worse dysphagia and increased use of feeding tubes.⁶ Although organ preservation with CRT has similar outcomes compared with S+PORT in other cancers of the pharyngeal axis,^7-9 studies^10,11 have found conflicting results regarding the equivalence of CRT and S+PORT for OCSCC. Pederson et al¹⁰ reported 20-year locoregional control rates approaching 90% and overall survival (OS) rates of 76%. By contrast, other studies^1-5,12 have reported substantially worse outcomes for definitive CRT in locally advanced OCSCC. Scher et al⁴ reported 2-year locoregional control rates of 41% with concurrent CRT. Sher et al⁵ reported 2-year local regional control rates of 64% for CRT compared with 91% for S+PORT. Furthermore, in a randomized clinical trial of S+PORT compared with CRT, the oral cavity subset of patients undergoing CRT for head and neck squamous cell carcinomas fared significantly worse than those receiving S+PORT.³

Preclinical studies suggest enhanced anti-tumor activity with combined radioimmunotherapy. We hypothesized that radiation (RT) + immunotherapy would associate with improved overall survival (OS) compared to immunotherapy or chemotherapy alone for patients with newly diagnosed metastatic non-small-cell lung cancer (NSCLC). The National Cancer Database was queried for patients with stage IV NSCLC receiving chemotherapy or immunotherapy from 2013 to 2014. RT modality was classified as stereotactic radiotherapy (SRT) to intra- and/or extracranial sites or non-SRT external beam RT (EBRT). OS was analyzed using the Kaplan-Meier method and Cox proportional hazards models. In total, 44,498 patients were included (13% immunotherapy, 46.8% EBRT, and 4.7% SRT). On multivariate analysis, immunotherapy (hazard ratio [HR]:0.81, 95% confidence interval [CI]:0.78–0.83) and SRT (HR:0.78, 95%CI:0.70–0.78) independently associated with improved OS; however, the interaction term for SRT + immunotherapy was insignificant (p = 0.89). For immunotherapy patients, the median OS for no RT, EBRT, and SRT was 14.5, 10.9, and 18.2 months, respectively (p < 0.0001), and EBRT (HR:1.37, 95%CI:1.29–1.46) and SRT (HR:0.78, 95%CI:0.66–0.93) associated with OS on multivariate analysis. In the SRT subset, median OS for immunotherapy and chemotherapy was 18.2 and 14.3 months, respectively (p = 0.004), with immunotherapy (HR:0.82, 95%CI:0.69–0.98) associating with OS on multivariate analysis. Furthermore, for patients receiving SRT, biologically effective dose (BED) > 60 Gy was independently associated with improved OS (HR:0.79, 95%CI:0.70–0.90, p < 0.0001) on multivariate analysis with a significant interaction between BED and systemic treatment (p = 0.008). Treatment with SRT associated with improved OS for patients with metastatic NSCLC irrespective of systemic treatment. The high survival for patients receiving SRT + immunotherapy strongly argues for evaluation in randomized trials.

Radiotherapy techniques have evolved from 3D conformal radiotherapy (3D-CRT) to intensity modulated radiotherapy (IMRT) where boost fields are delivered either sequentially (IMRTseq) or with a simultaneous integrated boost (IMRT+SIB). Our goal was to compare the outcomes of patients treated with IMRT+SIB to traditional standards. We analyzed the efficacy and toxicity of patients treated with concurrent chemoradiation using 3D-CRT, IMRTseq or IMRT+SIB. Between 1993 and 2012, 379 patients with non-metastatic Stage III-IV head and neck squamous cell cancer were treated with concurrent chemoradiation using 3D-CRT (n = 125), IMRTseq (n = 120) and IMRT+SIB (n = 134). Patients treated with any technique had similar rates of 2y local control, 2y regional control, 2y progression free survival and 2y overall survival. Patients treated with IMRT+SIB had lower rates acute toxicity according to Grade 3 or greater mucositis (3D-CRT: 44.0% vs. IMRTseq: 36.7% vs. IMRT+SIB: 22.4%; P<.0001), dermatitis (3D-CRT: 44.0% vs. IMRTseq: 20.0% vs. IMRT+SIB: 7.5%; P<.0001) and feeding tube placement during radiotherapy (3D-CRT: 80.0% vs. IMRTseq: 50.8% vs. IMRT+SIB: 44.0%; P<.0001) as well as late toxicity as measured by feeding tube use (P<.0001) and tracheostomy use (P<.0001). On multivariate analysis, IMRT+SIB predicted for less mucositis, dermatitis and feeding tube use compared to 3D-CRT and for less dermatitis compared to IMRTseq. Compared to 3D-CRT and IMRTseq, IMRT+SIB provided similar outcomes and potentially less toxicity indicating it is a feasible technique for chemoradiation in locally advanced head and neck cancer.