The anal canal is delimited superiorly by the proximal extent of the levator-external anal sphincter complex and inferiorly by the anal verge (the junction between the anal mucosa and the hair-bearing skin). Lesions that involve the hair-bearing skin (peri-anal skin within 5 cm of the anal verge) are considered cancers of the anal margin and should also be treated as anal cancers.
This guideline was developed to outline the management recommendations for patients with squamous cell carcinomas that arise within the anal canal. Adenocarcinomas of the anal canal should be treated like rectal cancers (see the Early-Stage Rectal Cancer Clinical Practice Guideline).

# Search Strategy
Randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data.

# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with squamous cell carcinomas that arise within the anal canal. Different principles may apply to pediatric patients.

# Suggested Diagnostic Work-Up
The incidence of squamous cell carcinomas that arise within the anal canal has increased with the prevalence of Human Papilloma Virus (HPV) infection, Human Immunodeficiency Virus (HIV) infection, and immunosuppression required for organ transplantation. If the use of chemotherapy or radiotherapy is considered and HIV infection is suspected, HIV serology and an evaluation of the CD4 count are suggested in addition to the complete blood count and both liver and renal function tests.
CT chest abdomen pelvis, MRI of the pelvis are recommended. The addition of a PET/CT scan to the staging workup has a significant impact on therapy planning, particularly identifying those patients who need higher-dose RT to the groin and those with otherwise occult metastatic disease. A metaanalysis of 12 studies concluded that a PET CT changed nodal status in 28% of patients and should be considered 1. Suspicious lymph nodes should be evaluated with a biopsy by fine-needle aspirate.
Female patients should have a gynecological assessment (including a Pap smear) to exclude a synchronous cervical cancer. A colonoscopy should be performed to detect synchronous lesions.

# Stage Information

# Goals of Therapy and Recommendations for Potentially Curable Cancer of the Anal Canal
- To render the patient free of disease and to delay or prevent recurrence. 2. To improve the patient's quality of life (to eliminate tumour-related symptoms) and to preserve continence.
Consider treatment on a clinical trial, if available. - Consider a wide local excision provided that surgical resection can be completed to achieve negative margins and to preserve continence (no involvement of the anal sphincter).

# Stage I
- Consider a wide local excision provided that surgical resection can be completed to achieve negative margins and to preserve continence (no involvement of the anal sphincter). - Consider primary chemoradiotherapy (as described for stage II and IIIA disease) if sphincter
Recommendations preservation (maintenance of continence) is not possible with a wide local excision. - Consider an abdominoperineal resection for residual or recurrent disease.

# Stage II Stage IIIA
- Primary chemoradiotherapy  involves the sequential administration of Mitomycin C (10 to 12 mg/m 2 IV) followed by a continuous intravenous infusion of 5-Fluorouracil (4,000 mg/m 2 over ninetysix hours) during week one (and, possibly, week five) of a course of radiation (4,500 to 5,400 cGy to the perineum and regional lymph nodes). Randomized trials have used a single dose of Mitomycin C at 12 mg/m 2. This is an evidence based option that is also supported by real world data. 8 This regimen requires placement of a central venous catheter ("CVC") or a peripherally inserted central catheter ("PICC line"). - Consider an abdominoperineal resection for residual or recurrent disease. Stage IIIB - Primary chemoradiotherapy (as described for stage II and IIIA disease). Consider a boost, if indicated. - Consultation with the multidisciplinary and surgical team should be sought to determine the role of further surgery.

# Post-Curative Therapy Guidelines
- Perform a digital rectal examination and consider anoscopy at six to eight weeks after completion of the therapy. Consider biopsy of any suspicious lesions at three months after completion of therapy, but recognize that tumors may continue to respond up to six months after the radiation 9. - Perform salvage surgery for biopsy-proven persistent, progressive, or recurrent disease.
- After achieving a complete response, repeat digital rectal examination, anoscopy, and examination of the inguinal lymph nodes every four months for two years then every six months for the balance of five years. - Female patients should have a gynecological assessment (including a Pap smear) due to the increased risk of cervical cancer. A colonoscopy should be obtained as outlined in the colorectal cancer screening guidelines.

# Recommendations for Locally Recurrent Cancer of the Anal Canal
- For patients whose disease recurs despite prior radical chemoradiotherapy, consider surgical resection, if possible after repeating full staging investigations. Consider palliative therapy (see below) if surgical resection is not possible. 2. For patients whose disease recurs after not having received prior chemoradiotherapy, consider radical chemoradiotherapy (see above) with or without surgery.

# Goals of Therapy and Recommendations for Metastatic Cancer of the Anal Canal
- To maintain or to improve the patient's quality of life (to control or to delay the onset of tumorrelated symptoms). 2. To prolong life, if possible.
Metastatic anal canal cancer describes the situation where a cancer that originated within the anal canal has spread beyond the regional lymph nodes to other organs. This represents an incurable situation for which palliative options (e.g.: best supportive care, palliative chemotherapy) may be considered.
Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable.
Carboplatin/paclitaxel (Carboplatin AUC 5 on day 1 every 28 days and paclitaxel at 80 mg/m2 on days 1, 8, 15 every 28 days). The InterAACT randomized phase II trial demonstrated the superiority of carboplatin/paclitaxel compared to cisplatin and infusional 5FU in inoperable, locally recurrent or metastatic SCC of the anal canal for overall survival (OS). OS was a secondary endpoint of this trial. Preliminary findings presented at ESMO 2018 demonstrated OS was 12.3 months with cisplatin/5FU versus 20 months with carboplatin and paclitaxel, hazard ratio  2.0 (p = 0.014). There was no difference in response rate, the primary endpoint of this trial (57.1% with cisplatin/5-FU compared to 59.0% with carboplatin/paclitaxel). Median PFS was 5.7 months for cisplatin/5-FU versus 8.1 months for carboplatin/paclitaxel (p = 0.375). The incidence of serious adverse events (SAEs) was lower with carboplatin/paclitaxel; SAEs were reported in 62% of cisplatin/5-FU patients compared with 36% of patients receiving carboplatin/paclitaxel (p = 0.016). There are no randomized phase III trials in this setting, and patients should be encouraged to participate in clinical trials 10.

# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2008, and updated in 2010, 2011, 2013, and 2020.

# Levels of Evidence