Risk factors of secondary cancer in laryngeal, oropharyngeal, or hypopharyngeal cancer after definitive therapy

Risk factors of secondary cancer in laryngeal, oropharyngeal, or hypopharyngeal cancer after definitive therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk factors of secondary cancer in laryngeal, oropharyngeal, or hypopharyngeal cancer after definitive therapy Goshi Nishimura, Hideaki Takahashi, Daisuke Sano, Yasuhiro Arai, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3026392/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Dec, 2023 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Our previous research showed that a high rate of secondary carcinogenesis is observed during follow-up after transoral surgery in patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We speculate that the contributing factors are alcohol drinking, smoking, and aging; however, we could not provide clear evidence. In this study, we aimed to identify the risk factors for secondary carcinogenesis in patients with these cancers, particularly factors associated with drinking and/or smoking. Methods The medical records of all-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who had undergone definitive treatment were retrospectively analyzed. Assessments included visual and endoscopic observations of the primary site, enhanced cervical CT or US of the primary site and regional lymph nodes, PET-CT, and enhanced whole-body CT. Clinical characteristics were compared in patients with and without secondary carcinogenesis and in patients with hypopharyngeal cancer and patients with other cancers. Results Hypopharyngeal cancer was an independent risk factor for secondary cancer. The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. Radiotherapy was defined as an independent risk factor in hypopharyngeal cancer patients with secondary cancers. No direct correlation was found between secondary carcinogenesis and alcohol consumption, smoking, or aging. Conclusions Patients with hypopharyngeal cancer require close follow-up as they are at high risk of developing secondary cancer, possibly because out-of-field radiation exposure may induce systemic secondary carcinogenesis in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption. Laryngeal cancer Oropharyngeal cancer Hypopharyngeal cancer Newly diagnosed secondary cancer Radiotherapy Figures Figure 1 Figure 2 INTRODUCTION Head and neck cancers account for approximately 5% of all malignancies in Japan 1) . About 60% of head and neck cancers—with the exception of glottis and oral cancers—are diagnosed at an advanced stage because of the lack of definitive symptoms and lack of awareness of head and neck cancers. Moreover, advanced-stage patients are at high risk of local recurrence or regional lymph node metastasis. Between 60% and 70% of these cases have treatment failure within the first year after diagnosis, and 90–100% within 2 years. Moreover, the incidence rate of second primary cancers exceeds that of primary head and neck cancer recurrence, which occurs at an average of 4 years after the diagnosis of the primary cancer 2–4) . On the other hand, the number of early-stage patients has increased following the advent of advanced diagnostic techniques such as positron emission tomography-computed tomography (PET-CT) and narrow-band imaging (NBI) endoscopy 5, 6) . This increase is also due to an increased awareness of head and neck cancers among doctors in other fields 7) . In general, long-term survival is expected in patients with early-stage cancer, which can be associated with an increased risk of secondary carcinogenesis. We have previously reported that patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancer treated by transoral surgery (TOS) had a high incidence rate of newly diagnosed secondary cancer during the observation period after TOS 8, 9) . In these patients, the primary site of the hypopharynx was an independent risk factor for secondary cancer. We presumed the reasons to be alcohol drinking, smoking, and aging; however, we could not provide clear evidence. In this study, to identify the risk factors for secondary carcinogenesis, we retrospectively analyzed all-stage patients who underwent radical treatment for laryngeal, oropharyngeal, and hypopharyngeal cancers, particularly factors associated with drinking and/or smoking. Patients and methods Study setting This was a single institute (academic hospital), retrospective observational study. Enrollment and eligibility Patients who visited our department for the first time for treatment of laryngeal, oropharyngeal, and hypopharyngeal cancer between January 1, 2013 and December 31, 2021 were enrolled. To evaluate the incidence rate and related factors during the observation period after definitive therapy, patients who met the following criteria were excluded: pure human papilloma virus (HPV)-related oropharyngeal cancer with p16 positivity and no alcohol drinking or smoking habit, because it was not possible to assess alcohol consumption and smoking history; distant metastasis, because definitive surgery or chemoradiotherapy was not adapted; and previous history of malignant disease, because we aimed to analyze the risk factors for the second carcinogenesis after the first cancer. Endpoints The endpoint was the clinical risk factor for the incidence of newly diagnosed malignancy in patients with laryngeal, oropharyngeal, and hypopharyngeal cancers. Secondary new cancer was defined as follows: pathologically diagnosed as a malignant disease; the disease appeared in other organs (e.g., the first cancer was hypopharyngeal cancer and the second was esophageal cancer), in other subsites of the same region of the head and neck (e.g., the first cancer was piriform sinus type and the second was postcricoid type of the hypopharynx), or the disease was found in the same subsite but the disease was separated from the first cancer mediating normal mucosa (e.g., both first and second cancers appeared on the same side of the piriform sinus of the hypopharynx). Treatment methods Definitive surgery included both complete resection for the primary site and neck dissection for patients with lymph node metastasis. Postoperative radiotherapy was performed based on the pathological evaluation after surgery with or without chemotherapy. Postoperative chemoradiotherapy was adapted to have positive surgical margins and/or extranodal extension to lymph nodes. Postoperative radiotherapy alone was adapted to have T3 and T4 pathologies, positive perineural invasions and/or vascular tumor embolism of the primary site, and/or multiple positive metastases to lymph nodes. The radiation doses were 56–60 Gy for radiotherapy alone and 60–66 Gy for chemoradiotherapy. The chemotherapeutic reagent was cis -platinum 10, 11) , or a combination of docetaxel and cetuximab 12) . Radiotherapy was performed 5 days a week with a single daily fraction of 1.8–2.0 Gy using six MV X-ray linear accelerators for a total dose of 66.0–72.0 Gy. The radiation dose and field were modified according to the primary site and clinical stage. Radiotherapy alone was administered to early-stage patients, and chemoradiotherapy was administered to advanced-stage patients. The concurrent chemotherapy regimens were decided on the basis of age and/or comorbidity. The chemotherapy regimens were as follows: the TPF regimen consisting of docetaxel, cis -platinum, and 5-fluorouracil 13, 14) ; the TPE regimen consisting of docetaxel, cis -platinum, and cetuximab 15) ; the cis -platinum regimen 16) ; the cetuximab regimen 17) ; and the S-1 regimen consisting of the oral administration of S-1 18) . Induction chemotherapy was performed prior to the definitive surgery or chemoradiotherapy using a combination of docetaxel, cis -platinum, and 5-fluorouracil 19) . Follow-up Visual and endoscopic observations of the primary site were performed every month for the first and second years and every 2–3 months from the third to the fifth year. Enhanced cervical CT or US of the primary site and regional lymph nodes was performed every 3–6 months for the first and second years and every 6–12 months from the third to fifth years. Finally, PET-CT was performed every year for the first and second years, and enhanced whole-body CT was performed every year from the third to fifth years for the evaluation of distant metastasis. In case of the presence of a new second primary cancer, the patient was referred to the appropriate department. Statistical analysis Patient characteristics were compared between patient groups using the Fisher’s exact test. The Fisher’s exact test and the Cox proportional hazards model were used for univariate and multivariate comparisons, respectively. The Kaplan–Meier method was used to evaluate the incidence rate of secondary cancer. The log-rank test was used to analyze statistical differences. Results Patient characteristics and examination results The patients’ clinical courses are shown diagrammatically in Fig. 1 . Five-hundred and ninety-five patients were enrolled, and seven patients were excluded because of pure HPV-related oropharyngeal cancer, 22 patients were excluded because of distant metastasis positive at the diagnosis of head and neck cancer, and 138 patients were excluded because of a past history of malignant disease. In total, 428 patients were included in this study. The patient characteristics are summarized in Table 1-a. As definitive therapy, radical surgery was performed in 264 patients and chemoradiotherapy in 164 patients. Among the operated patients, 48 received postoperative chemoradiotherapy, 43 received postoperative radiotherapy alone due to pathological evaluation for recurrence risk, and four received induction chemotherapy prior to surgery. Among the patients who received definitive chemoradiotherapy, 39 patients received radiotherapy alone and 117 patients received concurrent chemoradiotherapy depending on the clinical stage. Induction chemotherapy was performed prior to radiotherapy alone for four patients and chemoradiotherapy for four patients. For tumor depth evaluated by pathological examination, the cut-off value was defined by the receiver operating characteristic (ROC) curve between the presence of secondary cancer and tumor depth in patients who underwent definitive surgery. The cutoff value for tumor depth was 12,000 µm. Three hundred and thirty-six patients showed no evidence of secondary cancer during the observation period, while 92 patients were newly diagnosed with secondary cancer (Fig. 1 ). Comparing these groups, the primary site of the hypopharynx, existence of synchronous double cancer, pathological diagnosis of lymphatic invasion, and vascular invasion showed significant effects on univariate analysis using the Fisher’s exact test. Other clinical factors were not significantly different. Based on the univariate analysis results, multivariate logistic regression analysis was performed using the Cox proportional hazards model, and hypopharyngeal cancer and the pathological diagnosis of lymphatic invasion were independent significant clinical factors for the newly detected presence of secondary cancer (Table 1-b). The time course of secondary cancer incidence, classified by the primary site, is shown in Fig. 2 . The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. The p value was 0.0039, and hypopharyngeal cancer patients had a significantly higher incidence rate of secondary cancer than laryngeal and oropharyngeal cancer patients as determined by a log-rank test. The crude incidence of secondary cancer per 100 patient-years was 8.1 in all patients, and 6.2, 6.4, and 11.3 in laryngeal, oropharyngeal, and hypopharyngeal cancer patients, respectively. Analysis for hypopharyngeal cancer patients compared to other primary cancers Based on the prior results of the multivariate logistic regression analysis (Table 1-b), the patients were divided into a hypopharyngeal cancer group and other cancer (laryngeal and oropharyngeal) group. While another independent clinical factor, lymphatic invasion, had a significantly lower risk of secondary cancer, it was difficult to explain this logically. In general, tumor lymphatic invasion is considered associated with lymphatic metastasis, and there is no obvious evidence supporting its relationship with the incidence of secondary cancer. 20 We therefore dismissed this result as a computational error. The patients’ characteristics are summarized according to the primary site in Table 2-a. The Fisher’s exact test showed that smoking history; alcohol consumption; clinical T stage of T0, T3, and T4; clinical N stage of N1, N2, and N3; definitive therapy; radiotherapy; pathological diagnosis of carcinoma in situ; and lymphatic invasion were significantly different between the groups. Based on the univariate analysis results, multivariate logistic regression analysis was performed using the Cox proportional hazards model and alcohol flush reaction; clinical T stage of T3; and clinical N stage of N1, N2, and N3 were independent clinical factors (Table 2-b). Among these factors, the alcohol flush reaction was associated with carcinogenesis of hypopharyngeal cancer. Clinical T stage of T3, and clinical N stage of N1, N2, and N3 showed a trend toward an association with advanced-stage hypopharyngeal cancer at the first medical examination. Analysis of the incidence rate of secondary cancer in hypopharyngeal cancer and other cancers Secondary cancer-positive patients were divided into a hypopharyngeal cancer and other cancer group. The patient characteristics are summarized in Table 3-a. The Fisher’s exact test showed that the clinical N stage of N3 and radiotherapy were significantly different in the two groups. Based on the univariate analysis results, multivariate logistic regression analysis was performed using the Cox proportional hazards model, and clinical T stage of T2 and radiotherapy were the independent clinical factors (Table 3-b). T2 indicated a significantly lower risk of secondary cancer, and we considered that early-stage cancer was associated with a low risk of development of secondary cancer, considering that hypopharyngeal cancer patients tended to have advanced-stage disease at the first visit (Table 2-a). Therefore, we reorganized the factors of clinical stages; that is, clinical T stage was divided into T0–2 and T3–4, and N stage was divided into N0 and N1–3. Multivariate logistic regression analysis was performed using the Cox proportional hazards model, and radiotherapy was the independent clinical factor for the development of secondary cancer (Table 3-c). Discussion Conventionally, most patients with head and neck cancer have had advanced cancer, and even after definitive treatment, locoregional recurrence has been common, and the prognosis has been poor. Locoregional recurrence occurs in the majority of cases within 2 years after diagnosis, and in patients who achieve good control of the primary disease, second cancers begin to outnumber locoregional recurrence rates 4 years after the diagnosis 2–4) . Recently, developments in medical technology have increased the chances of detecting head and neck cancer at an early-stage and have enabled a long-term prognosis. We have previously reported that early-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who were treated with TOS showed a good prognosis, even though a high rate of secondary carcinogenesis occurred 8, 9) . Among these cancers, hypopharyngeal cancer was found to be an independent risk factor for secondary carcinogenesis, and although associations with alcohol consumption, smoking, and aging were inferred, no direct relationship could be demonstrated. Alcohol is a risk factor for breast, cervix, colon, esophagus, larynx, liver, oral cavity, pharynx, prostate, and stomach cancers. The risk increases with the amount of alcohol consumed. Even if the amount of consumption is light to moderate, the incidence risk for bladder, breast, colorectal, esophagus, larynx, liver, oral cavity, pharynx, prostate, and stomach cancers increases. 21 One of the mechanisms of alcohol-induced carcinogenesis is chemical mucositis by ethanol directly in the upper aerodigestive tract, which includes the esophagus, larynx, oral cavity, and pharynx cancers. Another mechanism involves carcinogenesis caused by acetaldehyde, a degradation product of ethanol by acetaldehyde dehydrogenase (ALDH) 2, which affects the entire body. Forty-four percent of Japanese have the heterozygous genotype of normal and inactive ones (ND type) or the homozygous genotype of an inactive one (DD type) of ALDH2, and these people are exposed to acetaldehyde for a long period of time whenever they drink. Prolonged exposure to acetaldehyde may increase the likelihood of inducing carcinogenesis or pre-cancerous genetic abnormalities. Smoking is another risk factor for carcinogenesis, which induces DNA damage. Smoking increases the risk of at least 17 classes of cancer, that is acute myeloid leukemia, bladder, cervix, colorectal, esophagus (adenocarcinoma and squamous cell carcinoma), kidney, lung (adenocarcinoma, small cell carcinoma, and squamous cell carcinoma), larynx, liver, oral cavity, ovary, pancreas, pharynx, and stomach cancers 22) . Tobacco carcinogens directly and indirectly induce DNA mutations in lung adenocarcinoma, lung squamous cell carcinoma, larynx, and liver cancers. Moreover, these carcinogens also indirectly induce DNA damage in acute myeloid leukemia and bladder, cervix, colorectal, kidney, ovarian, pancreatic, and stomach cancers. In Japan, smoking is defined as a risk factor for bladder, esophagus, larynx, liver, lung, nasal and paranasal sinuses, oral cavity, pancreas, pharynx, stomach, and uterine cervix cancers. A study showed that 30% of male and 5% of female cancers are derived from smoking 23) . Furthermore, the incidence of all types of cancer was found to be increased with smoking in habitual alcohol drinkers 24) . In the non-smoking group, the incidence did not increase in accordance with an increase in alcohol consumption. Meanwhile, in the smoking group, the incidence increased in accordance with an increase in alcohol consumption, and people who had been drinking more than 81 g of alcohol every day with customary smoking demonstrated a 2.3 times higher incidence of all cancers. In the present study, we attempted to identify risk factors for secondary carcinogenesis by retrospectively analyzing definitively treated patients with all-stage laryngeal, HPV-unrelated oropharyngeal, and hypopharyngeal cancers, particularly factors related to alcohol consumption and smoking. Similar to the results of our previous report on early-stage cancer patients, hypopharyngeal cancer was shown to be an independent risk factor for secondary carcinogenesis. Even though a comparison with nonsmokers and nondrinkers in terms of secondary cancer was difficult because 88% of the patients were drinkers and 89% were smokers in this study, in patients with hypopharyngeal carcinoma, the alcohol flush reaction was an independent risk factor, suggesting an association between ALDH2 inactivity and hypopharyngeal carcinogenesis. This relationship was consistent with a previous report that the ALDH2 genotype, which is mutated in 44% of the Japanese population, and alcohol flush reaction are risk factors for hypopharyngeal and esophageal squamous cell carcinoma 25, 26) . Age was not identified as a risk factor for any of these cancers as there was a similar age distribution. In the future, it will be desirable to conduct an analysis using an objective index for aging other than calendar age. Radiotherapy has been shown to be an independent risk factor in patients who develop a second cancer after definitive treatment for hypopharyngeal cancer. Hypopharyngeal cancer patients tend to be diagnosed at a locoregionally advanced stage at the time of initial diagnosis and often require chemoradiotherapy after radical surgery, or chemoradiotherapy is often chosen as a definitive treatment in the hope of preserving organ function. In hypopharyngeal cancer patients, alcohol consumption, smoking, and inadequate alcohol metabolism due to ALDH2 inactivity may cause genetic mutations that result in a precancerous state throughout the body. We speculate that out-of-field radiation exposure by whole-neck irradiation results in systemic inflammation 27) , and in such a precancerous condition, this can cause secondary cancer. In the case of out-of-field radiation exposure of normal tissues, the latency period for the development of radiation-induced cancer is 5–20 years for solid tumors. On the other hand, it is quite possible that solid tumors induced by out-of-field radiation exposure will become apparent within 5 years of initial head and neck cancer treatment, as hypopharyngeal cancer patients have already accumulated genetic abnormalities due to alcohol consumption and smoking. In the future, it is desirable to establish a method for detecting and evaluating genetic abnormalities at the time of initial diagnosis of hypopharyngeal carcinoma in patients who will be treated with radiotherapy and for observing mutations over time after treatment. The limitations of the present study were that it was conducted at a single institution and its retrospective design which limit the generalizability of the results and raise the possibility of selection bias, respectively. Conclusions We analyzed patients with all-stage laryngeal, oropharyngeal, and hypopharyngeal cancers treated with definitive therapy. The independent predictive factor for newly diagnosed secondary cancers was hypopharyngeal cancer. Hypopharyngeal cancer patients were highly positive for alcohol flush reaction. Radiotherapy for hypopharyngeal cancer is an independent risk factor for secondary carcinogenesis. The probable mechanism is the induction of systemic secondary carcinogenesis by out-of-field radiation exposure in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption, particularly ALDH2 inactive patients. Abbreviations PET-CT, positron emission tomography-computed tomography; NBI, narrow-band imaging; TOS, transoral surgery; HPV, human papilloma virus; ROC, receiver operating characteristic; ALDH2, acetaldehyde dehydrogenase 2 Declarations Acknowledgements Not applicable. Funding Not applicable. Availability of data The datasets used in the present study are available from the corresponding author upon request. All data generated or analyzed in this study are included in this published article. Authors’ contributions GN and NO conceived the study, performed statistical analyses, and edited the manuscript. GN and HT designed the study. GN, DS, YA, TH, and YK acquired, analyzed, and interpreted the data. GN and HT evaluated the quality of the data and algorithms. GN prepared the manuscript and all authors reviewed and approved the final version of the manuscript. Ethics approval and consent to participate Ethical approval for the study was obtained from the Yokohama City University Institutional Review Board (#F230200009). Written informed consent was obtained from the participants to publish their data. Patients consent for publication Not applicable. Competing interests The authors declare no conflicts of interest. References National Cancer Center, Japan. Cancer Statistics. Accessed June 1, 2023. http://ganjoho.jp/reg_stat/ Vikram B. (1984) Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol 110(9):564-565. Vokes EE, Kies M, Haraf DJ, et al. (1995) Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease. J Clin Oncol 13(4): 876-883. 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(2019) Hypopharyngeal cancer risk in Japanese: Genetic polymorphisms related to the metabolism of alcohol- and tobacco-associated carcinogens. J Cancer Res Ther 15(3):556-563. Mesbahi A, Seyednejad F, Gasemi-Jangjoo A. (2010) Estimation of organs doses and radiation-induced secondary cancer risk from scattered photons for conventional radiation therapy of nasopharynx: a Monte Carlo study. Jpn J Radiol 28(5):398-403. Tables Tables 1 to 3 are available in the Supplementary Files section. Supplementary Files tables.xlsx Table 1. Patient characteristics and the results of the multivariate analysis. a) The patients are divided into no evidence of secondary cancer patients (negative) and secondary cancer patients (positive). Fisher’s exact test shows that the primary site of hypopharynx, existence of synchronous double cancer, pathological diagnosis of lymphatic invasion, and vascular invasion are significantly different between the two groups. Other clinical factors are not significantly different. Statistical significance is defined as a p value < 0.05 (5E-02). b) The results of the multivariate analysis using the Cox proportional hazards model. The independent significant clinical factor is hypopharyngeal cancer. The odds ratio, 95% CI and p value are calculated by Fisher’s exact test. Statistical significance is defined as a p value < 0.05 (5E-02). Abbreviations: CI: confidence interval. Table 2. Patient characteristics and the results of the multivariate analysis a) The patients are divided into hypopharyngeal cancer patients and other (laryngeal and oropharyngeal) cancer patients. Fisher’s exact test shows that smoking history; alcohol consumption; clinical T stage of T0, T3, and T4; clinical N stage of N1, N2 and N3; definitive therapy; radiotherapy; and pathological diagnosis of carcinoma in situ and lymphatic invasion are significantly different in the two groups. Other clinical factors are not significantly different. Statistical significance is defined as a p value < 0.05 (5E-02). b) The results of the multivariate analysis using the Cox proportional hazards model. The independent significant clinical factors are flushing reaction; clinical T stage of T3; and clinical N stage of N1, N2, and N3. The odds ratio, 95% CI and p value are calculated by Fisher’s exact test. Statistical significance is defined as a p value < 0.05 (5E-02). Abbreviations: CI: confidence interval. Table 3. Patient characteristics and the results of the multivariate analysis a) The secondary cancer patients are divided into hypopharyngeal cancer patients and other (laryngeal and oropharyngeal) cancer patients. Fisher’s exact test shows that clinical N stage of N3 and radiotherapy are significantly different in the two groups. Other clinical factors are not significantly different. Statistical significance is defined as a p value < 0.05 (5E-02). b) The results of the multivariate analysis using the Cox proportional hazards model. The independent significant clinical factors are radiotherapy and clinical T stage of T2. c) The clinical factor of TN stage is classified into early-stage and advanced-stage, i.e., T stage is divided into T0–2 and T3–4, N stage is divided into N0 and N1–3. The independent significant clinical factors are radiotherapy by multivariate analysis using the Cox proportional hazards model. The odds ratio, 95% CI and p value are calculated by Fisher’s exact test. Statistical significance is defined as a p value < 0.05 (5E-02). Abbreviations: CI: confidence interval. Cite Share Download PDF Status: Published Journal Publication published 07 Dec, 2023 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 13 Aug, 2023 Reviewers agreed at journal 08 Jun, 2023 Reviewers invited by journal 08 Jun, 2023 Editor assigned by journal 06 Jun, 2023 First submitted to journal 05 Jun, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3026392","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":207947512,"identity":"5ee554ea-2d9c-47fb-9a8d-657fb8772772","order_by":0,"name":"Goshi Nishimura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie3QsUoDMRjA8e8I3JRyjpGieYUcB+J0L9LFENClge4KBg7ipmuKoq9QKRTHyIEufYCDCiJCJwfLgZOIlw5FywUdBfOfPgi/jyQAodCfLFIIGEACgJr528EPZFP9nrjtTcyuE1+0VxT1YDDh40qUbHGT9xKF5gSOckDn7QvSh1vdNWzGJ9W+4MOpkMbGOwTuBEQXtp0YrhFekn5WdjSS6vElJhBbiMyejxS1I2OzJMfyyuKGfPgJJVx1HRmRfiY6upQjRyLtJ4xw7UhmpnORDvW9vLZxtstPBfa9hZqD5xq/z7bOTkRJFvpQXlr0VL2+5dup58fYatPG12s0M05NqwC62pSsX4OSdhIKhUL/rk9PZmLg6JgKMgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-9944-4474","institution":"Yokohama City University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Goshi","middleName":"","lastName":"Nishimura","suffix":""},{"id":207947513,"identity":"d63c7d34-b027-427f-86b9-d3d054b44332","order_by":1,"name":"Hideaki Takahashi","email":"","orcid":"","institution":"Yokohama City University: Yokohama Shiritsu Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hideaki","middleName":"","lastName":"Takahashi","suffix":""},{"id":207947514,"identity":"c4bb8569-fc1b-473d-826f-1aa4dd9f3dbe","order_by":2,"name":"Daisuke Sano","email":"","orcid":"","institution":"Yokohama City University: Yokohama Shiritsu Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Sano","suffix":""},{"id":207947515,"identity":"4d423c24-f919-4022-bdd8-86e6412e0cd0","order_by":3,"name":"Yasuhiro Arai","email":"","orcid":"","institution":"Yokohama City University: Yokohama Shiritsu Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Arai","suffix":""},{"id":207947516,"identity":"ab6f4454-d95c-4a47-932f-0d388f151a23","order_by":4,"name":"Takashi Hatano","email":"","orcid":"","institution":"Yokohama City University: Yokohama Shiritsu Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Hatano","suffix":""},{"id":207947517,"identity":"e6ef641e-fb67-4a98-9ed4-a3dcb51a2ae7","order_by":5,"name":"Yosuke Kitani","email":"","orcid":"","institution":"Yokohama City University: Yokohama Shiritsu Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Kitani","suffix":""},{"id":207947518,"identity":"8d1336df-c0a4-4bf8-8567-c86ad2c0f04f","order_by":6,"name":"Nobuhiko Oridate","email":"","orcid":"","institution":"Yokohama City University: Yokohama Shiritsu Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nobuhiko","middleName":"","lastName":"Oridate","suffix":""}],"badges":[],"createdAt":"2023-06-05 22:40:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3026392/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3026392/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-023-02433-8","type":"published","date":"2023-12-07T15:02:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":38301296,"identity":"5252fd89-44c0-45de-be9a-564cdf87c01b","added_by":"auto","created_at":"2023-06-09 16:11:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55690,"visible":true,"origin":"","legend":"\u003cp\u003eDiagram of the patients’ clinical course. Five-hundred and ninety-five patients are enrolled in this study. One-hundred and sixty patients are excluded, and 435 patients are analyzed. Abbreviations: HPC: hypopharyngeal cancer, HPV: human papilloma virus, H\u0026amp;N: head and neck, ML: malignant lymphoma, OPC: oropharyngeal cancer.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3026392/v1/16f597891f8234203b4ca79a.png"},{"id":38302066,"identity":"76fcdc83-8be9-479a-80f8-7674cdb6a536","added_by":"auto","created_at":"2023-06-09 16:19:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":23916,"visible":true,"origin":"","legend":"\u003cp\u003eThe incidence of secondary cancer is determined by the Kaplan–Meier method. The \u003cem\u003ep\u003c/em\u003e value is 0.0029, and hypopharyngeal cancer patients have a significantly higher incident rate than laryngeal and oropharyngeal cancer patients by log-rank test. The 5-year incident rate of secondary cancer is 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancer, respectively.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3026392/v1/8c4965acedaea8f28f8a994f.png"},{"id":47989728,"identity":"f2dbb30a-ce1a-45e7-b1f6-17b3f991d1ac","added_by":"auto","created_at":"2023-12-11 15:10:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":397025,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3026392/v1/f62ded1c-d66a-4f89-bebd-40a9ad083478.pdf"},{"id":38301298,"identity":"243fcfbb-d4a9-4e07-8de8-a56e065640ca","added_by":"auto","created_at":"2023-06-09 16:11:49","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38684,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Patient characteristics and the results of the multivariate analysis.\u003c/p\u003e\n\u003cp\u003ea) The patients are divided into no evidence of secondary cancer patients (negative) and secondary cancer patients (positive). Fisher’s exact test shows that the primary site of hypopharynx, existence of synchronous double cancer, pathological diagnosis of lymphatic invasion, and vascular invasion are significantly different between the two groups. Other clinical factors are not significantly different. Statistical significance is defined as a \u003cem\u003ep\u003c/em\u003evalue \u0026lt; 0.05 (5E-02). b) The results of the multivariate analysis using the Cox proportional hazards model. The independent significant clinical factor is hypopharyngeal cancer. The odds ratio, 95% CI and \u003cem\u003ep\u003c/em\u003e value are calculated by Fisher’s exact test. Statistical significance is defined as a \u003cem\u003ep\u003c/em\u003e value \u0026lt; 0.05 (5E-02). Abbreviations: CI: confidence interval.\u003c/p\u003e\n\u003cp\u003eTable 2. Patient characteristics and the results of the multivariate analysis\u003c/p\u003e\n\u003cp\u003ea) The patients are divided into hypopharyngeal cancer patients and other (laryngeal and oropharyngeal) cancer patients. Fisher’s exact test shows that smoking history; alcohol consumption; clinical T stage of T0, T3, and T4; clinical N stage of N1, N2 and N3; definitive therapy; radiotherapy; and pathological diagnosis of carcinoma in situ and lymphatic invasion are significantly different in the two groups. Other clinical factors are not significantly different. Statistical significance is defined as a \u003cem\u003ep\u003c/em\u003evalue \u0026lt; 0.05 (5E-02). b) The results of the multivariate analysis using the Cox proportional hazards model. The independent significant clinical factors are flushing reaction; clinical T stage of T3; and clinical N stage of N1, N2, and N3. The odds ratio, 95% CI and \u003cem\u003ep\u003c/em\u003e value are calculated by Fisher’s exact test. Statistical significance is defined as a \u003cem\u003ep\u003c/em\u003e value \u0026lt; 0.05 (5E-02). Abbreviations: CI: confidence interval.\u003c/p\u003e\n\u003cp\u003eTable 3. Patient characteristics and the results of the multivariate analysis\u003c/p\u003e\n\u003cp\u003ea) The secondary cancer patients are divided into hypopharyngeal cancer patients and other (laryngeal and oropharyngeal) cancer patients. Fisher’s exact test shows that clinical N stage of N3 and radiotherapy are significantly different in the two groups. Other clinical factors are not significantly different. Statistical significance is defined as a \u003cem\u003ep\u003c/em\u003evalue \u0026lt; 0.05 (5E-02). b) The results of the multivariate analysis using the Cox proportional hazards model. The independent significant clinical factors are radiotherapy and clinical T stage of T2. c) The clinical factor of TN stage is classified into early-stage and advanced-stage, i.e., T stage is divided into T0–2 and T3–4, N stage is divided into N0 and N1–3. The independent significant clinical factors are radiotherapy by multivariate analysis using the Cox proportional hazards model. The odds ratio, 95% CI and \u003cem\u003ep\u003c/em\u003e value are calculated by Fisher’s exact test. Statistical significance is defined as a \u003cem\u003ep\u003c/em\u003e value \u0026lt; 0.05 (5E-02). Abbreviations: CI: confidence interval.\u003c/p\u003e","description":"","filename":"tables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3026392/v1/2a36a4679cd7ed873ffafed7.xlsx"}],"financialInterests":"","formattedTitle":"Risk factors of secondary cancer in laryngeal, oropharyngeal, or hypopharyngeal cancer after definitive therapy","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHead and neck cancers account for approximately 5% of all malignancies in Japan\u003csup\u003e1)\u003c/sup\u003e. About 60% of head and neck cancers\u0026mdash;with the exception of glottis and oral cancers\u0026mdash;are diagnosed at an advanced stage because of the lack of definitive symptoms and lack of awareness of head and neck cancers. Moreover, advanced-stage patients are at high risk of local recurrence or regional lymph node metastasis. Between 60% and 70% of these cases have treatment failure within the first year after diagnosis, and 90\u0026ndash;100% within 2 years. Moreover, the incidence rate of second primary cancers exceeds that of primary head and neck cancer recurrence, which occurs at an average of 4 years after the diagnosis of the primary cancer\u003csup\u003e2\u0026ndash;4)\u003c/sup\u003e. On the other hand, the number of early-stage patients has increased following the advent of advanced diagnostic techniques such as positron emission tomography-computed tomography (PET-CT) and narrow-band imaging (NBI) endoscopy\u003csup\u003e5, 6)\u003c/sup\u003e. This increase is also due to an increased awareness of head and neck cancers among doctors in other fields\u003csup\u003e7)\u003c/sup\u003e. In general, long-term survival is expected in patients with early-stage cancer, which can be associated with an increased risk of secondary carcinogenesis.\u003c/p\u003e \u003cp\u003eWe have previously reported that patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancer treated by transoral surgery (TOS) had a high incidence rate of newly diagnosed secondary cancer during the observation period after TOS\u003csup\u003e8, 9)\u003c/sup\u003e. In these patients, the primary site of the hypopharynx was an independent risk factor for secondary cancer. We presumed the reasons to be alcohol drinking, smoking, and aging; however, we could not provide clear evidence.\u003c/p\u003e \u003cp\u003eIn this study, to identify the risk factors for secondary carcinogenesis, we retrospectively analyzed all-stage patients who underwent radical treatment for laryngeal, oropharyngeal, and hypopharyngeal cancers, particularly factors associated with drinking and/or smoking.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eStudy setting\u003c/p\u003e \u003cp\u003eThis was a single institute (academic hospital), retrospective observational study.\u003c/p\u003e \u003cp\u003eEnrollment and eligibility\u003c/p\u003e \u003cp\u003ePatients who visited our department for the first time for treatment of laryngeal, oropharyngeal, and hypopharyngeal cancer between January 1, 2013 and December 31, 2021 were enrolled. To evaluate the incidence rate and related factors during the observation period after definitive therapy, patients who met the following criteria were excluded: pure human papilloma virus (HPV)-related oropharyngeal cancer with p16 positivity and no alcohol drinking or smoking habit, because it was not possible to assess alcohol consumption and smoking history; distant metastasis, because definitive surgery or chemoradiotherapy was not adapted; and previous history of malignant disease, because we aimed to analyze the risk factors for the second carcinogenesis after the first cancer.\u003c/p\u003e \u003cp\u003eEndpoints\u003c/p\u003e \u003cp\u003eThe endpoint was the clinical risk factor for the incidence of newly diagnosed malignancy in patients with laryngeal, oropharyngeal, and hypopharyngeal cancers. Secondary new cancer was defined as follows: pathologically diagnosed as a malignant disease; the disease appeared in other organs (e.g., the first cancer was hypopharyngeal cancer and the second was esophageal cancer), in other subsites of the same region of the head and neck (e.g., the first cancer was piriform sinus type and the second was postcricoid type of the hypopharynx), or the disease was found in the same subsite but the disease was separated from the first cancer mediating normal mucosa (e.g., both first and second cancers appeared on the same side of the piriform sinus of the hypopharynx).\u003c/p\u003e \u003cp\u003eTreatment methods\u003c/p\u003e \u003cp\u003eDefinitive surgery included both complete resection for the primary site and neck dissection for patients with lymph node metastasis. Postoperative radiotherapy was performed based on the pathological evaluation after surgery with or without chemotherapy. Postoperative chemoradiotherapy was adapted to have positive surgical margins and/or extranodal extension to lymph nodes. Postoperative radiotherapy alone was adapted to have T3 and T4 pathologies, positive perineural invasions and/or vascular tumor embolism of the primary site, and/or multiple positive metastases to lymph nodes. The radiation doses were 56\u0026ndash;60 Gy for radiotherapy alone and 60\u0026ndash;66 Gy for chemoradiotherapy. The chemotherapeutic reagent was \u003cem\u003ecis\u003c/em\u003e-platinum\u003csup\u003e10, 11)\u003c/sup\u003e, or a combination of docetaxel and cetuximab\u003csup\u003e12)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRadiotherapy was performed 5 days a week with a single daily fraction of 1.8\u0026ndash;2.0 Gy using six MV X-ray linear accelerators for a total dose of 66.0\u0026ndash;72.0 Gy. The radiation dose and field were modified according to the primary site and clinical stage. Radiotherapy alone was administered to early-stage patients, and chemoradiotherapy was administered to advanced-stage patients. The concurrent chemotherapy regimens were decided on the basis of age and/or comorbidity. The chemotherapy regimens were as follows: the TPF regimen consisting of docetaxel, \u003cem\u003ecis\u003c/em\u003e-platinum, and 5-fluorouracil\u003csup\u003e13, 14)\u003c/sup\u003e; the TPE regimen consisting of docetaxel, \u003cem\u003ecis\u003c/em\u003e-platinum, and cetuximab\u003csup\u003e15)\u003c/sup\u003e; the \u003cem\u003ecis\u003c/em\u003e-platinum regimen\u003csup\u003e16)\u003c/sup\u003e; the cetuximab regimen\u003csup\u003e17)\u003c/sup\u003e; and the S-1 regimen consisting of the oral administration of S-1\u003csup\u003e18)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eInduction chemotherapy was performed prior to the definitive surgery or chemoradiotherapy using a combination of docetaxel, \u003cem\u003ecis\u003c/em\u003e-platinum, and 5-fluorouracil\u003csup\u003e19)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003cp\u003eVisual and endoscopic observations of the primary site were performed every month for the first and second years and every 2\u0026ndash;3 months from the third to the fifth year. Enhanced cervical CT or US of the primary site and regional lymph nodes was performed every 3\u0026ndash;6 months for the first and second years and every 6\u0026ndash;12 months from the third to fifth years. Finally, PET-CT was performed every year for the first and second years, and enhanced whole-body CT was performed every year from the third to fifth years for the evaluation of distant metastasis. In case of the presence of a new second primary cancer, the patient was referred to the appropriate department.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePatient characteristics were compared between patient groups using the Fisher\u0026rsquo;s exact test. The Fisher\u0026rsquo;s exact test and the Cox proportional hazards model were used for univariate and multivariate comparisons, respectively. The Kaplan\u0026ndash;Meier method was used to evaluate the incidence rate of secondary cancer. The log-rank test was used to analyze statistical differences.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics and examination results\u003c/p\u003e\n\u003cp\u003eThe patients\u0026rsquo; clinical courses are shown diagrammatically in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Five-hundred and ninety-five patients were enrolled, and seven patients were excluded because of pure HPV-related oropharyngeal cancer, 22 patients were excluded because of distant metastasis positive at the diagnosis of head and neck cancer, and 138 patients were excluded because of a past history of malignant disease. In total, 428 patients were included in this study.\u003c/p\u003e\n\u003cp\u003eThe patient characteristics are summarized in Table\u0026nbsp;1-a. As definitive therapy, radical surgery was performed in 264 patients and chemoradiotherapy in 164 patients. Among the operated patients, 48 received postoperative chemoradiotherapy, 43 received postoperative radiotherapy alone due to pathological evaluation for recurrence risk, and four received induction chemotherapy prior to surgery. Among the patients who received definitive chemoradiotherapy, 39 patients received radiotherapy alone and 117 patients received concurrent chemoradiotherapy depending on the clinical stage. Induction chemotherapy was performed prior to radiotherapy alone for four patients and chemoradiotherapy for four patients. For tumor depth evaluated by pathological examination, the cut-off value was defined by the receiver operating characteristic (ROC) curve between the presence of secondary cancer and tumor depth in patients who underwent definitive surgery. The cutoff value for tumor depth was 12,000 \u0026micro;m.\u003c/p\u003e\n\u003cp\u003eThree hundred and thirty-six patients showed no evidence of secondary cancer during the observation period, while 92 patients were newly diagnosed with secondary cancer (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Comparing these groups, the primary site of the hypopharynx, existence of synchronous double cancer, pathological diagnosis of lymphatic invasion, and vascular invasion showed significant effects on univariate analysis using the Fisher\u0026rsquo;s exact test. Other clinical factors were not significantly different. Based on the univariate analysis results, multivariate logistic regression analysis was performed using the Cox proportional hazards model, and hypopharyngeal cancer and the pathological diagnosis of lymphatic invasion were independent significant clinical factors for the newly detected presence of secondary cancer (Table 1-b). The time course of secondary cancer incidence, classified by the primary site, is shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. The \u003cem\u003ep\u003c/em\u003e value was 0.0039, and hypopharyngeal cancer patients had a significantly higher incidence rate of secondary cancer than laryngeal and oropharyngeal cancer patients as determined by a log-rank test. The crude incidence of secondary cancer per 100 patient-years was 8.1 in all patients, and 6.2, 6.4, and 11.3 in laryngeal, oropharyngeal, and hypopharyngeal cancer patients, respectively.\u003c/p\u003e\n\u003cp\u003eAnalysis for hypopharyngeal cancer patients compared to other primary cancers\u003c/p\u003e\n\u003cp\u003eBased on the prior results of the multivariate logistic regression analysis (Table\u0026nbsp;1-b), the patients were divided into a hypopharyngeal cancer group and other cancer (laryngeal and oropharyngeal) group. While another independent clinical factor, lymphatic invasion, had a significantly lower risk of secondary cancer, it was difficult to explain this logically. In general, tumor lymphatic invasion is considered associated with lymphatic metastasis, and there is no obvious evidence supporting its relationship with the incidence of secondary cancer.\u003csup\u003e20\u003c/sup\u003e We therefore dismissed this result as a computational error.\u003c/p\u003e\n\u003cp\u003eThe patients\u0026rsquo; characteristics are summarized according to the primary site in Table\u0026nbsp;2-a. The Fisher\u0026rsquo;s exact test showed that smoking history; alcohol consumption; clinical T stage of T0, T3, and T4; clinical N stage of N1, N2, and N3; definitive therapy; radiotherapy; pathological diagnosis of carcinoma in situ; and lymphatic invasion were significantly different between the groups. Based on the univariate analysis results, multivariate logistic regression analysis was performed using the Cox proportional hazards model and alcohol flush reaction; clinical T stage of T3; and clinical N stage of N1, N2, and N3 were independent clinical factors (Table\u0026nbsp;2-b). Among these factors, the alcohol flush reaction was associated with carcinogenesis of hypopharyngeal cancer. Clinical T stage of T3, and clinical N stage of N1, N2, and N3 showed a trend toward an association with advanced-stage hypopharyngeal cancer at the first medical examination.\u003c/p\u003e\n\u003cp\u003eAnalysis of the incidence rate of secondary cancer in hypopharyngeal cancer and other cancers\u003c/p\u003e\n\u003cp\u003eSecondary cancer-positive patients were divided into a hypopharyngeal cancer and other cancer group. The patient characteristics are summarized in Table\u0026nbsp;3-a. The Fisher\u0026rsquo;s exact test showed that the clinical N stage of N3 and radiotherapy were significantly different in the two groups. Based on the univariate analysis results, multivariate logistic regression analysis was performed using the Cox proportional hazards model, and clinical T stage of T2 and radiotherapy were the independent clinical factors (Table\u0026nbsp;3-b). T2 indicated a significantly lower risk of secondary cancer, and we considered that early-stage cancer was associated with a low risk of development of secondary cancer, considering that hypopharyngeal cancer patients tended to have advanced-stage disease at the first visit (Table\u0026nbsp;2-a). Therefore, we reorganized the factors of clinical stages; that is, clinical T stage was divided into T0\u0026ndash;2 and T3\u0026ndash;4, and N stage was divided into N0 and N1\u0026ndash;3. Multivariate logistic regression analysis was performed using the Cox proportional hazards model, and radiotherapy was the independent clinical factor for the development of secondary cancer (Table\u0026nbsp;3-c).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eConventionally, most patients with head and neck cancer have had advanced cancer, and even after definitive treatment, locoregional recurrence has been common, and the prognosis has been poor. Locoregional recurrence occurs in the majority of cases within 2 years after diagnosis, and in patients who achieve good control of the primary disease, second cancers begin to outnumber locoregional recurrence rates 4 years after the diagnosis\u003csup\u003e2\u0026ndash;4)\u003c/sup\u003e. Recently, developments in medical technology have increased the chances of detecting head and neck cancer at an early-stage and have enabled a long-term prognosis. We have previously reported that early-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who were treated with TOS showed a good prognosis, even though a high rate of secondary carcinogenesis occurred\u003csup\u003e8, 9)\u003c/sup\u003e. Among these cancers, hypopharyngeal cancer was found to be an independent risk factor for secondary carcinogenesis, and although associations with alcohol consumption, smoking, and aging were inferred, no direct relationship could be demonstrated.\u003c/p\u003e \u003cp\u003eAlcohol is a risk factor for breast, cervix, colon, esophagus, larynx, liver, oral cavity, pharynx, prostate, and stomach cancers. The risk increases with the amount of alcohol consumed. Even if the amount of consumption is light to moderate, the incidence risk for bladder, breast, colorectal, esophagus, larynx, liver, oral cavity, pharynx, prostate, and stomach cancers increases.\u003csup\u003e21\u003c/sup\u003e One of the mechanisms of alcohol-induced carcinogenesis is chemical mucositis by ethanol directly in the upper aerodigestive tract, which includes the esophagus, larynx, oral cavity, and pharynx cancers. Another mechanism involves carcinogenesis caused by acetaldehyde, a degradation product of ethanol by acetaldehyde dehydrogenase (ALDH) 2, which affects the entire body. Forty-four percent of Japanese have the heterozygous genotype of normal and inactive ones (ND type) or the homozygous genotype of an inactive one (DD type) of ALDH2, and these people are exposed to acetaldehyde for a long period of time whenever they drink. Prolonged exposure to acetaldehyde may increase the likelihood of inducing carcinogenesis or pre-cancerous genetic abnormalities.\u003c/p\u003e \u003cp\u003eSmoking is another risk factor for carcinogenesis, which induces DNA damage. Smoking increases the risk of at least 17 classes of cancer, that is acute myeloid leukemia, bladder, cervix, colorectal, esophagus (adenocarcinoma and squamous cell carcinoma), kidney, lung (adenocarcinoma, small cell carcinoma, and squamous cell carcinoma), larynx, liver, oral cavity, ovary, pancreas, pharynx, and stomach cancers\u003csup\u003e22)\u003c/sup\u003e. Tobacco carcinogens directly and indirectly induce DNA mutations in lung adenocarcinoma, lung squamous cell carcinoma, larynx, and liver cancers. Moreover, these carcinogens also indirectly induce DNA damage in acute myeloid leukemia and bladder, cervix, colorectal, kidney, ovarian, pancreatic, and stomach cancers. In Japan, smoking is defined as a risk factor for bladder, esophagus, larynx, liver, lung, nasal and paranasal sinuses, oral cavity, pancreas, pharynx, stomach, and uterine cervix cancers. A study showed that 30% of male and 5% of female cancers are derived from smoking\u003csup\u003e23)\u003c/sup\u003e. Furthermore, the incidence of all types of cancer was found to be increased with smoking in habitual alcohol drinkers\u003csup\u003e24)\u003c/sup\u003e. In the non-smoking group, the incidence did not increase in accordance with an increase in alcohol consumption. Meanwhile, in the smoking group, the incidence increased in accordance with an increase in alcohol consumption, and people who had been drinking more than 81 g of alcohol every day with customary smoking demonstrated a 2.3 times higher incidence of all cancers.\u003c/p\u003e \u003cp\u003eIn the present study, we attempted to identify risk factors for secondary carcinogenesis by retrospectively analyzing definitively treated patients with all-stage laryngeal, HPV-unrelated oropharyngeal, and hypopharyngeal cancers, particularly factors related to alcohol consumption and smoking. Similar to the results of our previous report on early-stage cancer patients, hypopharyngeal cancer was shown to be an independent risk factor for secondary carcinogenesis. Even though a comparison with nonsmokers and nondrinkers in terms of secondary cancer was difficult because 88% of the patients were drinkers and 89% were smokers in this study, in patients with hypopharyngeal carcinoma, the alcohol flush reaction was an independent risk factor, suggesting an association between ALDH2 inactivity and hypopharyngeal carcinogenesis. This relationship was consistent with a previous report that the ALDH2 genotype, which is mutated in 44% of the Japanese population, and alcohol flush reaction are risk factors for hypopharyngeal and esophageal squamous cell carcinoma\u003csup\u003e25, 26)\u003c/sup\u003e. Age was not identified as a risk factor for any of these cancers as there was a similar age distribution. In the future, it will be desirable to conduct an analysis using an objective index for aging other than calendar age.\u003c/p\u003e \u003cp\u003eRadiotherapy has been shown to be an independent risk factor in patients who develop a second cancer after definitive treatment for hypopharyngeal cancer. Hypopharyngeal cancer patients tend to be diagnosed at a locoregionally advanced stage at the time of initial diagnosis and often require chemoradiotherapy after radical surgery, or chemoradiotherapy is often chosen as a definitive treatment in the hope of preserving organ function. In hypopharyngeal cancer patients, alcohol consumption, smoking, and inadequate alcohol metabolism due to ALDH2 inactivity may cause genetic mutations that result in a precancerous state throughout the body. We speculate that out-of-field radiation exposure by whole-neck irradiation results in systemic inflammation\u003csup\u003e27)\u003c/sup\u003e, and in such a precancerous condition, this can cause secondary cancer. In the case of out-of-field radiation exposure of normal tissues, the latency period for the development of radiation-induced cancer is 5\u0026ndash;20 years for solid tumors. On the other hand, it is quite possible that solid tumors induced by out-of-field radiation exposure will become apparent within 5 years of initial head and neck cancer treatment, as hypopharyngeal cancer patients have already accumulated genetic abnormalities due to alcohol consumption and smoking. In the future, it is desirable to establish a method for detecting and evaluating genetic abnormalities at the time of initial diagnosis of hypopharyngeal carcinoma in patients who will be treated with radiotherapy and for observing mutations over time after treatment.\u003c/p\u003e \u003cp\u003eThe limitations of the present study were that it was conducted at a single institution and its retrospective design which limit the generalizability of the results and raise the possibility of selection bias, respectively.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe analyzed patients with all-stage laryngeal, oropharyngeal, and hypopharyngeal cancers treated with definitive therapy. The independent predictive factor for newly diagnosed secondary cancers was hypopharyngeal cancer. Hypopharyngeal cancer patients were highly positive for alcohol flush reaction. Radiotherapy for hypopharyngeal cancer is an independent risk factor for secondary carcinogenesis. The probable mechanism is the induction of systemic secondary carcinogenesis by out-of-field radiation exposure in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption, particularly ALDH2 inactive patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePET-CT, positron emission tomography-computed tomography; NBI, narrow-band imaging; TOS, transoral surgery; HPV, human papilloma virus; ROC, receiver operating characteristic; ALDH2, acetaldehyde dehydrogenase 2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used in the present study are available from the corresponding author upon request. All data generated or analyzed in this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGN and NO conceived the study, performed statistical analyses, and edited the manuscript. GN and HT designed the study. GN, DS, YA, TH, and YK acquired, analyzed, and interpreted the data. GN and HT evaluated the quality of the data and algorithms. GN prepared the manuscript and all authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was obtained from the Yokohama City University Institutional Review Board (#F230200009). Written informed consent was obtained from the participants to publish their data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNational Cancer Center, Japan. Cancer Statistics. Accessed June 1, 2023. http://ganjoho.jp/reg_stat/\u003c/li\u003e\n\u003cli\u003eVikram B. (1984) Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol 110(9):564-565.\u003c/li\u003e\n\u003cli\u003eVokes EE, Kies M, Haraf DJ, et al. (1995) Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease. 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N Engl J Med 350(19):1945-1952.\u003c/li\u003e\n\u003cli\u003eNishimura G, Shiono O, Sano D, et al. (2017) Efficacy and safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel for high-risk head and neck cancer patients in Japan. Cancer Chemother Pharmacol 80(1):203-207.\u003c/li\u003e\n\u003cli\u003eKatori H, Tsukuda M, Mochimatu I, et al. (2004) Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with locally advanced squamous cell carcinoma of head and neck (SCCHN). Br J Cancer 90(2):348-352.\u003c/li\u003e\n\u003cli\u003eTsukuda M, Ishitoya J, Matsuda H, et al. (2010) Randomized controlled phase II comparison study of concurrent chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil versus CCRT with cisplatin, 5-fluorouracil, methotrexate and 25 leucovorin in patients with locally advanced squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol 66(4):729-736.\u003c/li\u003e\n\u003cli\u003eNishimura G, Taguchi T, Takahashi M, et al. (2016) Phase II trial of concurrent bio-chemoradiotherapy using docetaxel, cisplatin, and cetuximab for locally advanced head and neck squamous cell carcinoma. Cancer Chemother Pharmacol 77(6):1315-1319.\u003c/li\u003e\n\u003cli\u003eAdelstein DJ, Li Y, Adams GL, et al. (2003) An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21(1):92-98.\u003c/li\u003e\n\u003cli\u003eBonner JA, Harari P, Giralt J, et al. (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of head and neck. N Engl J Med 354(6):567-578.\u003c/li\u003e\n\u003cli\u003eTsukuda M, Ishitoya J, Mikami Y, et al. (2009) Analysis of feasibility and toxicity of concurrent chemoradiotherapy with S-1 for locally advanced squamous cell carcinoma of the head and neck in elderly cases and/or cases with comorbidity. Cancer Chemother Pharmacol 64(5):945-952.\u003c/li\u003e\n\u003cli\u003eMumme AM, Laban S, Knecht R. (2012) New aspects of induction chemotherapy for head and neck cancer: POSTASCO 2011. Wur Arch Otorhinolaryngol 269(11):2303-2308.\u003c/li\u003e\n\u003cli\u003eFujimoto N, Dieterich LC. (2021) Mechanisms and clinical significance of tumor lymphatic invasion. Cells 10(10):2585.\u003c/li\u003e\n\u003cli\u003eZaitsu M, Takeuchi T, Kobayashi Y, et al. (2020) Light to moderate amount of lifetime alcohol consumption and risk of cancer in Japan. Cancer 126(5):1031-1040.\u003c/li\u003e\n\u003cli\u003eAlexandrov LB, Ju YS, Haase K, Van Loo P, et al. (2016) Mutational signatures associated with tobacco smoking in human cancer. Science 354(6312):618-622.\u003c/li\u003e\n\u003cli\u003eNational Cancer Center, Japan. Tobacco and cancer. Accessed June 1, 2023. https://ganjoho.jp/public/pre_scr/cause_prevention/smoking/index.html.\u003c/li\u003e\n\u003cli\u003eInoue M, Tsugane S; JPHC Study Group. (2005) Impact of alcohol drinking on total cancer risk: data from a large-scale population-based cohort study in Japan. Br J Cancer 92(1):182-187.\u003c/li\u003e\n\u003cli\u003eYokoyama A, Kumagai Y, YokoyamaT, et al. (2009) Health risk appraisal models for mass screening for esophageal and pharyngeal cancer: an endoscopic follow-up study of cancer-free Japanese men. Cancer Epidemiol Biomarkers Prev 18(2):651-655.\u003c/li\u003e\n\u003cli\u003eYamashita Y, Ikegami T, Suzuki M, et al. (2019) Hypopharyngeal cancer risk in Japanese: Genetic polymorphisms related to the metabolism of alcohol- and tobacco-associated carcinogens. J Cancer Res Ther 15(3):556-563.\u003c/li\u003e\n\u003cli\u003eMesbahi A, Seyednejad F, Gasemi-Jangjoo A. (2010) Estimation of organs doses and radiation-induced secondary cancer risk from scattered photons for conventional radiation therapy of nasopharynx: a Monte Carlo study. Jpn J Radiol 28(5):398-403.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Laryngeal cancer, Oropharyngeal cancer, Hypopharyngeal cancer, Newly diagnosed secondary cancer, Radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-3026392/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3026392/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOur previous research showed that a high rate of secondary carcinogenesis is observed during follow-up after transoral surgery in patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We speculate that the contributing factors are alcohol drinking, smoking, and aging; however, we could not provide clear evidence. In this study, we aimed to identify the risk factors for secondary carcinogenesis in patients with these cancers, particularly factors associated with drinking and/or smoking.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe medical records of all-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who had undergone definitive treatment were retrospectively analyzed. Assessments included visual and endoscopic observations of the primary site, enhanced cervical CT or US of the primary site and regional lymph nodes, PET-CT, and enhanced whole-body CT. Clinical characteristics were compared in patients with and without secondary carcinogenesis and in patients with hypopharyngeal cancer and patients with other cancers.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eHypopharyngeal cancer was an independent risk factor for secondary cancer. The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. Radiotherapy was defined as an independent risk factor in hypopharyngeal cancer patients with secondary cancers. No direct correlation was found between secondary carcinogenesis and alcohol consumption, smoking, or aging.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePatients with hypopharyngeal cancer require close follow-up as they are at high risk of developing secondary cancer, possibly because out-of-field radiation exposure may induce systemic secondary carcinogenesis in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption.\u003c/p\u003e","manuscriptTitle":"Risk factors of secondary cancer in laryngeal, oropharyngeal, or hypopharyngeal cancer after definitive therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-09 16:11:45","doi":"10.21203/rs.3.rs-3026392/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2023-08-14T03:18:59+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-06-08T12:07:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-06-08T07:54:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-06-06T06:44:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2023-06-05T18:40:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fcb74926-3a26-40d8-9df1-24ecd1be1d97","owner":[],"postedDate":"June 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-12-11T15:08:58+00:00","versionOfRecord":{"articleIdentity":"rs-3026392","link":"https://doi.org/10.1007/s10147-023-02433-8","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2023-12-07 15:02:03","publishedOnDateReadable":"December 7th, 2023"},"versionCreatedAt":"2023-06-09 16:11:45","video":"","vorDoi":"10.1007/s10147-023-02433-8","vorDoiUrl":"https://doi.org/10.1007/s10147-023-02433-8","workflowStages":[]},"version":"v1","identity":"rs-3026392","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3026392","identity":"rs-3026392","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}