第一部分：题目:调强放疗年代口咽癌治疗生存结果及预后因素分析：单中心大样本回顾性分析

  目的：回顾性分析我院口咽癌的临床特征、治疗疗效、失败模式、早晚期不良反应及影响预后的因素。为口咽癌未来治疗优化提供参考。

   材料与方法：回顾性分析2010年1月至2020年12月我院收治的511例经病理证实的，初诊无远转，明确p16状态（AJCC及ASCO提出，采用p16检测替代HPV荧光原位杂交检测（fluorescence in situhy bridization，FISH），我院采用AJCC标准），接受的放疗均为调强放疗（intensity modulated radiotherapy，IMRT）的口咽癌患者的临床资料（其中95%(486/511)例均接受了IMRT，5%(25/511)为根治性手术治疗）。其中p16阴性248例，p16阳性263例。全部病例采用AJCC第八版分期系统重新分期，p16阴性患者中I期、II期、III期、IVA和IVB期患者占比分别为：3.6%、4.0%、11.8%、56.0%和24.6%；p16阳性患者中I期、II期和III期患者占比分别为：39.2%、20.9%和39.9%。Kaplan-Meier法计算生存率并Log rank法检验和单因素预后分析，Cox法多因素预后分析。

  研究结果：p16阳性组共263例，中位随访时间为51.7个月，5年OS、PFS、DSS、LRFFS、DMFS分别为75.1%、71.9%、83.8%、72.7%、73.7%。根据第八版AJCC分期，I、II、III期的5年OS分别为86.9%、84.2%、58.1%（p＜0.001）；p16阴性组中位随访时间为64.3个月，5年OS、PFS、DSS、LRFFS、DMFS分别为53.5%、46.8%、63.2%、49.2%、49.6%。根据第八版AJCC分期I-II、III、IV期（除远转）的5年OS分别为61.0%、61.8%、51.5（p=0.374）。不论p16状态，局部区域失败和远转均是主要失败模式，常见的远转部位依次为肺、骨、肝。对于p16阳性口咽癌，疗前BMI指≤18.5、原发部位为非扁桃体、总分期为III期是影响OS、LRFFS、DMFS的独立预后不良因素；原发部位为非扁桃体、总分期为III期是影响PFS、DSS的独立预后不良因素。对于p16阴性口咽癌，年龄＞58岁，吸烟年包数＞10，N3是影响OS、LRFFS的独立预后不良因素；吸烟年包数＞10，N3是影响PFS、DSS、DMFS的独立预后不良因素。在p16阳性组和阴性组分别对比不同分期下放疗为主和手术为主的治疗方式，后者未显示出优势。急性及远期不良反应均以I-II级为主，急性II级及以上放射性黏膜炎的发生率较高，p16阳性组85%，p16阴性组为81%，同步放化疗相比单纯放疗更易发生白细胞降低。远期反应中，p16阴性患者发生III级吞咽困难的比例略高（6/52，11.5%）。    结论：HPV相关口咽癌相比非HPV相关口咽癌在临床特点及预后方面具有根本差异。调强放疗年代下的治疗模式有待进一步探究。HPV相关口咽癌个体化去强化治疗的最佳模式将是今后的主要研究方向。非HPV相关口咽癌对治疗反应较差，是目前治疗的难点，有待新的技术手段或药物来突破。

第二部分：题目：口咽癌合并第二原发肿瘤的临床特征及预后分析

  目的：在真实世界中分析口咽癌合并第二原发肿瘤的临床特征及预后。

  材料与方法：回顾性分析2010年1月至2020年12月中国医学科学院肿瘤医院收治的468例经病理证实的，明确p16状态的（AJCC及ASCO提出，采用p16蛋白检测替代HPV FISH检测,我院采用AJCC标准）,排除远转，以口咽为首发肿瘤的患者，分析口咽癌合并第二原发肿瘤的临床特征及预后。

  研究结果：468例初治口咽癌患者中，其中p16阴性222例，中位随访时间64.3个月，66例（29.3%）发生第二原发癌，其中42例（63.6%）为同时性，24例（36.4%）为异时性，食管为最常见累及部位，p16阴性口咽癌合并同时性第二原发癌、异时性第二原发癌组和无第二原发癌三组的5年生存率（overall survival OS）分别为26.3%，57.3%和73.2%（p=0.001）；第二原发癌占全组死因的11.2%（12/107），其中异时性第二原发占75%（9/12）。p16阳性246例，中位随访时间52.4个月，20例（8.1%）发生了第二原发癌，其中13例（65%）为同时性，7例（35%）为异时性，食管为最常见累及部位，p16阳性同时性第二原发癌组和不合并第二原发癌组4年OS分别为51.9%vs 80.7%（p=0.006）；p16阳性同时性第二原发癌组和合并异时性第二原发癌组4年OS分别51.9%vs.83.3％（p=0.068）。第二原发癌占全组死因的3.8%（2/52）。

  结论：p16阴性口咽癌发生第二原发癌概率高于p16阳性患者。无论p16状态，合并同时性第二原发癌的生存差于不合并第二原发癌组；食管均为最常见累及部位；p16阴性口咽癌，合并异时性第二原发癌预后较好，第二原发癌是其主要死因之一。

Part I：Survival outcomes and prognostic factors of oropharyngeal carcinoma in the era of intensity-modulated radiotherapy: a single center large sample retrospective analysis

  Objective：To retrospectively analyze the clinical characteristics, treatment efficacy, failure patterns, acute adverse reactions and prognostic factors of oropharyngeal carcinoma in a single center. To provide reference for the future treatment optimization of oropharyngeal carcinoma.

  Materials and Methods：The clinical data of 511 patients with pathologically confirmed oropharyngeal carcinoma in

our Hospital, Sciences from January 2010 to December 2020 were retrospectively analyzed, excluding distant metastasis and definite p16 status （AJCC and ASCO proposed that p16 protein test should be used instead of HPV FISH test, and AJCC criteria was adopted in our hospital). All oropharyngeal cancer patients received intensity-modulated radiotherapy (IMRT) (95%(486/511) of them received IMRT, and 5%(25/511) received radical surgery).Among them, 248 cases were p16 negative and 263 cases were p16 positive. All patients were re-staged according to the 8th edition of the AJCC staging system. Among the p16-negative patients, stage I, II, III, IVA and IVB accounted for 3.6%, 4.0%, 11.8%, 56.0% and 24.6%, respectively. The proportion of stage I, II and III patients in p16 positive patients was 39.2%, 20.9% and 39.9%, respectively. The Kaplan-Meier method was used to calculate survival rates, Log rank test was used for univariate prognostic analysis, and Cox regression was used for multivariate prognostic analysis.

  Results：With a median follow-up of 51.7 months, 263 patients were in the p16-positive group. The 5-year OS, PFS, DSS, LRFFS, and DMFS rates were 75.1%, 71.9%, 83.8%, 72.7%, and 73.7%, respectively. According to the 8th edition of the AJCC staging system, the 5-year OS rates for stage I, II, and III were 86.9%, 84.2%, and 58.1%, respectively (p < 0.001); In the p16-negative group, the median follow-up time was 64.3 months, and the 5-year OS, PFS, DSS, LRFFS, and DMFS rates were 53.5%, 46.8%, 63.2%, 49.2%, and 49.6%, respectively. According to the 8th edition of the AJCC staging system, the 5-year OS rates of stage I-II, III, and IV (excluding distant metastasis) were 61.0%, 61.8%, and 51.5%, respectively (p=0.374). Regardless of p16 status, locoregional failure and distant metastasis were the main failure modes, and the most common distant metastasis sites were lung, bone, and liver. For p16-positive oropharyngeal carcinoma, pre-treatment BMI ≤18.5, non-tonsil primary site, and overall stage III were independent prognostic factors for OS, LRFFS, and DMFS. Non-tonsil primary site and overall stage III were independent poor prognostic factors for PFS and DSS. For p16-negative oropharyngeal cancer, age > 58 years, pack-years of smoking > 10 and N3 were independent poor prognostic factors for OS and LRFFS. Pack-years of smoking > 10 and N3 were independent adverse prognostic factors for PFS, DSS and DMFS. In the p16-positive group and p16-negative group, radiotherapy-based and surgery-based treatment methods were compared in different stages, and the latter showed no advantage. The incidence of acute grade II and above radiation mucositis was high, which was 85% in the p16 positive group and 81% in the p16 negative group. Compared with radiotherapy alone, concurrent chemoradiotherapy was more likely to cause leukopenia. In the long-term response, the proportion of grade III dysphagia was slightly higher in p16-negative patients (6/52, 11.5%).

  Conclusions：Compared with non-HPV-OPSCC, HPV-OPSCC has fundamental differences in clinical features, biological manifestations, treatment sensitivity, and prognosis. The treatment mode in the era of IMRT needs to be further explored.The optimal mode of individualized de-intensification treatment for HPV-OPSCC will be the main research direction in the future. Non-HPV-OPSCC has a poor response to treatment, which is a difficulty at present, and needs to be broken through by new technical means or drugs.

Part II Clinical characteristics and efficacy of oropharyngeal carcinoma with secondary primary tumor

  Objective：To analysis the clinical features and prognosis in oropharyngeal carcinoma with secondary primary tumor.

  Materials and Methods：A retrospective analysis was performed on 468 pathologically confirmed oropharyngeal cancer as the primary tumor patients with p16 status（AJCC and ASCO proposed that p16 protein test should be used instead of HPV FISH test, and AJCC criteria was adopted in our hospital), excluded distant metastasis, and admitted to the Chinese Academy of Medical Sciences from January 2010 to December 2020. The clinical features and prognosis of the secondary primary tumor were analyzed.

  Results：Among 468 patients with oropharyngeal cancer treated at initial diagnosed,  222 cases were P16-negative. With a median follow-up time of 64.3 months, 66 cases developed second primary cancer, with an incidence of 29.3%, among which 63.6% (42/66) were synchronous and 36.4% (24/66) were heterochronous, esophagus was the most commonly involved site. The 5-year OS of p16-negative oropharyngeal carcinoma with synchronous second primary cancer, without second primary cancer and with heterogeneous second primary cancer were 26.3% and 57.3% and 73.2% (p=0.001); The second primary cancer accounted for 11.2% (12/107) of the deaths in the whole group,  among them, the heterochronous second primary accounted for 75% (9/12). There were 246 patients with p16 positive, with a median follow-up time of 52.4 months,  20 patients developed second primary cancer (8.1%). Among them, 65% (13/20) were synchronous and 35% (7/20) were heterochronous. Esophagus was the most commonly involved site. The  4-year OS of p16-positive with synchronous,  heterochronous and non-second primary cancer group were 51.9% , 80.7% and 83.3%. Secondary primary cancer accounted for 3.8% (2/52) of all deaths in p16 positvie group.

  Conclusions：The incidence of second primary cancer of p16 positive and negative oropharyngeal carcinoma were different. The esophagus was the most commonly involved site regardless of p16 status. Regardless of P16 status, the survival of patients with synchronous second primary cancer was worse than those without second primary cancer. For p16-negative oropharyngeal carcinoma, the prognosis was better in patients with heterogeneous second primary cancer, the second primary cancer is one of the main causes of death.