This multicenter study led by the MGH group retrospectively analyzed 96 patients with unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated-RT (HF-RT), and reported that HF-RT-related lymphopenia was an independent prognostic factor for survival. This study included 96 patients treated to a median total dose of 58.05 Gy in 15 fractions. Severe lymphopenia was associated with a 1.7-fold increased risk of death (P=0.04); 1-year OS rates were 63% vs 77% (P=0.03). Receipt of photon versus proton-based RT (OR=3.50, P=0.02), higher mean liver dose (OR=1.19, P<0.01), and longer RT duration (OR=1.49, P=0.02) predicted severe lymphopenia. In conclusion, the authors suggested that use of proton therapy, minimizing mean liver dose, and avoiding treatment breaks may reduce RT-related lymphopenia.