Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆

•This ESMO Clinical Practice Guideline provides key recommendations for managing anal cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment, follow-up and survivorship.•Treatment algorithms for locoregional and advanced anal cancer are provided.•Opportunities for personalised medicine in anal cancer are discussed.•Recommendations were compiled by the authors based on available scientific data and the authors' collective expert opinions. Anal cancer is a rare disease that accounts for <1% and <3% of all new cancer diagnoses and gastrointestinal tumours, respectively. The most common histological subtype is squamous-cell carcinoma of the anus (SCCA) with an annual incidence of 0.5-2.0 in 100 000.1Islami F. Ferlay J. Lortet-Tieulent J. et al.International trends in anal cancer incidence rates.Int J Epidemiol. 2017; 46: 924-938PubMed Google Scholar However, the incidence of anal cancer in Europe, Australia and the United States is increasing.1Islami F. Ferlay J. Lortet-Tieulent J. et al.International trends in anal cancer incidence rates.Int J Epidemiol. 2017; 46: 924-938PubMed Google Scholar Globally, there were ∼40 000 new cases of anal cancer estimated in 2012, and in the United States, there has been a more than doubling increase in the reported number of new, age-adjusted cases per 100 000 people per year over last 40 years.1Islami F. Ferlay J. Lortet-Tieulent J. et al.International trends in anal cancer incidence rates.Int J Epidemiol. 2017; 46: 924-938PubMed Google Scholar Five-year overall survival (OS) has increased from a mean estimate of 64% [95% confidence interval (CI) 58% to 71%] in 1980 to 75% (95% CI 70% to 79%) in 2010 (P = 0.046).2Sekhar H. Zwahlen M. Trelle S. et al.Nodal stage migration and prognosis in anal cancer: a systematic review, meta-regression, and simulation study.Lancet Oncol. 2017; 18: 1348-1359Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar SCCA and its precursor lesion, anal intraepithelial neoplasia (AIN), are mostly attributable to human papillomavirus (HPV) infection, which represents the causative agent in 80%-85% of patients (especially the HPV16 and HPV18 subtypes).3Daling J.R. Madeleine M.M. Johnson L.G. et al.Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.Cancer. 2004; 101: 270-280Crossref PubMed Scopus (620) Google Scholar Factors increasing the risk of HPV infection and/or modulating a host response and the persistence of this infection appear to affect the epidemiology of this tumour. Anal intercourse and a high lifetime number of sexual partners increase the risk of persistent HPV infection in men and women, eventually leading to malignancy. Other important risk factors include human immunodeficiency virus (HIV) infection, prior history of anogenital warts, lower genital tract malignancies, immune suppression in transplant recipients, a history of other HPV-related cancers, autoimmune disorders and cigarette smoking.3Daling J.R. Madeleine M.M. Johnson L.G. et al.Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.Cancer. 2004; 101: 270-280Crossref PubMed Scopus (620) Google Scholar, 4de Martel C. Plummer M. Vignat J. et al.Worldwide burden of cancer attributable to HPV by site, country and HPV type.Int J Cancer. 2017; 141: 664-670Crossref PubMed Scopus (783) Google Scholar, 5Bower M. Powles T. Newsom-Davis T. et al.HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome?.J Acquir Immune Defic Syndr. 2004; 37: 1563-1565Crossref PubMed Scopus (159) Google Scholar, 6Edgren G. Sparen P. Risk of anogenital cancer after diagnosis of cervical intraepithelial neoplasia: a prospective population-based study.Lancet Oncol. 2007; 8: 311-316Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Cigarette smoking and HIV infection may also be important in the modulation/persistence of HPV infection and, hence, outcomes from treatment. SCCA often presents with bleeding but diagnosis may be delayed because bleeding is attributed to haemorrhoids. SCCA may also present with any combination of a mass, non-healing ulcer, pain, bleeding, itching, discharge, faecal incontinence and fistulae. Digital anorectal examination is an essential low-cost clinical tool for detection of lesions in the anal area. The diagnosis of anal cancer is made by biopsy-proven histology. The diagnostic algorithm for anal cancer is shown in Figure 1 and the diagnostic work-up for SCCA is shown in Table 1.Table 1Diagnostic work-up of SCCAMandatoryRecommendedOptionalBiopsyHIV testEndo-anal ultrasoundDREPET-CTUltrasound-guided FNA of inguinal nodesComplete medical historyP16/HPV assessmentExamination under anaesthesiaFull clinical examinationHigh-resolution pelvic MRICT of thorax, abdomen and pelvisAnoscopy/proctoscopyGynaecological examinationCT, computed tomography; DRE, digital rectal examination; FNA, fine needle aspiration; HIV, human immunodeficiency virus; HPV, human papillomavirus; MRI, magnetic resonance imaging; PET, positron emission tomography; SCCA, squamous-cell carcinoma of the anus. Open table in a new tab CT, computed tomography; DRE, digital rectal examination; FNA, fine needle aspiration; HIV, human immunodeficiency virus; HPV, human papillomavirus; MRI, magnetic resonance imaging; PET, positron emission tomography; SCCA, squamous-cell carcinoma of the anus. Histological confirmation is mandatory as histopathological entities other than squamous-cell carcinomas (SCCs) are amongst the differentials, including adenocarcinoma, melanoma, gastrointestinal stromal tumours, poorly differentiated neuroendocrine tumours and lymphoma. SCCs can harbour various patterns and interpretation is subject to interobserver variability. Histological sub-classifications of basaloid, transitional, spheroidal and cloacogenic cell cancers have no impact on management, and the recent World Health Organization classification system of anal carcinoma includes all subtypes under the same heading of SCC.7Digestive system tumours.in: WHO Classification of Tumours, Editorial Board WHO Classification of Tumours. Vol 1, 5th ed. World Health Organization, 2019Google Scholar Anal verrucous carcinomas (VCs) are similar to VCs of other sites, and newer studies imply that these lesions are a separate entity not to be included with giant condylomas, also named Buschke–Löwenstein tumours.8Zidar N. Langner C. Odar K. et al.Anal verrucous carcinoma is not related to infection with human papillomaviruses and should be distinguished from giant condyloma (Buschke-Lowenstein tumour).Histopathology. 2017; 70: 938-945Crossref PubMed Scopus (14) Google Scholar VC seems to be unrelated to HPV infections while low-risk HPV genotypes are found in giant condylomas. VCs are regarded as low-grade carcinomas while giant condylomas can be regarded as benign tumours. Histologically, it can be difficult to make a distinction between the two entities but features such as koilocytosis favour condyloma. Occasionally, SCCs arise within giant condylomas. Anal cancer may arise from a precursor dysplastic lesion, also known as squamous AIN. The American Joint Committee on Cancer recommends dividing these lesions into ‘low-grade’ and ‘high-grade’ squamous intraepithelial lesions (LSILs and HSILs, respectively) with AIN stage I corresponding to LSIL and AIN stages II-III corresponding to HSIL.9Darragh T.M. Colgan T.J. Thomas Cox J. et al.The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.Int J Gynecol Pathol. 2013; 32: 76-115Crossref PubMed Scopus (327) Google Scholar The prevalence of AIN in the general population is low, but high-risk sexual behaviour is associated with greater rates of AIN. Further details are described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.annonc.2021.06.015. The anal canal extends from the anorectal junction to the anal margin (see Supplementary Figure S1, available at https://doi.org/10.1016/j.annonc.2021.06.015). Useful landmarks are the puborectal sling and the anal verge which roughly coincide with the inter-sphincteric groove. The columnar, or cylindric epithelium of the rectum, extends to ∼1 cm above the dentate line where the anal transitional zone begins. Below the dentate line, the epithelium is all squamous. Outside the anal verge lies the anal margin. The anal margin is the pigmented skin immediately surrounding the anal orifice, extending laterally to a radius of ∼5 cm. Cancer in the anal margin is regarded as anal cancer, while cancer outside 5 cm from the anus is classified as skin cancer (as shown in Supplementary Tables S1 and S2, available at https://doi.org/10.1016/j.annonc.2021.06.015). Proximally, lymphatic drainage is to perirectal and paravertebral lymph nodes. Immediately above the dentate line, drainage is to internal pudendal nodes and to the internal iliac system. Infra-dentate and perianal skin drains to the inguinal, femoral and external iliac nodes. The existence of an identified viral aetiological agent, biological similarities to cervical cancer and the ability to detect pre-neoplastic lesions may allow the development of screening and prevention programmes. Vaccination against oncogenic HPV is now being recommended for the prevention of cervical cancer, and this may also be of importance for SCCA as infection with HPV is detected in over 90% of invasive anal cancers.10Serrano B. de Sanjose S. Tous S. et al.Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions.Eur J Cancer. 2015; 51: 1732-1741Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 11Baricevic I. He X. Chakrabarty B. et al.High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: different implications for vaccine prevention and prognosis.Eur J Cancer. 2015; 51: 776-785Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 12De Vuyst H. Clifford G.M. Nascimento M.C. et al.Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis.Int J Cancer. 2009; 124: 1626-1636Crossref PubMed Scopus (702) Google Scholar HPV vaccination programmes are expected to result in lower incidence rates of SCCA. There are, however, many unanswered questions, including anal HPV natural history, with unknown factors determining rates of progression and regression of the presumed anal cancer precursor, HSIL. Moreover, performance of anal cytology is debatable and outcomes vary based on training and skills of the operator. Psychological and quality-of-life (QoL) aspects of a screening programme should also be considered. A prospective cohort study exploring the epidemiology of anal HPV infection and related abnormalities in a cohort of gay, bisexual and other men who have sex with men (GBMSM) over 35 years of age showed that patient perception of abnormal results may cause poor health-related QoL 2 weeks after screening.13Cvejic E. Poynten I.M. Kelly P.J. et al.Psychological and utility-based quality of life impact of screening test results for anal precancerous lesions in gay and bisexual men: baseline findings from the Study of the Prevention of Anal Cancer.Sex Transm Infect. 2020; 96: 177-183Crossref PubMed Scopus (5) Google Scholar In summary, screening programmes using anal cytology and high-resolution anoscopy have been proposed for high-risk populations (GBMSM and HIV-negative women with a history of anal intercourse or other HPV-related anogenital malignancies) based on achievements obtained in cervical cytology screening.14Giuliano A.R. Palefsky J.M. Goldstone S. et al.Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males.N Engl J Med. 2011; 364: 401-411Crossref PubMed Scopus (780) Google Scholar,15Kreimer A.R. Gonzalez P. Katki H.A. et al.Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial.Lancet Oncol. 2011; 12: 862-870Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar However, no randomised controlled study has yet demonstrated a preventive effect of screening in these high-risk populations and thus it cannot be routinely advocated at present. •Digital anorectal examination is an essential clinical tool for detection of lesions in the anal area [I, A].•Biopsy is mandatory to confirm SCCA [I, A].•All suspicious anal lesions should be excised or biopsied. Targeted biopsy of anal lesions suspicious for AIN is mandatory in high-risk groups to exclude invasive disease [I, B].•Female patients with AIN should be screened for synchronous cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia and vaginal intraepithelial neoplasia [I, A].•Consider HIV testing in patients with recurrent or multifocal AIN [V, A]. A comprehensive history is required to elicit symptoms, other relevant medical conditions, current medications and predisposing factors, which should all be documented. Examination should include digital rectal examination (DRE) to evaluate the anal lesion and any perirectal nodal involvement and, in women (particularly with low anteriorly placed tumours), a vaginal examination to determine the site and size of the primary tumour, vaginal/vaginal septal involvement, mucosal involvement and exophytic or ulcerative tumour or the presence of a fistula. The presence of a large mass with near obstructing symptoms or a tumour with associated faecal incontinence may require a defunctioning stoma. In women, vaginal involvement may require a prophylactic stoma because of the risk of an anorectal–vaginal fistula. However, since most initial colostomies are not reversed, this decision should be weighed carefully. Palpation of the inguinal nodes is important, particularly superficial inguinal nodes, medial and close to the pubis. Fine needle aspiration (FNA) or biopsy of the suspicious nodes may be considered. Colonoscopy is not required to assess pathology in the proximal bowel because synchronous colonic lesions are not reported for SCCA. HIV testing should be considered in patients with unknown HIV status (see Figure 1). Clinical assessment of the diameter of the tumour has been the modality upon which the TNM (tumour–node–metastasis) classification of SCCA is based (Supplementary Tables S1 and S2, available at https://doi.org/10.1016/j.annonc.2021.06.015).16Brierley J.D. Gospodarowicz M.K. Wittekind C. TNM Classification of Malignant Tumours.8th ed. John Wiley & Sons, Inc, Oxford2016Google Scholar A more detailed assessment of the local tumour and its precise anatomic extent using high-resolution T2-weighted magnetic resonance imaging (MRI) scanning techniques enables optimal assessment [III, A].17Koh D.M. Dzik-Jurasz A. O'Neill B. et al.Pelvic phased-array MR imaging of anal carcinoma before and after chemoradiation.Br J Radiol. 2008; 81: 91-98Crossref PubMed Scopus (43) Google Scholar, 18Kochhar R. Renehan A.G. Mullan D. et al.The assessment of local response using magnetic resonance imaging at 3- and 6-month post chemoradiotherapy in patients with anal cancer.Eur Radiol. 2017; 27: 607-617Crossref PubMed Scopus (20) Google Scholar, 19Gourtsoyianni S. Goh V. MRI of anal cancer: assessing response to definitive chemoradiotherapy.Abdom Imaging. 2014; 39: 2-17Crossref PubMed Scopus (16) Google Scholar, 20Goh V. Gollub F.K. Liaw J. et al.Magnetic resonance imaging assessment of squamous cell carcinoma of the anal canal before and after chemoradiation: can MRI predict for eventual clinical outcome?.Int J Radiat Oncol Biol Phys. 2010; 78: 715-721Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar The tumour needs to be identified in relation to clinical and anatomical landmarks for the purposes of radiotherapy (RT) planning. On MRI, the tumour is shown as a relatively high signal intensity compared with the low signal intensity of the muscle layers that form the internal and external sphincter in the anal canal and the muscularis propria of the rectal wall.17Koh D.M. Dzik-Jurasz A. O'Neill B. et al.Pelvic phased-array MR imaging of anal carcinoma before and after chemoradiation.Br J Radiol. 2008; 81: 91-98Crossref PubMed Scopus (43) Google Scholar,21Salerno G. Daniels I.R. Brown G. Magnetic resonance imaging of the low rectum: defining the radiological anatomy.Colorectal Dis. 2006; 8: 10-13Crossref PubMed Scopus (34) Google Scholar Conventionally, the radiology report should state the relationship of the lower borders of the tumour to the anal margin, the extent with quadrant involvement of the anal canal or rectum, the craniocaudal length of the tumour and its depth of invasion. Any evidence of adjacent T4 organ infiltration such as vagina, prostate, urethra or bladder wall should also be recorded.22Brown G. Rimmer M. Williams S. Colon, rectum and anal canal cancer.in: Vol 2019, 2nd ed. Recommendations for Cross-Sectional Imaging in Cancer Management. The Royal College of Radiologists, London2014Google Scholar In addition, it may be helpful to note the relationship of the tumour/nodes to the sacral segment levels, which would also assist in RT planning [III, B]. The MRI scanning technique uses the same sequences and parameters that have been validated for rectal cancer staging, making use of the anatomic and tumour depiction afforded by high-resolution T2-weighted sequences [III, A].22Brown G. Rimmer M. Williams S. Colon, rectum and anal canal cancer.in: Vol 2019, 2nd ed. Recommendations for Cross-Sectional Imaging in Cancer Management. The Royal College of Radiologists, London2014Google Scholar,23Brown G. Daniels I.R. Richardson C. et al.Techniques and trouble-shooting in high spatial resolution thin slice MRI for rectal cancer.Br J Radiol. 2005; 78: 245-251Crossref PubMed Scopus (109) Google Scholar Scans should also cover both inguinal regions, the pelvic sidewall compartments and the top of the mesorectum to the level of L5 so that the primary tumour, as well as draining nodal disease sites, can be imaged. In addition, the lower border of scans should cover the cutaneous anal margin to enable assessment of the anal margin tumours. Lymph node assessment is notoriously difficult to predict using imaging modalities, and validation of nodal assessment criteria has not been possible due to the paucity of surgical specimens for histopathology correlation. Enlarged inguinal nodes are frequently reactive, and nodes, whether benign or malignant, will reduce in size following pelvic RT. In general, nodes are more likely to be malignant if they exhibit mixed signal intensity; they are also likely to be malignant if breach of the lymph node capsule by tumour signal intensity is observed. These features are best assessed using high-resolution T2-weighted MRI [III, A].17Koh D.M. Dzik-Jurasz A. O'Neill B. et al.Pelvic phased-array MR imaging of anal carcinoma before and after chemoradiation.Br J Radiol. 2008; 81: 91-98Crossref PubMed Scopus (43) Google Scholar Primary tumour assessment has now been superseded by MRI; however, contrast-enhanced computed tomography (CT) scanning of the thorax, abdomen and pelvis is a requirement in all patients to assess potential metastatic disease sites at diagnosis and follow-up [III, A]. Reports have shown that positron emission tomography (PET)-CT with [18F]2-fluoro-2-deoxy-D-glucose (FDG–PET-CT) is able to characterise inguinal lymph nodes, with two studies providing sufficient data to allow analysis of diagnostic information for PET-CT. A meta-analysis published in 2017 concluded that PET-CT seemed to add value to conventional imaging in the initial staging of patients with T2-4 disease but further high-quality research was required to validate this, mainly because the conventional imaging comparators were highly heterogeneous in the studies analysed. However, there was insufficient evidence to recommend the routine use of PET-CT in the assessment of treatment response or follow-up [III, C].24Mahmud A. Poon R. Jonker D. PET imaging in anal canal cancer: a systematic review and meta-analysis.Br J Radiol. 2017; 90: 20170370Crossref PubMed Scopus (35) Google Scholar PET-CT can be used to help confirm suspicious features seen on MRI, particularly if such information will alter the RT plan, for example, in characterising smooth-bordered homogeneous signal intensity enlarged nodes that do not fulfil criteria for malignancy on MRI. Because of the potential additional morbidity from irradiation of the inguinal regions and a high prevalence of enlarged and reactive inguinal lymphadenopathy, further characterisation of enlarged inguinal nodes by ultrasound (US)-guided FNA is helpful when confirmatory features of malignancy are not evident on either MRI or PET-CT scanning [V, C]. Occasionally, an early anal cancer has been inadvertently totally excised before histological confirmation and there is no visible anal tumour on MRI or PET-CT. These are staged as Tx tumours. Reviews of the pathological specimen and of the operative notes are imperative. Commonly these resections are R1 and patients should be considered for chemoradiotherapy (CRT). The presence of HPV infection measured directly or by overexpression of the surrogate marker p16 has a significant effect on patient outcomes. Individuals with HPV-negative tumours are less likely to respond to CRT than those with HPV-positive tumours.25Serup-Hansen E. Linnemann D. Skovrider-Ruminski W. et al.Human papillomavirus genotyping and p16 expression as prognostic factors for patients with American Joint Committee on Cancer stages I to III carcinoma of the anal canal.J Clin Oncol. 2014; 32: 1812-1817Crossref PubMed Scopus (122) Google Scholar, 26Gilbert D.C. Williams A. Allan K. et al.p16INK4A, p53, EGFR expression and KRAS mutation status in squamous cell cancers of the anus: correlation with outcomes following chemo-radiotherapy.Radiother Oncol. 2013; 109: 146-151Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 27Meulendijks D. Tomasoa N.B. Dewit L. et al.HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53.Br J Cancer. 2015; 112: 1358-1366Crossref PubMed Scopus (67) Google Scholar A meta-analysis has shown that patients with HPV-positive/p16-positive tumours have improved disease-free survival (DFS)/disease-specific survival/relapse-free survival (RFS), progression-free survival (PFS) and OS compared with patients with either HPV-negative/p16-positive or HPV-positive/p16-negative tumours.28Sun G. Dong X. Tang X. et al.The prognostic value of HPV combined p16 status in patients with anal squamous cell carcinoma: a meta-analysis.Oncotarget. 2018; 9: 8081-8088Crossref PubMed Scopus (18) Google Scholar The European Organisation for Research and Treatment of Cancer (EORTC) 22861 study demonstrated that skin ulceration, nodal involvement and male sex were independent factors associated with locoregional failure (LRF) and adverse OS.29Bartelink H. Roelofsen F. Eschwege F. et al.Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.J Clin Oncol. 1997; 15: 2040-2049Crossref PubMed Scopus (990) Google Scholar The Radiation Therapy Oncology Group (RTOG) 9811 analysis supported some of the factors previously reported in EORTC 22861 (clinically involved nodes and male sex) and also established tumour diameter of >5 cm as an independent variable predicting DFS and OS.30Flam M. John M. Pajak T.F. et al.Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.J Clin Oncol. 1996; 14: 2527-2539Crossref PubMed Scopus (838) Google Scholar HIV testing is recommended in any patient with a lifestyle that puts them at risk of contracting HIV infection. Recent evidence suggests that, compared with HIV-negative patients, HIV-positive patients treated with highly active antiretroviral therapy may have similar treatment outcomes.31Martin D. Balermpas P. Fokas E. et al.Are there HIV-specific differences for anal cancer patients treated with standard chemoradiotherapy in the era of combined antiretroviral therapy?.Clin Oncol (R Coll Radiol). 2017; 29: 248-255Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar When treating HIV-positive patients with anal cancer, coordinated follow-up with a HIV specialist should be encouraged. Histologically, a high tumour-infiltrating lymphocyte (TIL) count has been found to be significantly associated with RFS in p16-positive tumours.32Gilbert D.C. Serup-Hansen E. Linnemann D. et al.Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer.Br J Cancer. 2016; 114: 134-137Crossref PubMed Scopus (51) Google Scholar The biological understanding of HPV-positive and -negative tumours is increasing and may be of importance for the design of future clinical trials.33Jones C.M. Goh V. Sebag-Montefiore D. et al.Biomarkers in anal cancer: from biological understanding to stratified treatment.Br J Cancer. 2017; 116: 156-162Crossref PubMed Scopus (37) Google Scholar •All patients with anal tumours should be referred and discussed in a multidisciplinary team (MDT) meeting with a pre-specified interest in anal cancer [V, C].•Clinical examination including DRE (and vaginal examination in women) and palpation of the inguinal lymph nodes should be carried out for assessment of tumour extent [V, B].•High-resolution T2-weighted MRI is needed for optimal assessment of primary tumour and lymph nodes [III, A].•MRI may also be helpful to note the relationship of tumour/nodes to the sacral segment levels, which would also assist in RT planning [III, B].•Lymph nodes can be difficult to interpret on MRI. Generally, they are more likely to be malignant if they exhibit mixed signal intensity and if breach of the lymph node capsule by tumour signal intensity is observed on high-resolution T2-weighted MRI [III, A].•Contrast-enhanced CT scanning of the thorax, abdomen and pelvis is a requirement for all patients to assess potential metastatic disease sites at diagnosis and follow-up [III, A].•Further characterisation of enlarged inguinal nodes by US-guided FNA may be helpful when confirmatory features of malignancy are not evident on either MRI or PET-CT [V, C].•PET-CT may be considered for staging and assist in RT planning [III, C].•HIV testing may be considered in at-risk patients [III, C]. Assessment of HPV or p16 status may be considered as they have treatment response predictive value [V, C]. The primary aim of treatment is to achieve cure with locoregional control, preservation of anal function and the best possible QoL. Treatment of anal cancer differs dramatically from that of adenocarcinomas of the lower rectum. Combinations of mitomycin C (MMC) and 5-fluorouracil (5-FU)-based CRT have been established as the standard of care, leading to complete tumour regression in 80%-90% of patients, with LRFs of ∼15%; other cytotoxic agents (mainly cisplatin) can be considered, if clinically indicated.34Nigro N.D. Vaitkevicius V.K. Considine Jr., B. Combined therapy for cancer of the anal canal: a preliminary report.Dis Colon Rectum. 1974; 17: 354-356Crossref PubMed Scopus (749) Google Scholar,35Glynne-Jones R. Nilsson P.J. Aschele C. et al.Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up.Eur J Surg Oncol. 2014; 40: 1165-1176Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar A multidisciplinary approach is mandatory, involving radiation oncologists, medical oncologists, surgeons, radiologists and pathologists. The role of surgery as a salvage treatment is accepted. Recommendations are based on results of phase II and six randomised phase III trials [EORTC 22861, United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) Anal Cancer Trial I (ACT I), RTOG 87-04, RTOG 98-11, ACCORD-03 and Cancer Research United Kingdom (CRUK) ACT II].29Bartelink H. Roelofsen F. Eschwege F. et al.Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.J Clin Oncol. 1997; 15: 2040-2049Crossref PubMed Scopus (990) Google Scholar,30Flam M. John M. Pajak T.F. et al.Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.J Clin Oncol. 1996; 14: 2527-2539Crossref PubMed Scopus (838) Google Scholar,36Northover J. Glynne-Jones R. Sebag-Montefiore D. et al.Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).Br J Cancer. 2010; 102: 1123-1128Crossref PubMed Scopus (249) Google Scholar, 37Peiffert D. Tournier-Rangeard L. Gerard J.P. et al.Induction chemotherapy and dose intensification of the radiation boost in