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Chuanben Chen,1,2 Zhaodong Fei,1,2 Chaoxiong Huang,2 Jianming Ding,1,2 Lisha Chen1,2 1Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People’s Republic of China; 2Provincial Clinical College, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China Background: The prognostic value of primary tumor volume (TV) in nasopharyngeal carcinoma (NPC) has been confirmed. However, studies of the prognosis value of tumor burden, including TV and nodal volume (NV), have been relatively infrequent. Therefore, the aim of this study was to evaluate the prognostic value of tumor burden in NPC patients treated with intensity-modulated radiotherapy.Methods: Receiver operating characteristics curves were generated to determine rational cutoff points for TV and NV. The volumes identified included 12.5, 25.0, and 50.0 mL, and 0, 12.5, and 25 mL, respectively. According to these cutoff volumes, four subgroups were established for TV as TV1–TV4, and four subgroups were established for NV as NV0–NV3. Then, the entire cohort (992 NPC patients) was divided into 16 subgroups according to these four levels of TV and NV. Based on similarities in the 5-year overall survival (OS) rates for these 16 subgroups, four patient groups were established, G1–G4.Results: The mean TV and NV values for our cohort were 39.5±30.8 mL and 16.5±17.6 mL, respectively. The 5-year distant failure-free rate, the 5-year disease-free survival rate, and the 5-year OS rate for G3 and G4 were significantly lower than those for G1 and G2. In particular, the OS curves of the four patient groups were significantly separated. A multivariate analysis identified TV >50 mL, T-stage (3–4), and N-stage (2–3) as adverse prognostic factors for OS.Conclusions: The results of this study demonstrate that tumor burden has a significant prognostic value for NPC patients treated with intensity-modulated radiotherapy. Hence, tumor burden, including TV and NV, should be incorporated into the current staging system for NPC to improve prognostic significance. Keywords: prognostic value, tumor burden, primary tumor volume , nodal volume, nasopharyngeal carcinoma

Chun-Bing Chen,1–6 Ming-Ying Wu,1–4 Chau Yee Ng,1–5 Chun-Wei Lu,1–6 Jennifer Wu,1–4,6 Pei-Han Kao,1–4,6 Chan-Keng Yang,4–7 Meng-Ting Peng,4,6–7 Chen-Yang Huang,4,6–7 Wen-Cheng Chang,4,6–7 Rosaline Chung-Yee Hui,1–4 Chih-Hsun Yang,1–4 Shun-Fa Yang,8,9 Wen-Hung Chung,1–4,6,10,11 Shih-Chi Su1–4,10 1Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; 2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; 3Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; 7Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; 8Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 9Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 10Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 11Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China Abstract: With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management. Keywords: acute generalized exanthematous pustulosis, drug rash, eosinophilia, Stevens–Johnson syndrome, toxic epidermal necrolysis, targeted therapy, immunotherapy