Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods:Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n ¼ 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and antithyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P ¼ 0.04).Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

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Purpose We compared gastrointestinal (GI) and hematologic toxicity in patients with locally advanced pancreas cancer (LAPC) undergoing definitive chemoradiation using intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3D-CRT) planning. Methods and Materials We retrospectively studied 205 patients with LAPC undergoing IMRT (n=134) and 3D-CRT (n=71) between 05/03 and 03/12. Patient, tumor, and treatment characteristics and acute GI/hematology toxicity according to Common Terminology Criteria for Adverse Events v3.0 were recorded. Multivariable logistic regression models were used to test association between acute grade 2+ GI and hematologic toxicity outcomes and predictors. Propensity score analysis for grade 2+ GI toxicity was performed to reduce bias for confounding variables: age, gender, radiation dose, field size, and chemotherapy type. Results Median follow-up time for survivors was 22 months, similar between groups. Median RT dose was significantly higher for IMRT vs. 3D-CRT (5600 cGy vs 5040 cGy, P<.001); concurrent chemotherapy was mainly gemcitabine (56%) or 5-fluorouracil (5-FU, 38%). Grade 2+ GI toxicity occurred in 34% (n=24) of 3D-CRT compared with 16% (n=21) of IMRT patients. Using propensity-score analysis, 3D-CRT had significantly higher grade 2+ GI toxicity (odds ratio, 1.26 [95%CI, 1.08-1.45], P=.001). Grade 2+ hematologic toxicity was similar between IMRT and 3D-CRT groups but was significantly greater in recipients of concurrent gemcitabine over 5-FU (62% vs 29%, P<.0001). Conclusions IMRT is associated with significant lower grade 2+ GI toxicity versus 3D-CRT for patients undergoing definitive chemoradiotherapy for LAPC. Since IMRT is better tolerated at higher doses and may allow further dose escalation, potentially improving local control for this aggressive disease. Further prospective studies of dose-escalated chemoradiation using IMRT are warranted.

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PurposeClinical target volumes (CTV) for radiotherapy (RT) in esophageal cancer (EC) are based on standard expansions of primary tumor volume. Data is needed to define regions at highest risk for occult disease, based on histology and location of the primary tumor. We therefore reviewed PET scans in EC patients to characterize the location of FDG-avid lymph node metastases (LNM).Materials and methodsWe identified 473 EC patients with reviewable pre-treatment PET-CT scans. Tumors were classified by histology and location; 85% were distal or GE junction tumors and 71% were adenocarcinoma. FDG-avid LNM were classified using standard radiographic nodal atlases, and distances from primary tumor to paraesophageal LNM were also measured.ResultsThe most common LNM in upper EC were supraclavicular, retrotracheal and paratracheal. The most common LNM in lower EC were paraesophageal and in the gastrohepatic space. Overall, 55% of paraesophageal LNM were adjacent to primary tumor. Of upper esophageal tumors with paraesophageal LNM, 87% were adjacent to the tumor and none were >6 cm from tumor. However, 57% of lower esophageal tumors with paraesophageal LNM had non-adjacent paraesophageal nodes, 24% of which were >8 cm from the tumor.ConclusionA more data-driven and individualized approach to CTV delineation could improve the therapeutic ratio of RT in esophageal cancer. These results can guide CTV delineation by indicating the potential distribution of nodal involvement in esophageal cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0731-6) contains supplementary material, which is available to authorized users.