Local excision versus radical surgery for anal squamous cell carcinoma –a multicenter study in Japan-

Local excision versus radical surgery for anal squamous cell carcinoma –a multicenter study in Japan- | 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 Local excision versus radical surgery for anal squamous cell carcinoma –a multicenter study in Japan- Shin Murai, Hiroaki Nozawa, Kazutaka Yamada, Yasumitsu Saiki, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3481888/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background The standard treatment for anal squamous cell carcinoma is chemoradiation therapy (CRT), but there is a possibility of overtreatment for early stage disease. cTisN0 and cT1N0 disease is currently indicated for local excision, but it is unclear whether the indication of local excision can be expanded to cT2N0 disease. Methods 126 patients with cTis-T2N0 anal cancer treated at 47 centers in Japan between 1991 and 2015 were included. Patients were first classified into the CRT group and surgical therapy group according to the initial therapy, and the latter was further divided into local excision (LE) and radical surgery (RS) groups. We compared prognoses among the groups, and analyzed risk factors for recurrence after local excision. Results The CRT group (n = 87) and surgical therapy group (n = 39) showed no difference in relapse-free survival (p = 0.29) and overall survival (p = 0.94). Relapse-free survival curves in the LE (n = 23) and RS groups (n = 16) overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p = 0.33). By contrast, there was no difference in overall survival between the two groups (p = 0.98). In the LE group, the majority of recurrences distributed in locoregional areas, which could be managed by salvage treatments. Muscular invasion was associated with recurrence after local excision (hazard ratio: 22.91, p = 0.011). Conclusion LE may be applied to selected patients with anal cancer of cT2N0 stage. Given the high risk of recurrence in cases with muscular invasion, it may be important to consider close surveillance and additional treatment in such patients. Anal cancer Local excision Radical surgery Figures Figure 1 Figure 2 Figure 3 Introduction Anal squamous cell cancer is an uncommon tumor that represents 4% of all cancers in the lower gastrointestinal tract [1]. In 1970s, radical surgery such as APR (abdominoperineal resection) was the mainstay of treatment for anal cancer. In 1980s, Nigro et al. performed chemoradiation therapy (CRT) for anal cancer which provided good prognosis and obviated permanent stoma in advanced stage patients. Based on the results, there was a paradigm shift from surgical therapy to CRT in the treatment of anal cancer [2] [3]. However, no studies directly compared radical surgery and CRT. Moreover, there are several concerns in implementing CRT. Late complications related to CRT can be problematic, including chronic diarrhea, fecal incontinence, and sexual dysfunction [4] [5]. Additionally, CRT is a risk for secondary carcinogenesis [6]. Therefore, there is an argument that CRT may be over-treatment for early-stage anal cancer [7]. In fact, satisfactory long-term outcomes of local excision for cT1N0 anal cancer were recently demonstrated [8]. Regarding cT2N0 anal cancers, only a couple of studies investigated the outcomes of local excision. One study concluded that local excision in cT2 tumors is not recommended due to insufficient margins [9], whereas the other argued that local excision is acceptable for cT1-2 cases because postoperative radiation therapy (RT)/CRT improves the prognosis [10]. These outcomes of local excision were not compared to those of other treatment strategies in both studies. In this study, we first addressed whether surgical therapy and CRT provide comparable prognosis for early-stage anal cancer including cTis-2N0 cases. Then, by confining the study subject to patients receiving surgical therapy, we compared outcomes of radical surgery and local excision to determine whether the latter treatment is feasible and pragmatic. Methods Patients A total of 436 patients with anal canal squamous cell carcinoma were treated at 47 tertiary centers in Japan (listed in Acknowledgements) between 1991 and 2015. Among these, 126 patients with cTis-2N0 anal canal squamous cell carcinoma were enrolled in this study. Disease was staged according to the UICC TNM classification (8 th edition) [15]. Patients were first classified into the CRT group and ‘Surgical therapy’ group according to the initial therapy, and the latter was further divided into ‘Local excision (LE)’ and ‘Radical surgery (RS)’ groups. Consent to conduct the research was provided by the JSCCR ethical committee. Outcome measurements Clinical parameters including sex and age, clinical T stage, and pathological differentiation of tumor were compared between the CRT group and Surgical therapy group. The same clinical parameters and pathological findings such as histological type, pathological T and N stage, lymphocytic invasion and venous invasion were compared between the LE group and RS group. Recurrence types were classified into locoregional recurrence and distant metastasis. Locoregional recurrence included pelvic, perineal, and inguinal lymph nodal recurrence. Distant metastasis was defined as recurrence in organs other than the local. Relapse-free survival (RFS) was defined as time between the date of surgery and relapse. Overall survival (OS) was defined as time between the starting date of initial therapy and death from any causes. RFS and OS were compared between the CRT group and Surgical therapy group, and also compared between the LE group and RS group. Statistical analysis An un-paired t test was used to compare continuous variables and the Yates’ correction or Fisher’s exact test was used to compare categorical data. RFS rate was estimated using the Kaplan-Meier method and compared with the log-rank test. All analyses were performed with the JMP 15.0 software program (SAS Institute, Inc., Cary, NC, USA), and differences with a p <0.05 were considered significant. Results Patient characteristics Among 126 patients with cTis-2N0 anal canal squamous cell carcinoma enrolled in this study, 87 and 39 patients were classified to the CRT group and Surgical therapy group, respectively. Moreover, 23 patients were classified to the LE group, and 16 patients to the RS group (Fig. 1). Comparison of the CRT and Surgical therapy groups Background characteristics in the CRT group and Surgical therapy group were shown in Table 1. Clinical T stage in the CRT group was more advanced than in the surgical therapy group (p=0.008). There was no significant difference in other parameters. There was no significant difference in RFS between the CRT group and Surgical therapy group (p=0.29). The 5-year RFS was 79% for the CRT group and 67% for the surgical therapy group (Fig. 2). In addition, OS was comparable between the CRT group and Surgical therapy group (p=0.94). The 5-year OS was 85% for the CRT group and 87% for the surgical therapy group (Fig. 2). Comparison of the LE and RS groups Patient characteristics in the LE group and RS group were shown in Table 2. Clinical T stage in the RS group were more advanced than in the LE (p=0.01). On the other hands, the LE group showed a broader range of pT stage than the RS group (p=0.003). Approximately 20% of the RS group showed regional node metastasis. More patients (74%) in the RS group showed muscular invasion compared to the LE group (18%, p=0.0001). There was no significant difference in other parameters. RFS curves in the LE and RS groups overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p=0.33). The 5-year RFS rate was 55.3% for the LE group and 71.9% for the RS group. By contrast, there was no significant difference in OS between the two groups (p=0.98). The 5-year OS rate was 87% for the LE group and 88% for the RS group (Fig. 3). Recurrence pattern in the LE and RS groups Seven patients (30%) relapsed in the LE group with the median follow up of 40 months, whereas three patients (19%) relapsed in the RS group (median follow up: 72 months, Table 3). Recurrence rate after LE was 27% for cTis-1 disease (4 of 15 patients) and 38% for cT2 disease (3 of 8 patients, p=0.66). All 10 patients with recurrence in both groups had primary cancer of the anal canal. One patient in each group developed distant metastasis. A male patient in the LE group had recurrence in para-aortic lymph nodes, and received radiotherapy. A female patient in the RS group had liver metastasis, and moved to another hospital. In the LE group, two patients with inguinal nodal metastases underwent nodal dissection. Locoregional recurrence was treated by rectal amputation in two patients and CRT in one patient. One female patient with locoregional recurrence in LE group was advised to receive CRT, but she preferred to be followed with palliative care. In the RS group, one patient with iliac nodal metastases underwent radiation therapy, and another with perineal recurrence received additional local excision followed by radiation therapy. Recurrence risk in the LE group Finally, we investigated factors associated with recurrence in patients of the LE groups. The presence of muscular invasion was the only risk factor for recurrence (hazard ratio: 22.91, 95% confidence interval: 2.05–256.6, p=0.011, Table 4). Other parameter had no significant associations with recurrence. Discussion There were a limited number of studies that investigated the outcomes between CRT and surgical treatment for anal squamous cell cancer; regarding cT1 disease, there was accumulating evidence that local excision is comparable to CRT in terms of prognosis [ 8 ]. However, for tumors of the anal canal origins, there is a concern that an adequate margin of dissection may not be obtained [13] [14]. The National Comprehensive Cancer Network guidelines recommend local excision only for cT1N0 lesions localized in the anal margin [16]. On the other hand, only a few reports investigated the efficacy of local excision for cT2N0 anal cancer [13] [14]. However, outcomes of CRT vs surgical treatment were not directly compared in the literature including the above studies [13] [14]. In our study, there was no difference in RFS and OS between CRT and surgical therapy for cTis-2N0 anal cancer (Fig. 2 ). Thus, both CRT and surgical therapy may be recommended in patients with anal cancer of these early stages. No previous reports compared the prognosis of LE and RS. Patients in the LE and RS groups showed comparable RFS for first three years, but the LE group was more likely to develop recurrence thereafter in our study (Fig. 3 ). The majority of patients in the LE group (86%) had locoregional recurrence (Table 3 ). Moreover, it was considered that all locoregional recurrent lesions could be potentially managed by CRT or salvage surgery in the LE group. Despite of the discrimination of RFS curve beyond 3 years after surgery in the LE and RS groups, OS curves of both groups were almost identical. The results suggest that effective salvage treatment contributed to a good prognosis even in recurrent cases in the LE group. To prescribe salvage therapy in a timely manner, close surveillance may be necessary for a long period in the LE group. Maccabe et al. reported that R1 resection rate in local excision was 54% for tumors of the anal margin and 93% for tumors of the anal canal [ 9 ]. They also reported that there was no difference in recurrence rate between the anal margin and anal canal origins, as adjuvant therapy was usually performed in cases with inadequate resection margin [ 9 ]. Similarly, Leon et al. also reported that postoperative RT/CRT after local excision improved OS and disease-free survival in patients who underwent local excision with positive resection margin [ 10 ]. These results suggested that recurrence in anal cancer may be manageable if appropriate adjuvant therapy is performed. In contrast, only a few patients received adjuvant therapy in the LE group in our cohort. In addition, recurrence after local excision was observed exclusively in cases of anal canal cancer. We imagine that R1 resection rate in cancer of the anal canal might be higher than these of the anal margin, although we do not have available information on surgical margin. Regarding the relationship between pathological findings and prognosis after local excision, Maccabe et al. reported that anal cancer with lymphovascular invasion carried a high risk for recurrence, but muscular invasion was not examined [ 9 ]. On the other hand, we demonstrated that muscular invasion was a risk factor for recurrence in anal cancer (Table 4 ). Alana et al. reported that anal superficially invasive squamous-cell carcinoma (SISCCA), defined as an invasive lesion within 3 mm vertically and 7 mm horizontally, showed a good prognosis when treated by local excision [17]. However, it is difficult to make a correct diagnosis of SISCCA preoperatively. In contrast, muscular infiltration of the tumor may be evaluated preoperatively with endoscopic ultrasound and magnetic resonance imaging [18] [19]. This study has several limitations. First, this study is a retrospective study, examining a small number of patients. Second, our database lacked information on resection margin. Third, the initial treatment at diagnosis and treatment at the time of recurrence depended on the discretion at each hospital due to a multi-institutional study. Lastly, we did not investigate anal function and quality of life after surgery, and did not assess patients' satisfaction with the treatment. Our study showed that local excision may be a possible treatment option for cTis-2N0 anal squamous cell carcinoma, as OS in the LE group was comparable to that in the RS group probably owing to salvage therapy for locoregional lesions that accounted for the majority of recurrent cases. Given the high risk of recurrence in cases showing muscular invasion, it may be important to perform close surveillance and to consider additional treatment in such patients. Declarations Acknowledgements The authors thank Dr. Koji Komori (Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Aichi), Dr. Akio Shiomi (Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka), Dr. Masashi Ueno (Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo), Dr. Masaaki Ito (Department of Colorectal Surgery, National Cancer Center Hospital East, Chiba), Dr. Koya Hida (Department of Surgery, Kyoto University Hospital, Kyoto), Dr. Seiichiro Yamamoto (Department of Gastroenterological Surgery, Tokai University School of Medicine, Kanagawa), Dr. Manabu Shiozawa (Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Kanagawa), Dr. Yukihide Kanemitsu (Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo), Dr. Hideki Ueno (Department of Surgery, National Defense Medical College, Saitama), Dr. Tatsuya Kinjo (Department of Digestive and General Surgery, Graduate School of Medicine, University of Ryukyus, Okinawa,), Dr. Kotaro Maeda (International Medical Center, Fujita Health University Hospital, Aichi), Dr. Junichiro Kawamura (Department of Surgery, Kindai University Faculty of Medicine, Osaka), Dr. Fumihiko Fujita (Department of Surgery, Kurume University School of Medicine, Fukuoka), Dr. Keiichi Takahashi (Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo), Dr. Tsunekazu Mizushima (Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka), Dr. Yasuhiro Shimada (Department of Clinical Oncology, Kochi Health Sciences Center, Kochi), Dr. Shin Sasaki (Department of Coloproctological Surgery, Japanese Red Cross Medical Center, Tokyo), Dr. Eiji Sunami (Department of Surgery, Kyorin University Faculty of Medicine, Tokyo), Dr. Fumio Ishida (Digestive Disease Center, Showa University Northern Yokohama Hospital, Kanagawa), Dr. Keiji Hirata (Department of Surgery1, School of Medicine, University of Occupational and Environmental Health, Fukuoka), Dr. Shinobu Ohnuma (Department of Surgery, Tohoku University Graduate School of Medicine, Miyagi), Dr. Kimihiko Funahashi (Department of Gastroenterological Surgery, Toho University Omori Medical Center, Tokyo), Dr. Jun Watanabe (Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Kanagawa), Dr. Yusuke Kinugasa (Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo), Dr. Shigeki Yamaguchi (Department of Gastroenterological Surgery, Saitama Medical University International Medical Center, Saitama), Dr. Yojiro Hashiguchi (Department of Surgery, Teikyo University School of Medicine, Tokyo), Dr. Masataka Ikeda (Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Hyogo), Dr. Takeshi Sudo (Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata), Dr. Yoshito Komatsu (Department of Cancer Center, Hokkaido University Hospital, Hokkaido), Dr. Keiji Koda (Department of Surgery, Teikyo University Chiba Medical Center, Chiba), Dr. Kazuhiro Sakamoto (Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo,), Dr. Masazumi Okajima (Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima), Dr. Hideyuki Ishida (Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama), Dr. Yuichi Hisamatsu (Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka), Dr. Taiki Masuda (Department of Surgery, Tokyo Metropolitan Hiroo Hospital, Tokyo), Dr. Shinichiro Mori (Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine and Dental Sciences, Kagoshima University, Kagoshima), Dr. Kazuhito Minami (Department of Surgery, Matsuyama Red Cross Hospital, Ehime), Dr. Seiji Hasegawa (Department of Surgery, Saiseikai Yokohamashi Nanbu Hospital, Kanagawa), Dr. Shungo Endo (Department of Coloproctology, Aizu Medical Center, Fukushima Medical University, Fukushima), Dr. Akinori Iwashita (Department of Pathology, Fukuoka University Chikushi Hospital, Fukuoka), Dr. Madoka Hamada (Division of Gastrointestinal Surgery, Kansai Medical University Hospital, Osaka), Dr. Koichiro Usuku and Dr. Tokunori Ikeda (Department of Medical Information Sciences and Administration Planning, Kumamoto University Hospital, Kumamoto), Dr. Kenichi Sugihara (Tokyo Medical and Dental University, Tokyo), Japanese Society for Cancer of the Colon and Rectum Committee (JSCCR) members. This study was conducted as part of JSCCR's research on the pathophysiology and staging of anal canal cancer. Conflict of interest The authors declare that they have no conflict of interest. Author contributions All authors contributed to the conception and design; acquisition of data, analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published Ethical approval This study was approved by the Institutional Review Board of the Japanese Society for Cancer of the Colon and Rectum. This study was also approved by the Hospital Review Board of each hospital. Informed consent was obtained using an “opt-out” method under the approval of the ethics committee. The study was performed in accordance with the Declaration of Helsinki. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. References Yamada K, Saiki Y, Komori K, Shiomi A, Ueno M, Ito M, Hida K, Yamamoto S, Shiozawa M, Ishihara S, Kanemitsu Y, Ueno H, Kinjo T, Maeda K, Kawamura J, Fujita F, Takahashi K, Mizushima T, Shimada Y, Sasaki S, Sunami E, Ishida F, Hirata K, Ohnuma S, Funahashi K, Watanabe J, Kinugasa Y, Yamaguchi S, Hashiguchi Y, Ikeda M, Sudo T, Komatsu Y, Koda K, Sakamoto K, Okajima M, Ishida H, Hisamatsu Y, Masuda T, Mori S, Minami K, Hasegawa S, Endo S, Iwashita A, Hamada M, Ajioka Y, Usuku K, Ikeda T, Sugihara K (2022) Characteristics of anal canal cancer in Japan. Cancer Med. 10.1002/cam4.4631 Nigro ND, Vaitkevicius VK, Considine B Jr. (1974) Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 17(3):354–356. 10.1007/bf02586980 Rao S, Guren MG, Khan K, Brown G, Renehan AG, Steigen SE, Deutsch E, Martinelli E, Arnold D (2021) Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol 32(9):1087–1100. 10.1016/j.annonc.2021.06.015 Pan YB, Maeda Y, Wilson A, Glynne-Jones R, Vaizey CJ (2018) Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review. Acta Oncol 57(11):1427–1437. 10.1080/0284186x.2018.1503713 Sauter C, Peeken JC, Borm K, Diehl C, Münch S, Combs SE, Dapper H (2022) Quality of life in patients treated with radiochemotherapy for primary diagnosis of anal cancer. Sci Rep 12(1). 10.1038/s41598-022-08525-1 Rombouts AJM, Hugen N, Elferink MAG, Poortmans PMP, Nagtegaal ID, de Wilt JHW (2020) Increased risk for second primary rectal cancer after pelvic radiation therapy. Eur J Cancer 124:142–151. 10.1016/j.ejca.2019.10.022 Miller E, Bazan J (2021) De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus. Cancers 13(9):2099. 10.3390/cancers13092099 Portale G, Parotto M, Pozza A, Scarpa M, Cavallin F (2022) Chemoradiation vs. local excision in the management of early squamous cell carcinoma of the anus: a systematic review. Int J Colorectal Dis 37(9):1937–1944. 10.1007/s00384-022-04241-4 Maccabe TA, Parwaiz I, Longman RJ, Thomas MG, Messenger DE (2021) Outcomes following local excision of early anal squamous cell carcinomas of the anal canal and perianal margin. Colorectal Dis 23(3):689–697. 10.1111/codi.15424 Leon O, Hagberg O, Johnsson A (2018) Primary surgery with or without postoperative radiotherapy in early stage squamous cell carcinoma in the anal canal and anal margin. Acta Oncol 57(9):1209–1215. 10.1080/0284186x.2018.1442931 Tables Table 1. Patient demographics and tumor characteristics in CRT and Surgical therapy groups CRT Surgical therapy P-value Number of patients 87 39 Sex Male 24 (28%) 14 (36%) 0.35 Age, year Median 65 67 0.42 cT stage cTis 1 (1%) 6 (15%) 0.008 cT1 37 (43%) 14 (36%) cT2 49 (56%) 19 (49%) Histology Well or mod 30 (34%) 18 (46%) 0.38 Others 13 (15%) 13 (33%) Unknown 44 (51%) 9 (21%) CRT: chemoradiation therapy well: well differentiated mod: moderately differentiated others: poorly differentiated, adenosquamous or basaloid Table 2. Patient demographics and tumor characteristics in Local excision and Radical surgery groups Local excision Radical surgery P-value Number of patients 23 16 Sex Male 10 (43%) 4 (25%) 0.23 Age, year Median 68 65 0.38 Location Anal canal 17 (74%) 15 (93%) 0.16 Anal margin 5 (26%) 1 (7%) cT stage cTis 6 (26%) 0 (0%) 0.013 cT1 9 (35%) 5 (31%) cT2 8 (39%) 11 (69%) pT stage pTis 5 (22%) 0 (0%) 0.031 pT1 8 (35%) 4 (25%) pT2 9 (39%) 12 (75%) pT3 1 (4%) 0 (0%) pT4 0 (0%) 0 (0%) pN stage pN0 0 (0%) 7 (44%) N/E pN1 0 (0%) 3 (19%) pNX 23 (100%) 6 (37%) Histology Well or mod 9 (39%) 9 (56%) 0.65 Others 5 (22%) 7 (44%) Unknown 9 (39%) 0 (0%) Lymphatic invasion Absent 14 (61%) 8 (50%) 0.50 Vascular invasion Absent 16 (70%) 7 (44%) 0.11 Muscular invasion Absent 17(74%) 3(18%) 0.0001 Adjuvant therapy Yes 5 (22%) 2 (13%) 0.45 N/E: not evaluated well: well differentiated mod: moderately differentiated others: poorly differentiated, adenosquamous or basaloid Table 3. Recurrence in surgical therapy group Local excision Radical surgery (n=23) (n=16) No. of patients with recurrence 7 (30%) 3 (19%) Recurrence site Locoregional Pelvic/perineal 4 (17%) 2 (13%) Inguinal lymph nodes 2 (9%) 0 (0%) Distant Para-aortic lymph nodes 1 (4%) 0 (0%) Liver 0 (0%) 1 (6%) Lung 0 (0%) 0 (0%) Follow up, months Median 40 72 Table 4. Recurrence risk in Local excision group Univariate analysis HR 95% CI P-value Sex Male vs Female 0.86 0.20–3.61 0.83 cT cTis-1 vs cT2 0.57 0.14–2.27 0.42 pT pTis-1 vs pT2 0.75 0.19–3.04 0.69 Histology Well or mod vs Others 0.48 0.12–1.95 0.31 Lymphatic invasion Present vs Absent 1.19 0.28–4.97 0.82 Vascular invasion Present vs Absent 0.79 0.16–3.97 0.78 Muscular invasion Present vs Absent 22.91 2.05–256.6 0.011 Adjuvant therapy Yes vs No 0.82 0.16–4.11 0.81 HR: hazard ratio CI: confidence interval well: well differentiated mod: moderately differentiated others: poorly differentiated, adenosquamous or basaloid Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 13 Nov, 2023 Reviewers agreed at journal 28 Oct, 2023 Reviewers invited by journal 27 Oct, 2023 Editor assigned by journal 26 Oct, 2023 First submitted to journal 22 Oct, 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. 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Nagai","email":"","orcid":"","institution":"University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuzo","middleName":"","lastName":"Nagai","suffix":""},{"id":243490258,"identity":"9ae7644e-5593-4fca-87cf-5524ff3d5af3","order_by":11,"name":"Yuichiro Yoshioka","email":"","orcid":"","institution":"University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuichiro","middleName":"","lastName":"Yoshioka","suffix":""},{"id":243490259,"identity":"576ac886-925c-40de-b878-f6ea4f071c73","order_by":12,"name":"Takahide Shinagawa","email":"","orcid":"","institution":"University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takahide","middleName":"","lastName":"Shinagawa","suffix":""},{"id":243490260,"identity":"994547d5-3733-4d24-8861-5a729175853e","order_by":13,"name":"Hirofumi Sonoda","email":"","orcid":"","institution":"University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hirofumi","middleName":"","lastName":"Sonoda","suffix":""},{"id":243490261,"identity":"6e547c8c-136f-40fa-8836-0ca1d0012c6b","order_by":14,"name":"Kenichi Sugihara","email":"","orcid":"","institution":"Tokyo Medical and Dental University Hospital: Tokyo Ika Shika Daigaku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kenichi","middleName":"","lastName":"Sugihara","suffix":""},{"id":243490262,"identity":"a1a80f61-4bdc-41a8-b2c7-21c45e54e7cf","order_by":15,"name":"Yoichi Ajioka","email":"","orcid":"","institution":"Niigata University Faculty of Medicine Graduate School of Medical and Dental Science: Niigata Daigaku Igakubu Igakuka Daigakuin Ishigaku Sogo Kenkyuka","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoichi","middleName":"","lastName":"Ajioka","suffix":""},{"id":243490263,"identity":"df85878f-e834-4f6d-8dd5-037211039e18","order_by":16,"name":"Soichiro Ishihara","email":"","orcid":"","institution":"University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Soichiro","middleName":"","lastName":"Ishihara","suffix":""}],"badges":[],"createdAt":"2023-10-23 13:50:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3481888/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3481888/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-024-02498-z","type":"published","date":"2024-03-25T15:01:11+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":45486286,"identity":"f8cefb8b-f4c1-4864-9e65-5f0281dec9cc","added_by":"auto","created_at":"2023-10-30 21:53:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":94737,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study cohort. Patients were first classified into the chemoradiation therapy (CRT) and surgical therapy groups according to the initial therapy, and the latter was further divided into local excision (LE) and radical surgery (RS) groups.\u003c/p\u003e","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3481888/v1/893b10d8eb269acdb0f21671.png"},{"id":45486288,"identity":"4745d175-9ead-4785-b241-088aec503e54","added_by":"auto","created_at":"2023-10-30 21:53:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":166576,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. \u003c/strong\u003eRelapse-free survival (RFS) in patients with cTis-2N0 anal squamous carcinoma. Bold line indicates RFS curve for surgical therapy group, and dashed line indicates RFS curve for CRT group. \u003cstrong\u003eB. \u003c/strong\u003eOverall survival (OS) in patients with cTis-2N0 anal squamous carcinoma. Bold line indicates OS curve for surgical therapy group, and dashed line indicates OS curve for CRT group.\u003c/p\u003e","description":"","filename":"OnlineFig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3481888/v1/d3aded854f106bfc2df73ec4.png"},{"id":45486289,"identity":"6b31a49b-93c3-4e6b-b360-2e688900e3f2","added_by":"auto","created_at":"2023-10-30 21:53:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":148411,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. \u003c/strong\u003eRelapse-free survival (RFS) in patients with cTis-2N0 anal squamous carcinoma. Bold line indicates RFS curve for local excision (LE) group, and dashed line indicates RFS curve for radical surgery (RS) group.\u003cstrong\u003e B. \u003c/strong\u003eOverall survival (OS) in patients with cTis-2N0 anal squamous carcinoma. Bold line indicates OS curve for local excision (LE) group, and dashed line indicates OS curve for radical surgery (RS) group.\u003c/p\u003e","description":"","filename":"OnlineFig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3481888/v1/790194e707bfe996aa947fb5.png"},{"id":53869806,"identity":"143fd16c-b3dc-42f1-b5d1-7fa5876a025e","added_by":"auto","created_at":"2024-04-01 15:11:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":583574,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3481888/v1/c663c1b1-64df-4178-9925-999640f110da.pdf"}],"financialInterests":"","formattedTitle":"Local excision versus radical surgery for anal squamous cell carcinoma –a multicenter study in Japan-","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnal squamous cell cancer is an uncommon tumor that represents 4% of all cancers in the lower gastrointestinal tract\u0026nbsp;[1]. In 1970s, radical surgery such as APR (abdominoperineal resection) was the mainstay of treatment for anal cancer. In 1980s, Nigro et al. performed chemoradiation therapy (CRT) for anal cancer which provided good prognosis and obviated permanent stoma in advanced stage patients. Based on the results, there was a paradigm shift from surgical therapy to CRT in the treatment of anal cancer\u0026nbsp;[2] [3]. However, no studies directly compared radical surgery and CRT. Moreover, there are several concerns in implementing CRT. Late complications related to CRT can be problematic, including chronic diarrhea, fecal incontinence, and sexual dysfunction [4] [5]. Additionally, CRT is a risk for secondary carcinogenesis [6]. Therefore, there is an argument that CRT may be over-treatment for early-stage anal cancer [7]. In fact, satisfactory long-term outcomes of local excision for cT1N0 anal cancer were recently demonstrated [8].\u003c/p\u003e\n\u003cp\u003eRegarding cT2N0 anal cancers, only a couple of studies investigated the outcomes of local excision. One study concluded that local excision in cT2 tumors is not recommended due to insufficient margins [9], whereas the other argued that local excision is acceptable for cT1-2 cases because postoperative radiation therapy (RT)/CRT improves the prognosis [10]. These outcomes of local excision were not compared to those of other treatment strategies in both studies.\u003c/p\u003e\n\u003cp\u003eIn this study, we first addressed whether surgical therapy and CRT provide comparable prognosis for early-stage anal cancer including cTis-2N0 cases. Then, by confining the study subject to patients receiving surgical therapy, we compared outcomes of radical surgery and local excision to determine whether the latter treatment is feasible and pragmatic.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 436 patients with anal canal squamous cell carcinoma were treated at 47 tertiary centers in Japan (listed in Acknowledgements) between 1991 and 2015. Among these, 126 patients with cTis-2N0 anal canal squamous cell carcinoma were enrolled in this study. Disease was staged according to the UICC TNM classification (8\u003csup\u003eth\u003c/sup\u003e edition) [15]. Patients were first classified into the CRT group and \u0026lsquo;Surgical therapy\u0026rsquo; group according to the initial therapy, and the latter was further divided into \u0026lsquo;Local excision (LE)\u0026rsquo; and \u0026lsquo;Radical surgery (RS)\u0026rsquo; groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent to conduct the research was provided by the JSCCR ethical committee.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOutcome measurements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eClinical parameters including sex and age, clinical T stage, and pathological differentiation of tumor were compared between the CRT group and Surgical therapy group.\u003c/p\u003e\n\u003cp\u003eThe same clinical parameters and pathological findings such as histological type, pathological T and N stage, lymphocytic invasion and venous invasion were compared between the LE group and RS group. Recurrence types were classified into locoregional recurrence and distant metastasis. Locoregional recurrence included pelvic, perineal, and inguinal lymph nodal recurrence. Distant metastasis was defined as recurrence in organs other than the local. Relapse-free survival (RFS) was defined as time between the date of surgery and relapse. Overall survival (OS) was defined as time between the starting date of initial therapy and death from any causes. RFS and OS were compared between the CRT group and Surgical therapy group, and also compared between the LE group and RS group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn un-paired t test was used to compare continuous variables and the Yates\u0026rsquo; correction or Fisher\u0026rsquo;s exact test was used to compare categorical data. RFS rate was estimated using the Kaplan-Meier method and compared with the log-rank test. All analyses were performed with the JMP 15.0 software program (SAS Institute, Inc., Cary, NC, USA), and differences with a p \u0026lt;0.05 were considered significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong 126 patients with cTis-2N0 anal canal squamous cell carcinoma enrolled in this study, 87 and 39 patients were classified to the CRT group and Surgical therapy group, respectively. Moreover, 23 patients were classified to the LE group, and 16 patients to the RS group (Fig. 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eComparison of the CRT and Surgical therapy groups\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBackground characteristics in the CRT group and Surgical therapy group were shown in Table 1. Clinical T stage in the CRT group was more advanced than in the surgical therapy group (p=0.008). There was no significant difference in other parameters.\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in RFS between the CRT group and Surgical therapy group (p=0.29). The 5-year RFS was 79% for the CRT group and 67% for the surgical therapy group (Fig. 2). In addition, OS was comparable between the CRT group and Surgical therapy group (p=0.94). The 5-year OS was 85% for the CRT group and 87% for the surgical therapy group (Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eComparison of the LE and RS groups\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics in the LE group and RS group were shown in Table 2. Clinical T stage in the RS group were more advanced than in the LE (p=0.01). On the other hands, the LE group showed a broader range of pT stage than the RS group (p=0.003). Approximately 20% of the RS group showed regional node metastasis. More patients (74%) in the RS group showed muscular\u0026nbsp;invasion compared to the LE group (18%, p=0.0001). There was no significant difference in other parameters.\u003c/p\u003e\n\u003cp\u003eRFS curves in the LE and RS groups overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p=0.33). The 5-year RFS rate was 55.3% for the LE group and 71.9% for the RS group. By contrast, there was no significant difference in OS between the two groups (p=0.98). The 5-year OS rate was 87% for the LE group and 88% for the RS group (Fig. 3).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRecurrence pattern in the LE and RS groups\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSeven patients (30%) relapsed in the LE group with the median follow up of 40 months, whereas three patients (19%) relapsed in the RS group (median follow up: 72 months, Table 3). Recurrence rate after LE was 27% for cTis-1 disease (4 of 15 patients) and 38% for cT2 disease (3 of 8 patients, p=0.66). All 10 patients with recurrence in both groups had primary cancer of the anal canal. One patient in each group developed distant metastasis. A male patient in the LE group had recurrence in para-aortic lymph nodes, and received radiotherapy. A female patient in the RS group had liver metastasis, and moved to another hospital.\u003c/p\u003e\n\u003cp\u003eIn the LE group, two patients with inguinal nodal metastases underwent nodal dissection. Locoregional recurrence was treated by rectal amputation in two patients and CRT in one patient. One female patient with locoregional recurrence in LE group was advised to receive CRT, but she preferred to be followed with palliative care. In the RS group, one patient with iliac nodal metastases underwent radiation therapy, and another with perineal recurrence received additional local excision followed by radiation therapy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRecurrence risk in the LE group\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFinally, we investigated factors associated with recurrence in patients of the LE groups. The presence of muscular invasion was the only risk factor for recurrence (hazard ratio: 22.91, 95% confidence interval: 2.05\u0026ndash;256.6, p=0.011, Table 4). Other parameter had no significant associations with recurrence.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere were a limited number of studies that investigated the outcomes between CRT and surgical treatment for anal squamous cell cancer; regarding cT1 disease, there was accumulating evidence that local excision is comparable to CRT in terms of prognosis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, for tumors of the anal canal origins, there is a concern that an adequate margin of dissection may not be obtained [13] [14]. The National Comprehensive Cancer Network guidelines recommend local excision only for cT1N0 lesions localized in the anal margin [16]. On the other hand, only a few reports investigated the efficacy of local excision for cT2N0 anal cancer [13] [14]. However, outcomes of CRT vs surgical treatment were not directly compared in the literature including the above studies [13] [14]. In our study, there was no difference in RFS and OS between CRT and surgical therapy for cTis-2N0 anal cancer (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Thus, both CRT and surgical therapy may be recommended in patients with anal cancer of these early stages.\u003c/p\u003e \u003cp\u003eNo previous reports compared the prognosis of LE and RS. Patients in the LE and RS groups showed comparable RFS for first three years, but the LE group was more likely to develop recurrence thereafter in our study (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The majority of patients in the LE group (86%) had locoregional recurrence (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Moreover, it was considered that all locoregional recurrent lesions could be potentially managed by CRT or salvage surgery in the LE group. Despite of the discrimination of RFS curve beyond 3 years after surgery in the LE and RS groups, OS curves of both groups were almost identical. The results suggest that effective salvage treatment contributed to a good prognosis even in recurrent cases in the LE group. To prescribe salvage therapy in a timely manner,\u003c/p\u003e \u003cp\u003eclose surveillance may be necessary for a long period in the LE group.\u003c/p\u003e \u003cp\u003eMaccabe et al. reported that R1 resection rate in local excision was 54% for tumors of the anal margin and 93% for tumors of the anal canal [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. They also reported that there was no difference in recurrence rate between the anal margin and anal canal origins, as adjuvant therapy was usually performed in cases with inadequate resection margin [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Similarly, Leon et al. also reported that postoperative RT/CRT after local excision improved OS and disease-free survival in patients who underwent local excision with positive resection margin [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These results suggested that recurrence in anal cancer may be manageable if appropriate adjuvant therapy is performed. In contrast, only a few patients received adjuvant therapy in the LE group in our cohort. In addition, recurrence after local excision was observed exclusively in cases of anal canal cancer. We imagine that R1 resection rate in cancer of the anal canal might be higher than these of the anal margin, although we do not have available information on surgical margin.\u003c/p\u003e \u003cp\u003eRegarding the relationship between pathological findings and prognosis after local excision, Maccabe et al. reported that anal cancer with lymphovascular invasion carried a high risk for recurrence, but muscular invasion was not examined [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. On the other hand, we demonstrated that muscular invasion was a risk factor for recurrence in anal cancer (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Alana et al. reported that anal superficially invasive squamous-cell carcinoma (SISCCA), defined as an invasive lesion within 3 mm vertically and 7 mm horizontally, showed a good prognosis when treated by local excision [17]. However, it is difficult to make a correct diagnosis of SISCCA preoperatively. In contrast, muscular infiltration of the tumor may be evaluated preoperatively with endoscopic ultrasound and magnetic resonance imaging [18] [19].\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, this study is a retrospective study, examining a small number of patients. Second, our database lacked information on resection margin. Third, the initial treatment at diagnosis and treatment at the time of recurrence depended on the discretion at each hospital due to a multi-institutional study. Lastly, we did not investigate anal function and quality of life after surgery, and did not assess patients' satisfaction with the treatment.\u003c/p\u003e \u003cp\u003eOur study showed that local excision may be a possible treatment option for cTis-2N0 anal squamous cell carcinoma, as OS in the LE group was comparable to that in the RS group probably owing to salvage therapy for locoregional lesions that accounted for the majority of recurrent cases. Given the high risk of recurrence in cases showing muscular invasion, it may be important to perform close surveillance and to consider additional treatment in such patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Dr. Koji Komori (Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Aichi), Dr. Akio Shiomi (Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka), Dr. Masashi Ueno (Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo), Dr. Masaaki Ito (Department of Colorectal Surgery, National Cancer Center Hospital East, Chiba), Dr. Koya Hida (Department of Surgery, Kyoto University Hospital, Kyoto), Dr. Seiichiro Yamamoto (Department of Gastroenterological Surgery, Tokai University School of Medicine, Kanagawa), Dr. Manabu Shiozawa (Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Kanagawa), Dr. Yukihide Kanemitsu (Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo), Dr. Hideki Ueno (Department of Surgery, National Defense Medical College, Saitama), Dr. Tatsuya Kinjo (Department of Digestive and General Surgery, Graduate School of Medicine, University of Ryukyus, Okinawa,), Dr. Kotaro Maeda (International Medical Center, Fujita Health University Hospital, Aichi), Dr. Junichiro Kawamura (Department of Surgery, Kindai University Faculty of Medicine, Osaka), Dr. Fumihiko Fujita (Department of Surgery, Kurume University School of Medicine, Fukuoka), Dr. Keiichi Takahashi (Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo), Dr. Tsunekazu Mizushima (Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka), Dr. Yasuhiro Shimada (Department of Clinical Oncology, Kochi Health Sciences Center, Kochi), Dr. Shin Sasaki (Department of Coloproctological Surgery, Japanese Red Cross Medical Center, Tokyo), Dr. Eiji Sunami (Department of Surgery, Kyorin University Faculty of Medicine, Tokyo), Dr. Fumio Ishida (Digestive Disease Center, Showa University Northern Yokohama Hospital, Kanagawa), Dr. Keiji Hirata (Department of Surgery1, School of Medicine, University of Occupational and Environmental Health, Fukuoka), Dr. Shinobu Ohnuma (Department of Surgery, Tohoku University Graduate School of Medicine, Miyagi), Dr. Kimihiko Funahashi (Department of Gastroenterological Surgery, Toho University Omori Medical Center, Tokyo), Dr. Jun Watanabe (Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Kanagawa), Dr. Yusuke Kinugasa (Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo), Dr. Shigeki Yamaguchi (Department of Gastroenterological Surgery, Saitama Medical University International Medical Center, Saitama), Dr. Yojiro Hashiguchi (Department of Surgery, Teikyo University School of Medicine, Tokyo), Dr. Masataka Ikeda (Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Hyogo), Dr. Takeshi Sudo (Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata), Dr. Yoshito Komatsu (Department of Cancer Center, Hokkaido University Hospital, Hokkaido), Dr. Keiji Koda (Department of Surgery, Teikyo University Chiba Medical Center, Chiba), Dr. Kazuhiro Sakamoto (Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo,), Dr. Masazumi Okajima (Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima), Dr. Hideyuki Ishida (Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama), Dr. Yuichi Hisamatsu (Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka), Dr. Taiki Masuda (Department of Surgery, Tokyo Metropolitan Hiroo Hospital, Tokyo), Dr. Shinichiro Mori (Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine and Dental Sciences, Kagoshima University, Kagoshima), Dr. Kazuhito Minami (Department of Surgery, Matsuyama Red Cross Hospital, Ehime), Dr. Seiji Hasegawa (Department of Surgery, Saiseikai Yokohamashi Nanbu Hospital, Kanagawa), Dr. Shungo Endo (Department of Coloproctology, Aizu Medical Center, Fukushima Medical University, Fukushima), Dr. Akinori Iwashita (Department of Pathology, Fukuoka University Chikushi Hospital, Fukuoka), Dr. Madoka Hamada (Division of Gastrointestinal Surgery, Kansai Medical University Hospital, Osaka), Dr. Koichiro Usuku and Dr. Tokunori Ikeda (Department of Medical Information Sciences and Administration Planning, Kumamoto University Hospital, Kumamoto), Dr. Kenichi Sugihara (Tokyo Medical and Dental University, Tokyo), Japanese Society for Cancer of the Colon and Rectum Committee (JSCCR) members. This study was conducted as part of JSCCR\u0026apos;s research on the pathophysiology and staging of anal canal cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conception and design; acquisition of data, analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of the\u0026nbsp;Japanese Society for Cancer of the Colon and Rectum. This study was also approved by the Hospital Review Board of each hospital. Informed consent was obtained using an \u0026ldquo;opt-out\u0026rdquo; method under the approval of the ethics committee. The study was performed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYamada K, Saiki Y, Komori K, Shiomi A, Ueno M, Ito M, Hida K, Yamamoto S, Shiozawa M, Ishihara S, Kanemitsu Y, Ueno H, Kinjo T, Maeda K, Kawamura J, Fujita F, Takahashi K, Mizushima T, Shimada Y, Sasaki S, Sunami E, Ishida F, Hirata K, Ohnuma S, Funahashi K, Watanabe J, Kinugasa Y, Yamaguchi S, Hashiguchi Y, Ikeda M, Sudo T, Komatsu Y, Koda K, Sakamoto K, Okajima M, Ishida H, Hisamatsu Y, Masuda T, Mori S, Minami K, Hasegawa S, Endo S, Iwashita A, Hamada M, Ajioka Y, Usuku K, Ikeda T, Sugihara K (2022) Characteristics of anal canal cancer in Japan. Cancer Med. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cam4.4631\u003c/span\u003e\u003cspan address=\"10.1002/cam4.4631\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNigro ND, Vaitkevicius VK, Considine B Jr. (1974) Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 17(3):354\u0026ndash;356. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/bf02586980\u003c/span\u003e\u003cspan address=\"10.1007/bf02586980\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRao S, Guren MG, Khan K, Brown G, Renehan AG, Steigen SE, Deutsch E, Martinelli E, Arnold D (2021) Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol 32(9):1087\u0026ndash;1100. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annonc.2021.06.015\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2021.06.015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan YB, Maeda Y, Wilson A, Glynne-Jones R, Vaizey CJ (2018) Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review. Acta Oncol 57(11):1427\u0026ndash;1437. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/0284186x.2018.1503713\u003c/span\u003e\u003cspan address=\"10.1080/0284186x.2018.1503713\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSauter C, Peeken JC, Borm K, Diehl C, M\u0026uuml;nch S, Combs SE, Dapper H (2022) Quality of life in patients treated with radiochemotherapy for primary diagnosis of anal cancer. Sci Rep 12(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-022-08525-1\u003c/span\u003e\u003cspan address=\"10.1038/s41598-022-08525-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRombouts AJM, Hugen N, Elferink MAG, Poortmans PMP, Nagtegaal ID, de Wilt JHW (2020) Increased risk for second primary rectal cancer after pelvic radiation therapy. Eur J Cancer 124:142\u0026ndash;151. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejca.2019.10.022\u003c/span\u003e\u003cspan address=\"10.1016/j.ejca.2019.10.022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller E, Bazan J (2021) De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus. Cancers 13(9):2099. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers13092099\u003c/span\u003e\u003cspan address=\"10.3390/cancers13092099\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePortale G, Parotto M, Pozza A, Scarpa M, Cavallin F (2022) Chemoradiation vs. local excision in the management of early squamous cell carcinoma of the anus: a systematic review. Int J Colorectal Dis 37(9):1937\u0026ndash;1944. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00384-022-04241-4\u003c/span\u003e\u003cspan address=\"10.1007/s00384-022-04241-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaccabe TA, Parwaiz I, Longman RJ, Thomas MG, Messenger DE (2021) Outcomes following local excision of early anal squamous cell carcinomas of the anal canal and perianal margin. Colorectal Dis 23(3):689\u0026ndash;697. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/codi.15424\u003c/span\u003e\u003cspan address=\"10.1111/codi.15424\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeon O, Hagberg O, Johnsson A (2018) Primary surgery with or without postoperative radiotherapy in early stage squamous cell carcinoma in the anal canal and anal margin. Acta Oncol 57(9):1209\u0026ndash;1215. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/0284186x.2018.1442931\u003c/span\u003e\u003cspan address=\"10.1080/0284186x.2018.1442931\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Patient demographics and tumor characteristics in CRT and Surgical therapy groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"500\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eCRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eSurgical therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40%\" colspan=\"2\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e24 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e14 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eAge, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003ecT stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003ecTis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e6 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003ecT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e37 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e14 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003ecT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e49 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e19 (49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eWell or mod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e30 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e18 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e13 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e13 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e44 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e9 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCRT: chemoradiation therapy\u003c/p\u003e\n\u003cp\u003ewell: well differentiated\u003c/p\u003e\n\u003cp\u003emod: moderately differentiated\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eothers: poorly differentiated, adenosquamous or basaloid\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Patient demographics and tumor characteristics in Local excision and Radical surgery groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"521\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eLocal excision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eRadical surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.216890595009595%\" colspan=\"2\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e10 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eAge, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eLocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eAnal canal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e17 (74%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e15 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eAnal margin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e5 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e1 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003ecT stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003ecTis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e6 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003ecT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e9 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e5 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003ecT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e8 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e11 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003epT stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epTis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e5 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e8 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e4 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e9 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e12 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003epN stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epN0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e7 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003eN/E\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e3 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003epNX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e23 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e6 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eWell or mod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e9 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e9 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e5 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e7 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e9 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eLymphatic invasion\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e14 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e8 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eVascular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e16 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e7 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eMuscular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e17(74%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e3(18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.2552783109405%\"\u003e\n \u003cp\u003eAdjuvant therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e5 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.961612284069098%\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.859884836852208%\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eN/E: not evaluated\u003c/p\u003e\n\u003cp\u003ewell: well differentiated\u003c/p\u003e\n\u003cp\u003emod: moderately differentiated\u003c/p\u003e\n\u003cp\u003eothers: poorly differentiated, adenosquamous or basaloid\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3. Recurrence in surgical therapy group\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003eLocal excision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003eRadical surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003e(n=23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003e(n=16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"68.19787985865725%\" colspan=\"3\"\u003e\n \u003cp\u003eNo. of patients with recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.607773851590107%\"\u003e\n \u003cp\u003e7 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.19434628975265%\"\u003e\n \u003cp\u003e3 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\n \u003cp\u003eRecurrence site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\n \u003cp\u003eLocoregional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\n \u003cp\u003ePelvic/perineal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003e4 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\n \u003cp\u003eInguinal lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003e2 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\n \u003cp\u003eDistant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\n \u003cp\u003ePara-aortic lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003e1 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.929453262786595%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"18.51851851851852%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.80599647266314%\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57848324514991%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167548500881834%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.33922261484099%\" colspan=\"2\"\u003e\n \u003cp\u003eFollow up, months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.858657243816253%\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.607773851590107%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.19434628975265%\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Recurrence risk in Local excision group\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"540\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.247689463955638%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75970425138632%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.99260628465804%\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003eMale vs Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.20\u0026ndash;3.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003ecT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003ecTis-1 vs cT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.14\u0026ndash;2.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003epT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003epTis-1 vs pT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.19\u0026ndash;3.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003eWell or mod vs Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.12\u0026ndash;1.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003eLymphatic invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003ePresent vs Absent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.28\u0026ndash;4.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003eVascular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003ePresent vs Absent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.16\u0026ndash;3.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003eMuscular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003ePresent vs Absent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e22.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e2.05\u0026ndash;256.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.296296296296298%\"\u003e\n \u003cp\u003eAdjuvant therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.814814814814813%\"\u003e\n \u003cp\u003eYes vs No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.222222222222221%\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.40740740740741%\"\u003e\n \u003cp\u003e0.16\u0026ndash;4.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.25925925925926%\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eHR: hazard ratio\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u003c/p\u003e\n\u003cp\u003ewell: well differentiated\u003c/p\u003e\n\u003cp\u003emod: moderately differentiated\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eothers: poorly differentiated, adenosquamous or basaloid\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":"Anal cancer, Local excision, Radical surgery","lastPublishedDoi":"10.21203/rs.3.rs-3481888/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3481888/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe standard treatment for anal squamous cell carcinoma is chemoradiation therapy (CRT), but there is a possibility of overtreatment for early stage disease. cTisN0 and cT1N0 disease is currently indicated for local excision, but it is unclear whether the indication of local excision can be expanded to cT2N0 disease.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e126 patients with cTis-T2N0 anal cancer treated at 47 centers in Japan between 1991 and 2015 were included. Patients were first classified into the CRT group and surgical therapy group according to the initial therapy, and the latter was further divided into local excision (LE) and radical surgery (RS) groups. We compared prognoses among the groups, and analyzed risk factors for recurrence after local excision.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe CRT group (n\u0026thinsp;=\u0026thinsp;87) and surgical therapy group (n\u0026thinsp;=\u0026thinsp;39) showed no difference in relapse-free survival (p\u0026thinsp;=\u0026thinsp;0.29) and overall survival (p\u0026thinsp;=\u0026thinsp;0.94). Relapse-free survival curves in the LE (n\u0026thinsp;=\u0026thinsp;23) and RS groups (n\u0026thinsp;=\u0026thinsp;16) overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p\u0026thinsp;=\u0026thinsp;0.33). By contrast, there was no difference in overall survival between the two groups (p\u0026thinsp;=\u0026thinsp;0.98). In the LE group, the majority of recurrences distributed in locoregional areas, which could be managed by salvage treatments. Muscular invasion was associated with recurrence after local excision (hazard ratio: 22.91, p\u0026thinsp;=\u0026thinsp;0.011).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eLE may be applied to selected patients with anal cancer of cT2N0 stage. Given the high risk of recurrence in cases with muscular invasion, it may be important to consider close surveillance and additional treatment in such patients.\u003c/p\u003e","manuscriptTitle":"Local excision versus radical surgery for anal squamous cell carcinoma –a multicenter study in Japan-","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-30 21:53:39","doi":"10.21203/rs.3.rs-3481888/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2023-11-13T19:48:15+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-10-28T05:20:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-28T01:23:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-27T01:37:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2023-10-22T23:16:16+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":"f7ad1dd7-15cc-4d84-bdc6-f5578d65a0c0","owner":[],"postedDate":"October 30th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-01T15:08:12+00:00","versionOfRecord":{"articleIdentity":"rs-3481888","link":"https://doi.org/10.1007/s10147-024-02498-z","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2024-03-25 15:01:11","publishedOnDateReadable":"March 25th, 2024"},"versionCreatedAt":"2023-10-30 21:53:39","video":"","vorDoi":"10.1007/s10147-024-02498-z","vorDoiUrl":"https://doi.org/10.1007/s10147-024-02498-z","workflowStages":[]},"version":"v1","identity":"rs-3481888","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3481888","identity":"rs-3481888","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}