臺灣博碩士論文加值系統

研究背景：頭頸部癌症在全世界常見癌症中排名第六，死亡及復發風險會被人口學特徵、生活習慣及遺傳因子影響。本研究的研究目的為找出影響頭頸癌預後的危險因子，並且根據不同腫瘤部位建立存活風險預測模型。
研究方法：以醫院為基礎的回溯性世代研究。採用結構化問卷收集人口學特徵和生活習慣因子。由耳鼻喉科醫生收集病人的臨床病理學特徵。
參與者：1999年3月至2020年5月在林口長庚醫院診斷為口腔、口咽、下咽癌的患者共2603人。
結果測量：以Cox比例風險模型測量整體存活率及無疾病存活率的風險比(hazard ratio, HR)，並且以逐步回歸建立預測模型。
研究結果：較低的BMI、曾經有飲酒習慣、較高的腫瘤TNM分期、較深的腫瘤浸潤深度及淋巴結莢膜外侵犯顯著的與口腔癌復發及死亡風險有關。喝茶習慣為口咽癌的復發(HR=1.94；95% CI=1.18-3.19)及死亡(HR=2.30；95% CI=1.28-4.16)的危險因子。此外，治療方式為手術合併放化療的口咽癌及下咽癌患者有較高的復發機率，風險比分別為2.24 (95% CI=1.25-4.00)及2.28 (95% CI=1.24-4.20)。基因多形性的MUTYH rs3219489及MSH2 rs3732183與口腔癌復發風險顯著關，ALDH7A1 rs12659017則有邊緣顯著相關。加入遺傳因子進入口腔癌預測模型能夠增加模型的預測能力(P=0.039)。
結論：本研究指出頭頸癌不同部位有特定的風險因子，應該根據不同的狀況實施相應適當的介入措施。

關鍵字：頭頸癌、腫瘤部位、基因多形性、預後、預測模型

Research Objectives：Head and neck cancer is the sixth most common cancer in the world. The risk of death and recurrence may be affected by demographic characteristics, living habits, and genetic factors. This study aims to find out the risk factors that affect the prognosis of head and neck cancer, and establish survival risk prediction models according to different tumor sites.
Design: This study is a hospital-based retrospective cohort study. Using structured questionnaires to collect demographic characteristics and living habits characteristics. Clinicopathological characteristics were collected by the otolaryngologist.
Participants: A total of 2,603 patients diagnosed with oral, oropharyngeal, and hypopharyngeal cancers at Linkou Chang-Gung Memorial Hospital from March 1999 to May 2020 were included in the study.
Outcome Measures: The Cox proportional hazards model was used to calculate the hazard ratio (HR) of overall survival rate and disease-free survival rate, and a predictive model was established by stepwise regression.
Results: The lower BMI, the habit of drinking alcohol, the higher tumor stage, the deeper depth of tumor infiltration, and the extracapsular invasion of lymph nodes are the significant risk factors for recurrence and death of oral cancer. Surprising, the habit of drinking tea was a risk factor for the recurrence (HR=1.94, 95% CI=1.18-3.19) and death (HR=2.30, 95% CI=1.28-4.16) of oropharyngeal cancer. Patients with oropharyngeal and hypopharyngeal cancers who were treated with concurrent chemo-radiotherapy after surgery had a higher risk of recurrence with HR=2.24 (95% CI=1.25-4.00) and HR=2.28 (95% CI=1.24-4.20), respectively. Polymorphisms of MUTYH rs3219489 and MSH2 rs3732183 were significantly associated with recurrence risk of oral cancer, while ALDH7A1 rs12659017 was marginally significant. Incorporating genetic factors into the oral cancer prediction model can increase the predictive ability of the model (P=0.039).
Conclusions: This study demonstrates that each subsite of head and neck cancer has specific risk factors and appropriate intervention should be implemented accordingly.

Key words: Head and neck cancer, tumor subsites, polymorphisms, prognosis, prediction model.

目錄
中文摘要 7
Abstract 8
第一章 緒論 10
第一節、 研究背景 10
第二節、 研究動機 11
第三節、 研究目的 11
第四節、 研究假說 11
第五節、 研究架構 12
第二章 文獻探討 13
第一節、 頭頸癌的流行病學特徵 13
(一) 全世界 13
(二) 台灣 13
第二節、 頭頸癌的位置 14
第三節、 頭頸癌分期 14
第四節、 頭頸癌的治療 14
第五節、 影響頭頸部癌預後的危險因子 15
(一) 人口學特徵 15
(二) 生活習慣 16
(三) 臨床病理學因子 18
(四) 遺傳因子 19
第六節、 頭頸癌預後預測模型的建立 22
第三章 研究材與方法 23
第一節、 研究族群 23
第二節、 資料蒐集 24
第三節、 癌症預後的測量 25
第四節、 統計分析 26
第四章 研究結果 27
第一節、 頭頸癌患者的基本人口學特徵及生活習慣分布 27
第二節、 頭頸癌患者的存活機率 27
第三節、 頭頸癌患者的復發風險 27
第四節、 頭頸癌患者的死亡風險 28
第五節、 口腔癌有基因變異資料者基本變項分布及死亡、復發風險分析 29
第六節、 基因變異與男性口腔癌患者復發、死亡風險的相關性 30
第七節、 建立口腔癌復發風險預測模型 31
第五章 討論 33
第一節、 主要研究結果 33
第二節、 影響頭頸癌復發及死亡風險的社會人口學因子 33
第三節、 影響頭頸癌復發及死亡風險的生活習慣因子 34
第四節、 影響頭頸癌復發及死亡風險的臨床病理學因子 36
第五節、 影響頭頸癌復發及死亡風險的遺傳因子 37
第六節、 研究限制 38
第六章 結論 40
參考文獻 ….. 41
表目錄
表一：文獻中與頭頸癌預後風險有關之基因變異 21
表二：研究中各變項的定義與分組 25
表三：頭頸癌患者基本變項分布 50
表四：單變量Cox比例風險模型計算復發風險(口腔癌) 52
表五：單變量Cox比例風險模型計算復發風險(口咽癌) 54
表六：單變量Cox比例風險模型計算復發風險(下咽癌) 56
表七：多變量Cox比例風險模型計算復發風險 58
表八：單變量Cox比例風險模型計算死亡風險(口腔癌) 60
表九：單變量Cox比例風險模型計算死亡風險(口咽癌) 62
表十：單變量Cox比例風險模型計算死亡風險(下咽癌) 64
表十一：多變量Cox比例風險模型計算存活風險 66
表十二：口腔癌有基因變異資料者的基本變項分布及復發風險分析 68
表十三：口腔癌有基因變異資料者的基本變項分布及整體死亡風險分析 71
表十四：基因變異與口腔癌患者復發風險的相關性 75
表十五：基因變異與整體死亡風險的相關性 81
表十六：口腔癌有基因變異資料者風險基因個數與口腔癌復發風險的相關性 87
表十七：風險基因與口腔癌復發的相關性 88
表十八：男性口腔癌有基因變異資料者復發風險預測模型 89
圖目錄
圖一：研究架構圖 12
圖二：樣本納入流程圖 23
圖三：樣本品質控制(quality control) 24
圖四：頭頸癌存活曲線 90
圖五：頭頸癌存活曲線(以腫瘤部位分層) 90
圖六：頭頸癌存活曲線(以期別分層) 91
圖八：口腔癌整體存活率 92
圖九：口咽癌無疾病存活率 93
圖十：口咽癌整體存活率 93
圖十一：下咽癌無疾病存活率 94
圖十二：下咽癌整體存活率 94
圖十三：網頁式列線圖頁面 95
圖十四：網頁式列線圖計算之存活曲線圖 95

1.　Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 71(3), 209-249. https://doi.org/10.3322/caac.21660
2.　Hashibe, M., Brennan, P., Chuang, S. C., Boccia, S., Castellsague, X., Chen, C., Curado, M. P., Dal Maso, L., Daudt, A. W., Fabianova, E., Fernandez, L., Wünsch-Filho, V., Franceschi, S., Hayes, R. B., Herrero, R., Kelsey, K., Koifman, S., La Vecchia, C., Lazarus, P., . . . Boffetta, P. (2009). Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev, 18(2), 541-550. https://doi.org/10.1158/1055-9965.Epi-08-0347
3.　 Health and Social Care Information Centre
4.　He, Y., Ji, P., Li, Y., Wang, R., Ma, H., & Yuan, H. (2020). Genetic Variants Were Associated With the Prognosis of Head and Neck Squamous Carcinoma. Front Oncol, 10, 372. https://doi.org/10.3389/fonc.2020.00372
5.　Siegel, R. L., Miller, K. D., Fuchs, H. E., & Jemal, A. (2021). Cancer Statistics, 2021. CA Cancer J Clin, 71(1), 7-33. https://doi.org/10.3322/caac.21654
6.　Garneau, J. C., Bakst, R. L., & Miles, B. A. (2018). Hypopharyngeal cancer: A state of the art review. Oral Oncol, 86, 244-250. https://doi.org/10.1016/j.oraloncology.2018.09.025
7.　衛生福利部國民健康署（2022，12月）。109年癌症登記報告。.
8.　Su, S. Y., Chen, W. T., Chiang, C. J., Yang, Y. W., & Lee, W. C. (2020). Oral cancer incidence rates from 1997 to 2016 among men in Taiwan: Association between birth cohort trends and betel nut consumption. Oral Oncol, 107, 104798. https://doi.org/10.1016/j.oraloncology.2020.104798
9.　衛生福利部統計處（2022，7月19日）。110年死因統計結果分析。
10. 衛生福利部統計處（2022，8月19日）。110年死因統計年報。
11.　NATIONAL CANCER INSTITUDE（May 25, 2021）。Head and Neck Cancers 。.
12.　Johnson, D. E., Burtness, B., Leemans, C. R., Lui, V. W. Y., Bauman, J. E., & Grandis, J. R. (2020). Head and neck squamous cell carcinoma. Nat Rev Dis Primers, 6(1), 92. https://doi.org/10.1038/s41572-020-00224-3
13.　Pfister, D. G., Spencer, S., Adelstein, D., Adkins, D., Anzai, Y., Brizel, D. M., Bruce, J. Y., Busse, P. M., Caudell, J. J., Cmelak, A. J., Colevas, A. D., Eisele, D. W., Fenton, M., Foote, R. L., Galloway, T., Gillison, M. L., Haddad, R. I., Hicks, W. L., Hitchcock, Y. J., . . . Darlow, S. D. (2020). Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 18(7), 873-898. https://doi.org/10.6004/jnccn.2020.0031
14.　Ferreira, A. K., Carvalho, S. H., Granville-Garcia, A. F., Sarmento, D. J., Agripino, G. G., Abreu, M. H., Melo, M. C., Caldas, A. D., Jr., & Godoy, G. P. (2021). Survival and prognostic factors in patients with oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal, 26(3), e387-e392. https://doi.org/10.4317/medoral.24242
15.　Oliveira, L. L., Bergmann, A., Melo, A. C., & Thuler, L. C. (2020). Prognostic factors associated with overall survival in patients with oral cavity squamous cell carcinoma. Med Oral Patol Oral Cir Bucal, 25(4), e523-e531. https://doi.org/10.4317/medoral.23558
16.　Cadoni, G., Giraldi, L., Petrelli, L., Pandolfini, M., Giuliani, M., Paludetti, G., Pastorino, R., Leoncini, E., Arzani, D., Almadori, G., & Boccia, S. (2017). Prognostic factors in head and neck cancer: a 10-year retrospective analysis in a single-institution in Italy. Acta Otorhinolaryngol Ital, 37(6), 458-466. https://doi.org/10.14639/0392-100X-1246 (Fattori prognostici del tumore testa-collo: un'analisi retrospettiva monocentrica di 10 anni.)
17.　Mazul, A. L., Naik, A. N., Zhan, K. Y., Stepan, K. O., Old, M. O., Kang, S. Y., Nakken, E. R., & Puram, S. V. (2021). Gender and race interact to influence survival disparities in head and neck cancer. Oral Oncol, 112, 105093. https://doi.org/10.1016/j.oraloncology.2020.105093
18.　Chen, P. H., Shieh, T. Y., Ho, P. S., Tsai, C. C., Yang, Y. H., Lin, Y. C., Ko, M. S., Tsai, P. C., Chiang, S. L., Tu, H. P., & Ko, Y. C. (2007). Prognostic factors associated with the survival of oral and pharyngeal carcinoma in Taiwan. BMC Cancer, 7, 101. https://doi.org/10.1186/1471-2407-7-101
19.　Chen, P. H., Ko, Y. C., Yang, Y. H., Lin, Y. C., Shieh, T. Y., Chen, C. H., & Tsai, C. C. (2004). Important prognostic factors of long-term oropharyngeal carcinoma survivors in Taiwan. Oral Oncol, 40(8), 847-855. https://doi.org/10.1016/j.oraloncology.2004.03.006
20.　Giraldi, L., Leoncini, E., Pastorino, R., Wünsch-Filho, V., de Carvalho, M., Lopez, R., Cadoni, G., Arzani, D., Petrelli, L., Matsuo, K., Bosetti, C., La Vecchia, C., Garavello, W., Polesel, J., Serraino, D., Simonato, L., Canova, C., Richiardi, L., Boffetta, P., . . . Boccia, S. (2017). Alcohol and cigarette consumption predict mortality in patients with head and neck cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Ann Oncol, 28(11), 2843-2851. https://doi.org/10.1093/annonc/mdx486
21.　Moore, R. J., Doherty, D. A., Do, K. A., Chamberlain, R. M., & Khuri, F. R. (2001). Racial disparity in survival of patients with squamous cell carcinoma of the oral cavity and pharynx. Ethn Health, 6(3-4), 165-177. https://doi.org/10.1080/13557850120078099
22.　Tomar, S. L., Loree, M., & Logan, H. (2004). Racial differences in oral and pharyngeal cancer treatment and survival in Florida. Cancer Causes Control, 15(6), 601-609. https://doi.org/10.1023/B:CACO.0000036166.21056.f9
23.　Powrózek, T., Mlak, R., Brzozowska, A., Mazurek, M., Gołębiowski, P., & Małecka-Massalska, T. (2018). Relationship between TNF-α -1031T/C gene polymorphism, plasma level of TNF-α, and risk of cachexia in head and neck cancer patients. J Cancer Res Clin Oncol, 144(8), 1423-1434. https://doi.org/10.1007/s00432-018-2679-4
24.　Gama, R. R., Song, Y., Zhang, Q., Brown, M. C., Wang, J., Habbous, S., Tong, L., Huang, S. H., O'Sullivan, B., Waldron, J., Xu, W., Goldstein, D., & Liu, G. (2017). Body mass index and prognosis in patients with head and neck cancer. Head Neck, 39(6), 1226-1233. https://doi.org/10.1002/hed.24760
25.　Beynon, R. A., Lang, S., Schimansky, S., Penfold, C. M., Waylen, A., Thomas, S. J., Pawlita, M., Waterboer, T., Martin, R. M., May, M., & Ness, A. R. (2018). Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all-cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer. Int J Cancer, 143(5), 1114-1127. https://doi.org/10.1002/ijc.31416
26.　Kawakita, D., Hosono, S., Ito, H., Oze, I., Watanabe, M., Hanai, N., Hasegawa, Y., Tajima, K., Murakami, S., Tanaka, H., & Matsuo, K. (2012). Impact of smoking status on clinical outcome in oral cavity cancer patients. Oral Oncol, 48(2), 186-191. https://doi.org/10.1016/j.oraloncology.2011.09.012
27.　López, R. V., Zago, M. A., Eluf-Neto, J., Curado, M. P., Daudt, A. W., da Silva-Junior, W. A., Zanette, D. L., Levi, J. E., de Carvalho, M. B., Kowalski, L. P., Abrahão, M., de Góis-Filho, J. F., Boffetta, P., & Wünsch-Filho, V. (2011). Education, tobacco smoking, alcohol consumption, and IL-2 and IL-6 gene polymorphisms in the survival of head and neck cancer. Braz J Med Biol Res, 44(10), 1006-1012. https://doi.org/10.1590/s0100-879x2011007500097
28.　Leoncini, E., Vukovic, V., Cadoni, G., Pastorino, R., Arzani, D., Bosetti, C., Canova, C., Garavello, W., La Vecchia, C., Maule, M., Petrelli, L., Pira, E., Polesel, J., Richiardi, L., Serraino, D., Simonato, L., Ricciardi, W., & Boccia, S. (2015). Clinical features and prognostic factors in patients with head and neck cancer: Results from a multicentric study. Cancer Epidemiol, 39(3), 367-374. https://doi.org/10.1016/j.canep.2015.02.004
29.　Denissoff, A., Huusko, T., Ventelä, S., Niemelä, S., & Routila, J. (2022). Exposure to alcohol and overall survival in head and neck cancer: A regional cohort study. Head Neck, 44(10), 2109-2117. https://doi.org/10.1002/hed.27125
30.　Sawabe, M., Ito, H., Oze, I., Hosono, S., Kawakita, D., Tanaka, H., Hasegawa, Y., Murakami, S., & Matsuo, K. (2017). Heterogeneous impact of alcohol consumption according to treatment method on survival in head and neck cancer: A prospective study. Cancer Sci, 108(1), 91-100. https://doi.org/10.1111/cas.13115
31.　Lee, W. T., Hsiao, J. R., Ou, C. Y., Huang, C. C., Chang, C. C., Tsai, S. T., Chen, K. C., Huang, J. S., Wong, T. Y., Lai, Y. H., Wu, Y. H., Hsueh, W. T., Wu, S. Y., Yen, C. J., Chang, J. Y., Lin, C. L., Weng, Y. L., Yang, H. C., Chen, Y. S., & Chang, J. S. (2019). The Influence of Prediagnosis Alcohol Consumption and the Polymorphisms of Ethanol-Metabolizing Genes on the Survival of Head and Neck Cancer Patients. Cancer Epidemiol Biomarkers Prev, 28(2), 248-257. https://doi.org/10.1158/1055-9965.Epi-18-0425
32.　Su, Y. Y., Chien, C. Y., Luo, S. D., Huang, T. L., Lin, W. C., Fang, F. M., Chiu, T. J., Chen, Y. H., Lai, C. C., Hsu, C. M., & Li, S. H. (2016). Betel nut chewing history is an independent prognosticator for smoking patients with locally advanced stage IV head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil. World J Surg Oncol, 14, 86. https://doi.org/10.1186/s12957-016-0844-2
33.　Yang, J., Wang, Z. Y., Huang, L., Yu, T. L., Wan, S. Q., Song, J., Zhang, B. L., & Hu, M. (2021). Do betel quid and areca nut chewing deteriorate prognosis of oral cancer? A systematic review, meta-analysis, and research agenda. Oral Dis, 27(6), 1366-1375. https://doi.org/10.1111/odi.13456
34.　Hildebrand, J. S., Patel, A. V., McCullough, M. L., Gaudet, M. M., Chen, A. Y., Hayes, R. B., & Gapstur, S. M. (2013). Coffee, tea, and fatal oral/pharyngeal cancer in a large prospective US cohort. Am J Epidemiol, 177(1), 50-58. https://doi.org/10.1093/aje/kws222
35.　Du, E., Mazul, A. L., Farquhar, D., Brennan, P., Anantharaman, D., Abedi-Ardekani, B., Weissler, M. C., Hayes, D. N., Olshan, A. F., & Zevallos, J. P. (2019). Long-term Survival in Head and Neck Cancer: Impact of Site, Stage, Smoking, and Human Papillomavirus Status. Laryngoscope, 129(11), 2506-2513. https://doi.org/10.1002/lary.27807
36.　Saroul, N., Puechmaille, M., Lambert, C., Hassan, A. S., Biau, J., Lapeyre, M., Mom, T., Bernadach, M., & Gilain, L. (2022). Prognosis in Head and Neck Cancer: Importance of Nutritional and Biological Inflammatory Status. Otolaryngol Head Neck Surg, 166(1), 118-127. https://doi.org/10.1177/01945998211004592
37.　Zanoni, D. K., Montero, P. H., Migliacci, J. C., Shah, J. P., Wong, R. J., Ganly, I., & Patel, S. G. (2019). Survival outcomes after treatment of cancer of the oral cavity (1985-2015). Oral Oncol, 90, 115-121. https://doi.org/10.1016/j.oraloncology.2019.02.001
38.　Lin, N. C., Hsu, J. T., & Tsai, K. Y. (2020). Survival and clinicopathological characteristics of different histological grades of oral cavity squamous cell carcinoma: A single-center retrospective study. PLoS One, 15(8), e0238103. https://doi.org/10.1371/journal.pone.0238103
39.　Asio, J., Kamulegeya, A., & Banura, C. (2018). Survival and associated factors among patients with oral squamous cell carcinoma (OSCC) in Mulago hospital, Kampala, Uganda. Cancers Head Neck, 3, 9. https://doi.org/10.1186/s41199-018-0036-6
40.　Caldeira, P. C., Soto, A. M. L., de Aguiar, M. C. F., & Martins, C. C. (2020). Tumor depth of invasion and prognosis of early-stage oral squamous cell carcinoma: A meta-analysis. Oral Dis, 26(7), 1357-1365. https://doi.org/10.1111/odi.13194
41.　Wreesmann, V. B., Katabi, N., Palmer, F. L., Montero, P. H., Migliacci, J. C., Gönen, M., Carlson, D., Ganly, I., Shah, J. P., Ghossein, R., & Patel, S. G. (2016). Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head Neck, 38 Suppl 1(Suppl 1), E1192-1199. https://doi.org/10.1002/hed.24190
42.　Galeano Machuca, M. P., Ng, D. L., Terng, S. D., Wu, W. C., & Cheng, C. T. (2021). Survival and complications with a surgical approach in advanced hypopharyngeal cancer. J Surg Oncol, 123(7), 1540-1546. https://doi.org/10.1002/jso.26440
43.　Wilkins, O. M., Titus, A. J., Salas, L. A., Gui, J., Eliot, M., Butler, R. A., Sturgis, E. M., Li, G., Kelsey, K. T., & Christensen, B. C. (2019). MicroRNA-Related Genetic Variants Associated with Survival of Head and Neck Squamous Cell Carcinoma. Cancer Epidemiol Biomarkers Prev, 28(1), 127-136. https://doi.org/10.1158/1055-9965.Epi-18-0002
44.　Farnebo, L., Tiefenböck, K., Ansell, A., Thunell, L. K., Garvin, S., & Roberg, K. (2013). Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients. Int J Cancer, 133(8), 1994-2003. https://doi.org/10.1002/ijc.28200
45.　Farnebo, L., Stjernström, A., Fredrikson, M., Ansell, A., Garvin, S., & Thunell, L. K. (2015). DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck. DNA Repair (Amst), 31, 64-72. https://doi.org/10.1016/j.dnarep.2015.05.003
46.　Supic, G., Jovic, N., Zeljic, K., Kozomara, R., & Magic, Z. (2012). Association of VEGF-A genetic polymorphisms with cancer risk and survival in advanced-stage oral squamous cell carcinoma patients. Oral Oncol, 48(11), 1171-1177. https://doi.org/10.1016/j.oraloncology.2012.05.023
47.　Kämmerer, P. W., Koch, F. P., Schiegnitz, E., Kumar, V. V., Berres, M., Toyoshima, T., Al-Nawas, B., & Brieger, J. (2013). Associations between single-nucleotide polymorphisms of the VEGF gene and long-term prognosis of oral squamous cell carcinoma. J Oral Pathol Med, 42(5), 374-381. https://doi.org/10.1111/jop.12026
48.　Muñoz-Guerra, M. F., Fernández-Contreras, M. E., Moreno, A. L., Martín, I. D., Herráez, B., & Gamallo, C. (2009). Polymorphisms in the hypoxia inducible factor 1-alpha and the impact on the prognosis of early stages of oral cancer. Ann Surg Oncol, 16(8), 2351-2358. https://doi.org/10.1245/s10434-009-0503-8
49.　Chen, F., He, B., Yan, L., Qiu, Y., Lin, L., & Cai, L. (2017). FADS1 rs174549 Polymorphism May Predict a Favorable Response to Chemoradiotherapy in Oral Cancer Patients. J Oral Maxillofac Surg, 75(1), 214-220. https://doi.org/10.1016/j.joms.2016.07.005
50.　Senghore, T., Chien, H. T., Wang, W. C., Chen, Y. X., Young, C. K., Huang, S. F., & Yeh, C. C. (2020). Predictive value of genetic variants XRCC1 rs1799782, APEX1 rs1760944, and MUTYH rs3219489 for adjuvant concurrent chemoradiotherapy outcomes in oral squamous cell carcinoma patients. Pharmacogenomics J, 20(6), 813-822. https://doi.org/10.1038/s41397-020-0170-5
51.　Lu, H. J., Chuang, C. Y., Chen, M. K., Su, C. W., Yang, W. E., Yeh, C. M., Lai, K. M., Tang, C. H., Lin, C. W., & Yang, S. F. (2022). The impact of ALDH7A1 variants in oral cancer development and prognosis. Aging (Albany NY), 14(10), 4556-4571. https://doi.org/10.18632/aging.204099
52.　Senghore, T., Wang, W. C., Chien, H. T., Chen, Y. X., Young, C. K., Huang, S. F., & Yeh, C. C. (2021). Association of XRCC2 rs2040639 with the survival of patients with oral squamous cell carcinoma undergoing concurrent chemoradiotherapy. Gene, 768, 145283. https://doi.org/10.1016/j.gene.2020.145283
53.　Bau, D. T., Tsai, C. W., Lin, C. C., Tsai, R. Y., & Tsai, M. H. (2011). Association of alpha B-crystallin genotypes with oral cancer susceptibility, survival, and recurrence in Taiwan. PLoS One, 6(9), e16374. https://doi.org/10.1371/journal.pone.0016374
54.　Wong, Y. K., Chang, K. W., Cheng, C. Y., & Liu, C. J. (2006). Association of CTLA-4 gene polymorphism with oral squamous cell carcinoma. J Oral Pathol Med, 35(1), 51-54. https://doi.org/10.1111/j.1600-0714.2005.00377.x
55.　Senghore, T., Wang, W. C., Chien, H. T., Chen, Y. X., Young, C. K., Huang, S. F., & Yeh, C. C. (2019). Polymorphisms of Mismatch Repair Pathway Genes Predict Clinical Outcomes in Oral Squamous Cell Carcinoma Patients Receiving Adjuvant Concurrent Chemoradiotherapy. Cancers (Basel), 11(5). https://doi.org/10.3390/cancers11050598
56.　Senghore, T., Chien, H. T., Wang, W. C., Chen, Y. X., Young, C. K., Huang, S. F., & Yeh, C. C. (2019). Polymorphisms in ERCC5 rs17655 and ERCC1 rs735482 Genes Associated with the Survival of Male Patients with Postoperative Oral Squamous Cell Carcinoma Treated with Adjuvant Concurrent Chemoradiotherapy. J Clin Med, 8(1). https://doi.org/10.3390/jcm8010033
57.　Hoesseini, A., van Leeuwen, N., Offerman, M. P. J., Zhang, J., Dronkers, E. A. C., Sewnaik, A., Lingsma, H. F., & Baatenburg de Jong, R. J. (2021). Predicting survival in head and neck cancer: External validation and update of the prognostic model OncologIQ in 2189 patients. Head Neck, 43(8), 2445-2456. https://doi.org/10.1002/hed.26716
58.　Ren, Z., Zhang, L., Ding, W., Luo, Y., Shi, Z., Shrestha, B., Kan, X., Zhang, Z., Ding, J., He, H., & Hu, X. (2021). Development and validation of a novel survival model for head and neck squamous cell carcinoma based on autophagy-related genes. Genomics, 113(1 Pt 2), 1166-1175. https://doi.org/10.1016/j.ygeno.2020.11.017
59.　Frare, J. C., Sawazaki-Calone, I., Ayroza-Rangel, A. L., Bueno, A. G., de Morais, C. F., Nagai, H. M., Kunz, R., & Lopes, M. A. (2016). Histopathological grading systems analysis of oral squamous cell carcinomas of young patients. Med Oral Patol Oral Cir Bucal, 21(3), e285-298. https://doi.org/10.4317/medoral.20953
60.　Yang, C. C., Su, Y. C., Lin, Y. W., Huang, C. I., & Lee, C. C. (2019). Differential impact of age on survival in head and neck cancer according to classic Cox regression and decision tree analysis. Clin Otolaryngol, 44(3), 244-253. https://doi.org/10.1111/coa.13274
61.　Ackerman, D., Laszlo, M., Provisor, A., & Yu, A. (2018). Nutrition Management for the Head and Neck Cancer Patient. Cancer Treat Res, 174, 187-208. https://doi.org/10.1007/978-3-319-65421-8_11
62.　Meadows, G. G., & Zhang, H. (2015). Effects of Alcohol on Tumor Growth, Metastasis, Immune Response, and Host Survival. Alcohol Res, 37(2), 311-322.
63.　McKillop, I. H., & Schrum, L. W. (2005). Alcohol and liver cancer. Alcohol, 35(3), 195-203. https://doi.org/10.1016/j.alcohol.2005.04.004
64.　Duffy, S. A., Ronis, D. L., McLean, S., Fowler, K. E., Gruber, S. B., Wolf, G. T., & Terrell, J. E. (2009). Pretreatment health behaviors predict survival among patients with head and neck squamous cell carcinoma. J Clin Oncol, 27(12), 1969-1975. https://doi.org/10.1200/jco.2008.18.2188
65.　Hoff, C. M., Grau, C., & Overgaard, J. (2012). Effect of smoking on oxygen delivery and outcome in patients treated with radiotherapy for head and neck squamous cell carcinoma--a prospective study. Radiother Oncol, 103(1), 38-44. https://doi.org/10.1016/j.radonc.2012.01.011
66.　Stähelin, H., Francisco, A. L. N., Mariano, F. V., Kowalski, L. P., & Gondak, R. (2021). Impact of smoking on dendritic cells in patients with oral squamous cell carcinoma. Braz Oral Res, 35, e075. https://doi.org/10.1590/1807-3107bor-2021.vol35.0075
67.　Lee, S. S., Tsai, C. H., Yu, C. C., Ho, Y. C., Hsu, H. I., & Chang, Y. C. (2013). The expression of O(6) -methylguanine-DNA methyltransferase in human oral keratinocytes stimulated with arecoline. J Oral Pathol Med, 42(8), 600-605. https://doi.org/10.1111/jop.12037
68.　Chiu, T. J., Chen, C. H., Chien, C. Y., Li, S. H., Tsai, H. T., & Chen, Y. J. (2011). High ERCC1 expression predicts cisplatin-based chemotherapy resistance and poor outcome in unresectable squamous cell carcinoma of head and neck in a betel-chewing area. J Transl Med, 9, 31. https://doi.org/10.1186/1479-5876-9-31
69.　Kim, Y. S., & Kim, C. H. (2014). Chemopreventive role of green tea in head and neck cancers. Integr Med Res, 3(1), 11-15. https://doi.org/10.1016/j.imr.2013.12.005
70.　Lubov, J., Labbé, M., Sioufi, K., Morand, G. B., Hier, M. P., Khanna, M., Sultanem, K., & Mlynarek, A. M. (2021). Prognostic factors of head and neck cutaneous squamous cell carcinoma: a systematic review. J Otolaryngol Head Neck Surg, 50(1), 54. https://doi.org/10.1186/s40463-021-00529-7
71.　Kim, Y. J., & Lee, R. (2018). Surgery vs. radiotherapy for locally advanced hypopharyngeal cancer in the contemporary era: A population-based study. Cancer Med, 7(12), 5889-5900. https://doi.org/10.1002/cam4.1811
72.　Seitz, H. K., & Stickel, F. (2010). Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr, 5(2), 121-128. https://doi.org/10.1007/s12263-009-0154-1
73.　Khanna, A. (2015). DNA damage in cancer therapeutics: a boon or a curse? Cancer Res, 75(11), 2133-2138. https://doi.org/10.1158/0008-5472.Can-14-3247
74.　Huang, R., & Zhou, P. K. (2021). DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther, 6(1), 254. https://doi.org/10.1038/s41392-021-00648-7
75.　Wang, C. P., Chen, T. C., Hsu, W. L., Hsiao, J. R., Chen, P. R., Chen, M. K., Hua, C. H., Tsai, M. H., Ko, J. Y., Lou, P. J., Chiang, C. J., Wu, C. T., & Chang, Y. L. (2022). Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common. BMC Cancer, 22(1), 296. https://doi.org/10.1186/s12885-022-09407-5