Guideline sources The following summarized guidelines for the evaluation and management of anal cancer are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2021), the American Society of Colon and Rectal Surgeons (ASCRS 2018), and the British HIV Association (BHIVA 2014). 1 2 3 Calculator Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s TNM class Guidelines https://web.pathway.md/diseases/recxPhkt7YVf0q1hh 1/6 6/23/23, 2:35 AM Anal cancer Pathway 1. Screening and diagnosis Indications for screening: Consider screening for anal squamous cancer in patients at high risk as part of a comprehensive screening program, using anal cytology or anal Pap test. C Consider screening for anal squamous cancer in patients at high risk, using high-resolution anoscopy, performed by clinicians with appropriate training in the procedure. C 2. Diagnostic investigations Clinical history and physical examination: As per ESMO 2021 guidelines: Perform digital anorectal examination for the detection of lesions in the anal area. A Perform clinical examination including DRE (and vaginal examination in female patients) and palpation of the inguinal lymph nodes for the assessment of tumor extenet. B As per ASCRS 2018 guidelines: Elicit history, perform physical examination and obtain laboratory testing to identify patients at increased risk for anal squamous neoplasms, such as human immunodeficiency virus-positive individuals, MSM, and females with a history of cervical dysplasia. B Elicit a disease-specific history and perform physical examination, emphasizing symptoms, risk factors, and signs of advanced disease. B Diagnostic imaging: As per ESMO 2021 guidelines, obtain high-resolution T2-weighted MRI for optimal assessment of primary tumor and lymph nodes. B Show 4 more As per ASCRS 2018 guidelines, obtain radiologic evaluation to determine tumor extension and assess for metastatic disease. B HPV testing: As per ESMO 2021 guidelines, consider obtaining HPV testing for the prediction of treatment response. C As per ASCRS 2018 guidelines, consider obtaining HPV testing as an adjunct to screening for anal cancer. C HIV testing: consider obtaining human immunodeficiency virus testing in at-risk patients C and in patients with recurrent or multifocal anal intraepithelial neoplasia. B Screening for other intraepithelial neoplasia: screen female patients with anal intraepithelial neoplasia for synchronous cervical, vulvar and vaginal intraepithelial neoplasia. A 3. Diagnostic procedures https://web.pathway.md/diseases/recxPhkt7YVf0q1hh 2/6 6/23/23, 2:35 AM Anal cancer Pathway Endoscopy: perform endoscopic evaluation to determine tumor extension and assess for metastatic disease. B Fine needle aspiration: consider performing US-guided FNA for further characterization of enlarged inguinal lymph nodes when confirmatory features of malignancy are not evident on either MRI or PET-CT. C Biopsy and pathology: As per ESMO 2021 guidelines, perform mandatory biopsy to confirm the diagnosis of SCC of the anus. A Show 2 more As per ASCRS 2018 guidelines: Report pathology specimens using a standardized nomenclature with a 2-tiered system. B Use biomarkers including p16 selectively to clarify equivocal high-grade lesions. B 4. Medical management General principles: As per ESMO 2021 guidelines, refer and discuss all patients with anal tumors in a multidisciplinary team meeting with a pre-specified interest in anal cancer. B As per ASCRS 2018 guidelines: Offer chemoradiotherapy as the primary treatment in all patients with squamous cell cancer of the anal canal, and in most patients with perianal squamous cell cancer. A Offer a combination of 5-fluorouracil and mitomycin C in conjunction with radiotherapy as first- line multimodal therapy in patients with SCC of the anus. A Management of in-situ lesions: Consider offering topical imiquimod, fluorouracil, trichloroacetic acid and cidofovir with close long-term follow-up for the treatment of patients with low-grade or high-grade squamous intraepithelial lesion. C Consider performing ablative therapy with conventional anoscopy or high-resolution anoscopy in patients with high-grade squamous intraepithelial lesion. C Management of local/locoregional disease, indications: As per ESMO 2021 guidelines, offer radiotherapy with concomitant 5-fluorouracil and mitomycin C as standard of care in patients with localized SCC of the anus. A Show 3 more As per ASCRS 2018 guidelines, offer multimodal therapy involving chemotherapy combined with radiotherapy rather than radiotherapy alone for better locoregional control. A Management of local/locoregional disease, radiotherapy techniques and doses: As per ESMO 2021 guidelines, administer chemoradiotherapy with a radiotherapy dose of > 50 Gy in patients with locally advanced anal cancer. Insufficient evidence to recommend optimal radiotherapy doses for different tumor stages. B https://web.pathway.md/diseases/recxPhkt7YVf0q1hh 3/6 6/23/23, 2:35 AM Anal cancer Pathway Show 3 more As per ASCRS 2018 guidelines, do not administer radiation doses of > 59 Gy. D Management of anal margin involvement: As per ESMO 2021 guidelines: Offer chemoradiotherapy in patients with anal margin cancer (T1N0M0) if the margin is 1 mm. B Consider performing local excision for definite treament of patients with early anal margin cancer (cT1N0M0) aiming to achieve histological clearance of > 1 mm without damaging the anal sphincter muscle. C As per ASCRS 2018 guidelines, perform wide-local excision (with 1 cm margins of resection) in patients with well-differentiated, node-negative, T1 perianal squamous cancers. B Show 2 more Management of advanced/metastatic disease: As per ESMO 2021 guidelines, consider offering carboplatin in combination with paclitaxel as standard of care in patients with chemotherpy-na ve advanced anal cancer. B Show 2 more As per ASCRS 2018 guidelines: Consider offering systemic chemotherapy in patients with distant metastatic disease. C Consider performing metastasectomy, radiation, and radiofrequency ablation in selected patients with distant metastatic disease. C 5. Therapeutic procedures Endoscopic ablation: consider performing ablative therapy with conventional anoscopy or high- resolution anoscopy in patients with high-grade squamous intraepithelial lesions. C Colostomy: consider performing pre-chemoradiotherapy colostomy in patients with locally advanced anal cancers with (or anticipated) anorectal pain or fecal incontinence and rectovaginal fistula. Counsel patients regarding the likelihood that their colostomy will be permanent. C 6. Surgical interventions Wide-local excision: As per ESMO 2021 guidelines, consider performing local excision for definite treament of patients with early anal margin cancer (cT1N0M0) aiming to achieve histological clearance of > 1 mm without damaging the anal sphincter muscle. C As per ASCRS 2018 guidelines, perform wide-local excision (with 1 cm margins of resection) in patients with well-differentiated, node-negative, T1 perianal squamous cancer. B Abdominoperineal resection: https://web.pathway.md/diseases/recxPhkt7YVf0q1hh 4/6 6/23/23, 2:35 AM Anal cancer Pathway As per ESMO 2021 guidelines, consider performing radical abdominoperineal resection instead of chemoradiotherapy as the primary treatment in uncommon scenarios, such as previous pelvic radiotherapy. C As per ASCRS 2018 guidelines, perform abdominoperineal resection as salvage therapy in patients with persistent or recurrent disease. B 7. Specific circumstances Patients with HIV/AIDS: As per ASCRS 2018 guidelines, treat patients with human immunodeficiency virus infection who present with anal cancer as the first manifestation of their immunosuppression according to the same regimens as immunocompetent patients, provided they are not medically deconditionned. B As per ESMO 2014 guidelines, offer chemoradiotherapy with 5-fluorouracil and mitomycin C in patients with anal cancer and human immunodeficiency virus infection. A Show 4 more 8. Patient education Counseling on treatment adherence: counsel patients on avoiding missed treatments, because they are strongly associated with poor disease control. B 9. Preventative measures HPV vaccination: Offer HPV immunization in < 26 years old males and females in order to prevent anal squamous cell cancer. B Do not offer immunization in individuals with anal dysplasia for the secondary prevention of dysplasia and cancer. D 10. Follow-up and surveillance Assessment of treatment response: assess tumor response after chemoradiotherapy in 26 weeks as an optimum time point. B Show 3 more Surveillance for toxicity: Assess patients for skin and hematological toxicity during chemoradiotherapy. B Inform patients about expected late effects, including changes in anorectal and sexual function, menopause and risk of infertility. B https://web.pathway.md/diseases/recxPhkt7YVf0q1hh 5/6 6/23/23, 2:35 AM Anal cancer Pathway Follow-up: As per ESMO 2021 guidelines, consider obtaining follow-up within a protocol-driven program by anal cancer multidisciplinary team in all patients with anal cancer. C Show 5 more As per ASCRS 2018 guidelines, start disease surveillance 8-12 weeks from the completion of chemoradiotherapy. B Show 3 more Patients with locally recurrent or residual disease: consider performing salvage surgery in patients with locally recurrent or residual anal cancer after chemoradiotherapy. C Show 6 more References 1. S Rao, M G Guren, K Khan et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Jun 24;S0923 7534 21 02064 0. Open 2. Stewart DB, Gaertner WB, Glasgow SC et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers Revised 2018 . Dis Colon Rectum. 2018 Jul;61 7 755 774. Open 3. Bower M, Palfreeman A, Alfa-Wali M et al. British HIV Association guidelines for HIV-associated malignancies 2014. HIV Med. 2014 Mar;15 Suppl 2 1 92. Open 4. Joel M Palefsky, Jeannette Y Lee, Naomi Jay et al. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med. 2022 Jun 16;386 24 2273 2282. Open https://web.pathway.md/diseases/recxPhkt7YVf0q1hh 6/6