Abstract
Background
The standard treatment for anal squamous cell carcinoma is chemoradiation therapy (CRT), but there is a possibility of over-treatment 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 cTis-T2N0 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.
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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 abdominoperineal resection (APR) 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 [8,9,10,11,12].
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 [13], whereas the other argued that local excision is acceptable for cT1–2 cases because postoperative radiation therapy (RT)/CRT improves the prognosis [14]. 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 (8th 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 stages, lymphocytic invasion and venous invasion, and resection margin 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. Surgical complications of Clavien–Dindo classification [16] grade 2 or higher were addressed for the LE group, while adverse events of the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [17] grade 2 or higher were reviewed for the CRT 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. Propensity score matching was used to minimize the selection bias due to unbalanced baseline characteristics in cT2 tumors between the CRT and LE groups. The parameters that were different between the two groups and other potential factors that could influence OS including sex, age, histology were selected to create a propensity score ranging from 0 to 1 using a logistic regression model. Then, a one-to-one match between the CRT and LE groups was performed using nearest-neighbor matching with a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score. 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 are 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).
In the LE group, there were no short-term complications of Clavien–Dindo classification grade 2 or higher. Only one female patient (4%) who underwent LE with positive resection margin followed by adjuvant CRT developed anal stenosis 5 years later. On the other hand, 41 of 87 patients (47%) of the CRT group had CTCAE grade 2 or higher adverse events (Table 2).
Comparison of the LE and RS groups
Patient characteristics in the LE group and RS group are shown in Table 3. 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). Five patients in the LE group had a positive resection margin; all underwent adjuvant therapy (ablation in 1, RT in 1, and CRT in 3 patients) and subsequently had no recurrence.
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 4). 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
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 5). Other parameter had no significant associations with recurrence.
Comparison of cT2 tumors in the CRT and LE groups
Finally, the prognosis of cT2 tumors was compared between the CRT and LE groups. The clinical and pathological data of patients in the CRT and LE groups were summarized in Table 6. Before propensity score matching, there was a difference in the proportion of various histologies. We applied a propensity score matching method to create 8 matched pairs from the original cohort to adjust for the bias for survival analyses (Table 6). There was no significant difference in OS between the CRT and LE groups both before and after matching (Fig. 4).
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 [18]. 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). No difference in OS was observed between the treatment groups even in the limited cohort with cT2N0 cancer (Fig. 4). Thus, both CRT and surgical therapy may be recommended in patients with anal cancer of these early stages. Moreover, LE seemed less invasive than CRT, since no perioperative complications related to LE were observed, whereas nearly half of the CRT group experienced CTCAE grade 2 or severer adverse events.
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 4). 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 [13]. 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 [13]. 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 [14]. These results suggested that recurrence in anal cancer may be manageable if appropriate adjuvant therapy is performed. In line with these previous reports, recurrence was evaded by the administration of adjuvant therapy in all cases with positive resection margin of the LE group in this study.
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 [13]. On the other hand, we demonstrated that muscular invasion was a risk factor for recurrence in anal cancer (Table 5). 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 [19]. 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 [20, 21].
This study has several limitations. First, this study is a retrospective study, examining a small number of patients. Especially, the similar prognosis of cT2N0 cancer between the CRT and LE groups, should be evaluated with caution because the very small number of cases might result in a type II error. Second, 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.
Data availability
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 et al (2022) Characteristics of anal canal cancer in Japan. Cancer Med. https://doi.org/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. https://doi.org/10.1007/bf02586980
Rao S, Guren MG, Khan K et al (2021) Anal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up☆. Ann Oncol 32(9):1087–1100. https://doi.org/10.1016/j.annonc.2021.06.015
Pan YB, Maeda Y, Wilson A et al (2018) Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review. Acta Oncol 57(11):1427–1437. https://doi.org/10.1080/0284186x.2018.1503713
Sauter C, Peeken JC, Borm K et al (2022) Quality of life in patients treated with radiochemotherapy for primary diagnosis of anal cancer. Sci Rep. https://doi.org/10.1038/s41598-022-08525-1
Rombouts AJM, Hugen N, Elferink MAG et al (2020) Increased risk for second primary rectal cancer after pelvic radiation therapy. Eur J Cancer 124:142–151. https://doi.org/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. https://doi.org/10.3390/cancers13092099
Portale G, Parotto M, Pozza A et al (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. https://doi.org/10.1007/s00384-022-04241-4
Chai CY, Tran Cao HS, Awad S et al (2018) Management of stage I squamous cell carcinoma of the anal canal. JAMA Surg 153(3):209. https://doi.org/10.1001/jamasurg.2017.3151
Deshmukh AA, Zhao H, Das P et al (2018) Clinical and economic evaluation of treatment strategies for T1N0 anal canal cancer. Am J Clin Oncol 41(7):626–631. https://doi.org/10.1097/coc.0000000000000339
Chakrabarti S, Jin Z, Huffman BM et al (2019) Local excision for patients with stage I anal canal squamous cell carcinoma can be curative. J Gastrointest Oncol 10(2):171–178. https://doi.org/10.21037/jgo.2018.12.12
Gao X, Goffredo P, Kahl AR et al (2020) Chemoradiation versus local excision in treatment of stage I anal squamous cell carcinoma: A population-based analysis. Eur J Surg Oncol 46(9):1663–1667. https://doi.org/10.1016/j.ejso.2020.03.003
Maccabe TA, Parwaiz I, Longman RJ et al (2021) Outcomes following local excision of early anal squamous cell carcinomas of the anal canal and perianal margin. Colorectal Dis 23(3):689–697. https://doi.org/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. https://doi.org/10.1080/0284186x.2018.1442931
Brierley JD, Gospodarowicz MK, Wittekind C (2017) Anal canal and perianal skin. TNM classification of malignant tumours, 8th edn. Wiley Blackwell, New Jersey, pp 77–79
Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240(2):205–213. https://doi.org/10.1097/01.sla.0000133083.54934.ae
National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAEv5.0). In:Cancer Therapy Evaluation Program. National cancer institute. Available via DIALOG. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
Benson AB, Venook AP, Al-Hawary MM et al (2018) Anal carcinoma, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 16(7):852–871. https://doi.org/10.6004/jnccn.2018.0060
Arana R, Fléjou JF, Si-Mohamed A et al (2015) Clinicopathological and virological characteristics of superficially invasive squamous-cell carcinoma of the anus. Colorectal Dis 17(11):965–972. https://doi.org/10.1111/codi.12951
Golia Pernicka JS, Sheedy SP, Ernst RD et al (2019) MR staging of anal cancer: what the radiologist needs to know. Abdominal Radiology 44(11):3726–3739. https://doi.org/10.1007/s00261-019-02020-4
Parikh J, Shaw A, Grant LA et al (2011) Anal carcinomas: the role of endoanal ultrasound and magnetic resonance imaging in staging, response evaluation and follow-up. Eur Radiol 21(4):776–785. https://doi.org/10.1007/s00330-010-1980-7
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.
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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.
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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.
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Murai, S., Nozawa, H., Yamada, K. et al. Local excision versus radical surgery for anal squamous cell carcinoma: a multicenter study in Japan. Int J Clin Oncol 29, 813–821 (2024). https://doi.org/10.1007/s10147-024-02498-z
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DOI: https://doi.org/10.1007/s10147-024-02498-z