Anal Cancer Guidelines

Guidelines for the management of anal cancer have been published by the following organizations:

• American Society of Colon and Rectal Surgeons (ASCRS) ^[30]
• National Comprehensive Cancer Network (NCCN) ^[31]
• European Society for Medical Oncology (ESMO) ^[75]
• Howard Brown Health ^[76]

Practice parameters, issued by the ASCRS in 2012 and revised in 2018, cover prevention, pretreatment evaluation, treatment, and post-treatment surveillance of anal squamous neoplasms. Recommendations for anal margin and anal intraepithelial neoplasia (AIN) are also provided. ^{[30, 77]}

Prevention

ASCRS recommendations for anal cancer prevention include the following:

• Use history, physical examination, and laboratory testing to identify patients at increased risk for anal squamous neoplasms (eg, HIV-positive individuals, men who have sex with men [MSM], women with a history of cervical dysplasia). (Strong recommendation based on moderate-quality evidence, 1B)
• Provide regular follow-up of patients with anal dysplasia, with history, physical examination, and discussion of screening options. (Weak recommendation based on moderate-quality evidence, 2B)
• Consider screening high-risk patients with anal cytology (or anal Papanicolaou tests [Pap smears]); HPV testing may be used as an adjunct. (Weak recommendations based on moderate-quality evidence, 2B)
• High-resolution anoscopy may be considered as a screening option for high-risk patients, when performed by appropriately trained clinicians. (Weak recommendation based on moderate-quality evidence, 2B)
• Topical imiquimod, fluorouracil, trichloroacetic acid, or cidofovir, with close long-term follow-up, are options for the treatment of low-grade or high-grade squamous intraepithelial lesions. (Weak recommendation based on moderate-quality evidence, 2B)
• Vaccination against human papillomavirus (HPV) in men and women under age 26 years for primary prevention is typically recommended; Vaccination of individuals with anal dysplasia for secondary prevention of dysplasia and cancer is not recommended. (Weak recommendation based on high-quality evidence, 2A)
• Patients who have been treated for anal dysplasia may be observed without regular cytology, HPV testing, or anoscopy; however, treatment of visible or palpable disease should be offered. (Weak recommendation based on low or very low-quality evidence, 2C)

Pretreatment evaluation

For the pretreatment evaluation, the ASCRS recommends performing the following:

• A disease-specific history and physical examination, emphasizing symptoms, risk factors, and signs of advanced disease (strong recommendation based on low-quality evidence, 1C)
• Endoscopic and radiologic evaluation, to help determine staging, and assess for metastatic disease (strong recommendation based on low-quality evidence, 1C)
• 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography (PET)/computed tomography (CT) may be considered as an adjunct radiologic study in the staging of anal SCCs, but does not replace CT scanning for clinical staging (strong recommendation based on low-quality evidence, 1C)

Treatment

ASCRS recommendations for treatment include the following:

• For all squamous cell carcinomas (SCCs) of the anal canal, and for most perianal SCCs, combined chemotherapy and radiation therapy is the primary treatment; chemoradiation therapy provides better locoregional control than radiotherapy alone (strong recommendation based on high-quality evidence, 1A).
• For the chemotherapy arm, mitomycin plus 5-fluorouracil (5-FU) is the first-line regimen for anal SCCs (strong recommendation based on high-quality evidence, 1A).
• Radiotherapy doses > 59 Gy provide no oncologic benefit (strong recommendation based on moderate-quality evidence, IB).
• Missed treatments should be avoided, because they are strongly associated with inferior disease control (Strong recommendation based on moderate-quality evidence, IB).
• Abdominoperineal resection is effective salvage therapy for persistent or recurrent disease (strong recommendation based on moderate-quality evidence, 1B).
• Consider systemic chemotherapy in pa­tients with distant metastasis. Metastasectomy, radiation, and radiofrequency ablation can be considered in selected cases (weak recommendation based on low- or very-low–quality evidence, 2C).

Additional treatment recommendations include the following:

• Perianal squamous cancers that are well-differentiated, node-negative, T1 lesions can be adequately treated with wide local excision with 1-cm margins of resection (strong recommendation based on low-quality evidence, IC)
• Patients with HIV or AIDS who present with anal cancer as the first manifestation of their immunosuppression, and who are not medically deconditioned, can be safely treated according to the same regimens as immunocompetent patients (strong rec-ommendation based on medium-quality evidence, IC).

Post-treatment surveillance

The ASCRS recommends that patients treated for anal cancer receive follow-up involving digital rectal examination, anoscopy, and imaging. Surveillance should typically start 8 to 12 weeks from the completion of chemoradiotherapy and should be continued for 5 years (strong recommendation based on moderate-quality evidence, 1B).

The NCCN guidelines cover the workup, treatment, and post-treatment surveillance of anal carcinoma. ^[31]

Workup

When biopsy confirms SCC of the anal canal or anal margin, the NCCN recommends the following workup:

• Digital rectal examination (DRE)
• Inguinal lymph node evaluation – Consider biopsy or fine needle aspiration (FNA) of suspicious nodes
• Chest/abdominal CT plus pelvic CT or MRI – Consider PET/CT scan
• Anoscopy
• Consider HIV testing + CD4 level if indicated
• Gynecologic exam for women, including screening for cervical cancer

Treatment

For primary treatment of locoregional SCC of the anal canal, recommended chemoradiation regimens include the following;

• Mitomycin/5-fluorouracil (5-FU) plus radiation therapy (RT)
• Mitomycin/capecitabine plus RT 
• 5-FU/cisplatin plus RT (category 2B)

For RT, the NCCN panel consensus was that intensity-modulated radiation therapy (IMRT) is preferred over 3-D conformal RT. Stereotactic body RT (SBRT) may be considered for patients with oligometastatic disease.

For metastatic SCC of the anal canal, the NCCN recommends primary treatment with 5-FU/cisplatin, with or without RT,  or enrolling the patient in a clinical trial.

For primary treatment of SCC of the anal margin, treatment recommendations vary by clinical stage, as follows:

• T1, N0, well differentiated – Local excision; if margins are adequate, observe; if margins are inadequate, treat with re-excision (preferred) or consider local RT with or without chemotherapy
• T1, N0, poorly differentiated; T2-T4, N0; or any T, N+  – Chemoradiation therapy
• Metastatic disease – 5-FU/cisplatin, with or without RT,  or clinical trial

Follow-up

The NCCN recommends evaluation in 8-12 weeks with physical examination plus DRE. For patients in complete remission, surveillance recommendations are as follows:

• DRE and inguinal node palpation every 3-6 mo for 5 y
• Anoscopy every 6-12 mo for 3 y
• For patients with T3-T4 disease or positive inguinal nodes – Chest/abdomen/pelvic CT with contrast annually for 3 y

If surveillance reveals recurrent disease, treatment recommendations are as follows:

• Local recurrence – Abdominopelvic resection (APR), plus groin resection if inguinal nodes are positive
• Inguinal node recurrence – Groin dissection; consider RT if patient had no prior groin RT, with or without 5-FU or mitomycin/capecitabine
• Distant metastasis – 5-FU/cisplatin or clinical trial

Surveillance after treatment for local recurrence includes the following:

• Inguinal node palpation every 3-6 mo for 5 y
• Chest/abdomen/pelvic CT with contrast annually for 3 y

Surveillance after treatment for inguinal node recurrence includes the following:

• DRE and inguinal node palpation every 3-6 mo for 5 y
• Anoscopy every 6-12 mo for 3 y
• Chest/abdomen/pelvic CT with contrast annually for 3 y

If initial post-treatment evaluation reveals persistent disease, the NCCN recommends re-evaluation in 4 wk; if serial exams show regression or stable disease, the NCCN recommends continued observation, re-evaluation in 3 mo, and biopsy at 6 mo. In cases of progressive disease, biopsy proven, recommendations are as follows:

• Locally recurrent – APR, plus groin resection if inguinal nodes are positive
• Metastatic disease – 5-FU/cisplatin or clinical trial

he ESMO guidelines cover diagnosis, treatment, and follow-up of anal cancer. ^[75]

Diagnosis

ESMO recommendations for diagnosis of anal cancer include the following:

• Digital anorectal examination (DRE) is essential for detection of lesions in the anal area.
• Biopsy is mandatory to confirm squamous cell carcinoma of the anus (SCCA)
• All suspicious anal lesions should be excised or biopsied. Targeted biopsy of anal lesions suspicious for anal intraepithelial neoplasia (AIN) is mandatory in high-risk groups to exclude invasive disease.
• Female patients with AIN should be screened for synchronous cervical, vulvar, and vaginal intraepithelial neoplasia.
• Consider HIV testing in patients with recurrent or multifocal AIN.
• High-resolution T2-weighted MRI is needed for optimal assessment of primary tumour and lymph nodes.
• Magnetic resonance imaging (MRI) may also be helpful to note the relationship of tumor/nodes to the sacral segment levels, which would also assist in RT planning.
• 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 tumor signal intensity is observed on high-resolution T2-weighted MRI.
• Contrast-enhanced computed tomography (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.
• Further characterization of enlarged inguinal nodes by ultrasound-guided fine needle aspiration may be helpful when confirmatory features of malignancy are not evident on either MRI or positron emission tomography/CT (PET-CT).
• PET-CT may be considered for staging and assist in RT planning.
• Assessment of human papillomavirus (HPV) or p16 status may be considered, as the results can help predict treatment response.

Treatment

Recommendations for primary treatment include the following:

• Radiation therapy (RT) with concomitant 5-fluorouracil (5-FU) and mitomycin C is recommended as standard of care for patients with localized SCCA. Capecitabine can be possibly used as an alternative to 5-FU.
• Chemoradiotherapy (CRT) for locally advanced anal cancer should be given with an RT dose of > 50 Gy; the optimal dose for different tumor stages is not known.
• Neoadjuvant or adjuvant chemotherapy is generally not recommended.
• Elderly patients who can tolerate treatment should be treated with curative CRT. Patients who cannot tolerate CRT may benefit from RT for local control.
• Intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), or 3D conformal RT are the recommended RT techniques, with RT dose constraints to normal tissue.
• The optimal RT dose for primary anal cancer is not known, but doses of at least  >45-50 Gy are recommended for T1-2N0 tumors, and doses of 50.4 Gy or higher for T3-4 or N1 tumors.

Recommendations for treatment of anal margin cancers include the following:

• Early anal margin cancers (cT1N0M0) can be treated definitively by local excision, with the goal of achieving histologic clearance of > 1 mm without damage to the anal sphincter muscle.
• CRT is recommended for anal margin cancers (T1N0M0) if the margin is ≤1 mm.

Recommendations for locally recurrent or residual disease include the following:

• Patients with locally residual or recurrent disease after CRT should be considered for salvage surgery.
• Residual or recurrent tumors may be considered for histologic confirmation.
• For patients with locally recurrent disease, MRI in conjunction with specialist multidisciplinary team assessment is important to optimize surgical cure].
• Involvement of the anal sphincter complex requires exenterative surgery, and imaging assessment should include a thorough assessment of the pelvic compartments to enable surgical planning (beyond total mesorectal excision).
• The mainstay of salvage surgery is abdomino-perineal excision, but more radical exenterative operations can be considered to achieve an R0 resection. APE for relapsed anal cancer is a different operation from that used for rectal cancer; perineal plastic reconstruction with musculo-cutaneous flaps should be considered in almost all cases.

Recommendations for advanced anal cancer in chemotherapy-naive patients include the following:

• Carboplatin plus paclitaxel should be considered a new standard of care.
• Cisplatin/5-FU/capecitabine, carboplatin, or docetaxel-based combinations are alternatives.
• Programmed cell death ligand 1 (PD-L1) inhibitors may be considered in patients whose disease has progressed on first-line therapy in clinical trials.

Follow-up

Patients in complete remission should be evaluated every 3-6 months for a period of 2 years, and every 6-12 months until 5 years, with clinical examination including DRE and palpation of the inguinal lymph nodes. Patients with locally advanced anal cancer may benefit from intensive MRI surveillance in the first 12 months.

The Howard Brown Health guidelines cover screening for anal cancer. Recommendations for screening include the following ^[76] :

• Persons living with HIV who are younger than 30 years of age should be screened annually with a DRE.
• Persons living with HIV at age 30 and above should be screened annually with anal cytology, DNA test for rectal high-risk HPV, and DRE.
• Persons of any age with a history of cancer of the cervix, vagina, and/or vulva should be screened immediately after diagnosis and then annually with anal cytology, DNA test for rectal high-risk HPV, and DRE.
• Persons age 30 and older with a history of high-grade squamous intra-epithelial lesions (HSIL) of the cervix, vagina, and/or vulva should be screened annually with anal cytology, DNA test for rectal high-risk HPV, and DRE.
• HIV-negative persons age 40 years and older who have regular anoreceptive penetrative sex or anoreceptive play with multiple partners should be screened annually. Screening should include anal cytology, DNA test for rectal high-risk HPV, and DRE.
• Recipients of solid organ transplants should be screened annually, starting 2 to 5 years post-transplant. Screening should include anal cytology, DNA test for rectal high-risk HPV, and DRE.

Additional considerations include the following:

• History of anogenital warts and cigarette smoking may help identifying risk but in and of itself is not an indication for anal dysplasia screening.
• Availability of a provider able to perform high-resolution anoscopy prior to cytology or DNA test for high-risk HPV is offered