Anal
Squamous cell carcinoma of the anal canal and margin
DefinitionClick to collapse
Anal carcinoma is a malignancy arising from the anal region, which is divided into the anal canal and the perianal region. The functional anal canal, which is primarily used for radical surgical treatment, is defined by the sphincter muscles. Its superior border is the palpable upper border of the anal sphincter and puborectalis muscles of the anorectal ring, and its inferior border starts at the anal verge, the lowermost edge of the sphincter muscles corresponding to the introitus of the anal orifice. This functional canal is approximately 3 to 5 cm in length. The anatomic anal canal begins at the anorectal ring and extends to the anal verge (squamous mucocutaneous junction with the perianal skin). The perianal region starts at the anal verge and includes the perianal skin over a 5-cm radius from the squamous mucocutaneous junction [ANAL-1, footnote a; ANAL-2, footnote l; MS-6]. Histologically, the proximal anal canal is lined by glandular columnar epithelium, the middle zone by transitional epithelium, and the distal third by nonkeratinizing squamous epithelium, which merges with keratinized perianal skin at the anal margin [MS-6]. Lymphatic drainage patterns differ based on tumor location: distal tumors drain mainly to superficial inguinal nodes, while proximal tumors drain to perirectal and internal iliac nodes, though overlap occurs [MS-7].
EpidemiologyClick to collapse
SubtypesClick to collapse
Squamous Cell Carcinoma (SCC)
The most common histologic type of primary anal cancer. The WHO 5th edition classification includes various histologic patterns (previously designated as cloacogenic, basaloid, or transitional) under a single diagnosis of SCC, as they share similar natural history and prognosis. Distinction by cell type is not made in these guidelines [MS-7].
Verrucous Carcinoma (VC)
A low-grade subtype of SCC characterized by marked exophytic and endophytic growth without features of HPV cytopathic effect or high-grade cytologic atypia on superficial biopsy. When conventional SCC is identified arising in VC, the diagnosis should be SCC as these lesions have similar biology [MS-7].
Superficially Invasive Squamous Cell Carcinoma (SISCCA)
A clinical-pathologic entity defined as anal cancer that has been completely excised, with ≤3-mm basement membrane invasion and a maximal horizontal spread of ≤7 mm (T1,NX). These are generally found incidentally in biopsies or excisions of benign lesions [ANAL-A; MS-16].
Molecular PathogenesisClick to collapse
The key molecular event in anal squamous cell carcinoma is infection with high-risk human papillomavirus (HPV), which is detected in 84% to 97% of anal cancer specimens [MS-2, MS-3]. The association with persistent infection by high-risk HPV forms, especially HPV-16 and HPV-18, is especially strong. A study found high-risk HPV DNA in 84% of anal cancer specimens (HPV-16 in 73%), while it was absent in rectal adenocarcinomas [MS-3]. The viral oncoproteins E6 and E7 from high-risk HPV types inactivate the tumor suppressor proteins p53 and pRb, respectively, leading to genomic instability and carcinogenesis. The guidelines do not detail specific frequencies of other driver mutations or chromosomal abnormalities beyond this HPV-driven pathway. Immunosuppression, as seen in HIV infection or after solid organ transplantation, is a critical co-factor that likely facilitates persistence of HPV infection [MS-3]. There is evidence that HPV- and/or p16-positivity are prognostic for improved overall survival, and p16-positivity was an independent prognostic factor for OS in one study (HR, 0.07; P = .016) [MS-8].
Risk FactorsClick to collapse
Human Papillomavirus (HPV) infection
Persistent infection with high-risk HPV (e.g., HPV-16, HPV-18) is the primary risk factor. High-risk HPV DNA is detected in 84%-97% of anal cancers [MS-3].
Human Immunodeficiency Virus (HIV) infection
People with HIV (PWH) have an approximately 15- to 35-fold increased likelihood of being diagnosed with anal cancer compared to the general population. The standardized incidence rate in the U.S. increased from 19.0 per 100,000 person-years (1992-1995) to 78.2 (2000-2003). Incidence is highest in men who have sex with men (MSM) with HIV (131 per 100,000 person-years) [MS-3].
Solid organ transplantation
Incidence rates rise with age and years since transplant. Rates can be as high as 24.5 and 29.6 per 100,000 person-years in males and females ≥10 years post-transplant, respectively [MS-3].
Receptive anal intercourse / sexually transmitted diseases
A history of receptive anal intercourse or sexually transmitted disease is a known risk factor [MS-3].
Smoking
Smoking is listed as an associated risk factor [MS-3].
Autoimmune disorders
Incidence rates of 10, 6, and 3 per 100,000 person-years have been reported for patients with systemic lupus erythematosus, ulcerative colitis, and Crohn’s disease, respectively [MS-3].
History of certain gynecologic cancers
A history of cervical, vulvar, or vaginal cancer, likely due to shared HPV risk [MS-3].
Male sex
Multivariate analyses have identified male sex as an independent prognostic factor for worse disease-free survival and overall survival [MS-8].
Clinical FeaturesClick to collapse
Typical Presentation
Anal carcinoma typically presents with rectal bleeding (approximately 45% of patients), pain, or the sensation of a rectal mass (approximately 30% of patients). The majority of primary cancers of the anal canal are of squamous cell histology. Superficially invasive squamous cell carcinoma (SISCCA) are anal cancers that are generally found incidentally in the setting of a biopsy or excision of what is thought to be a benign lesion such as a condyloma, hemorrhoid, or anal skin tag. Perianal squamous cell carcinomas are more likely than those of the anal canal to be well-differentiated and keratinizing large-cell types. The functional anal canal is approximately 3 to 5 cm in length, with its superior border defined as the palpable upper border of the anal sphincter and puborectalis muscles of the anorectal ring, and its inferior border starting at the anal verge, the lowermost edge of the sphincter muscles, corresponding to the introitus of the anal orifice. The perianal region starts at the anal verge and includes the perianal skin over a 5-cm radius from the squamous mucocutaneous junction.
Symptoms
Rectal bleeding
The most common presenting symptom, reported in approximately 45% of patients with anal carcinoma
Rectal pain
Approximately 30% of patients present with pain, which may be perianal or related to the anal mass
Rectal mass sensation
Approximately 30% of patients report a sensation of a rectal mass
Perianal skin lesion
Perianal cancers may present as discrete lesions arising from the perianal skin that can be visualized completely when the buttocks are gently pressed
Signs
Palpable anal mass on digital rectal examination (DRE)
DRE is a critical component of the initial evaluation; T stage is primarily determined through clinical examination including DRE
Inguinal lymphadenopathy
Inguinal lymph node evaluation is mandatory; synchronous inguinal node metastasis was observed in 6.4% of patients with T1/T2 tumors and 16% of patients with T3/T4 tumors
Perianal skin abnormality
Visible or palpable abnormality in the perianal region extending up to 5 cm from the squamous mucocutaneous junction
Anal canal mass on anoscopy
Anoscopic examination is part of the standard workup to visualize the anal canal and obtain biopsy
Red FlagsClick to collapse
Rectal bleeding requiring urgent investigation to exclude anal carcinoma, particularly in patients with risk factors such as HPV infection, HIV, immunosuppression, or history of receptive anal intercourse
Palpable inguinal lymphadenopathy requiring biopsy or fine-needle aspiration (FNA) if suspicious nodes are detected
Any perianal or anal lesion requiring biopsy to exclude squamous cell carcinoma or other malignancy
New anal symptoms in patients with HIV or other immunosuppression given 15- to 35-fold increased likelihood of anal cancer diagnosis
Progressive disease on serial examinations following primary chemoradiation treatment - biopsy-proven disease progression indicates need for further intensive treatment
Persistent disease that continues to progress rather than regress during the observation period following completion of radiation and chemotherapy
Symptomatic patients with metastatic disease who may benefit from palliative radiation therapy to the primary site
InvestigationsClick to collapse
Diagnostic
Biopsy (incisional, excisional, or punch biopsy)
Required for histologic confirmation of squamous cell carcinoma; definitive diagnosis; all primary cancers of the anal canal are of squamous cell histology in most cases
Digital rectal examination (DRE)
Essential component of the clinical evaluation; T stage is primarily performed through clinical examination
Anoscopy
Allows direct visualization of the anal canal and perianal region; facilitates biopsy
Inguinal lymph node evaluation (palpation ± biopsy/FNA)
Mandatory evaluation of regional lymph nodes; inguinal node metastasis is common especially with distal anal cancers
Staging
Chest/abdomen CT with IV and oral contrast + pelvis CT or MRI with contrast
Standard staging imaging for all patients; CT should be with IV and oral contrast; pelvis MRI with contrast provides superior soft tissue resolution for pelvic disease assessment
FDG-PET/CT or FDG-PET/MRI
Can be considered to verify staging before treatment; reported to be useful in evaluation of pelvic nodes even with normal-sized lymph nodes on CT; pooled sensitivity and specificity for detection of lymph node involvement reported as 93% and 76% respectively in a recent meta-analysis; FDG-PET/CT led to upstaging in 5% to 38% of patients and downstaging in 8% to 27% of patients; treatment plan modifications occurred in 12% to 59% of patients based on FDG-PET/CT results
Pelvic MRI with contrast
Provides superior soft tissue resolution compared to CT; recommended for pelvic staging
Chest CT without contrast
Intravenous contrast is not required for the chest CT; evaluates for pulmonary metastases since veins of the anal region are part of the venous network associated with systemic circulation
Biomarkers
HIV testing
Risk of anal carcinoma is 15- to 35-fold increased in people with HIV (PWH); approximately 13% of people in the United States infected with HIV are not aware of their infection status; identification of HIV infection has the potential to improve clinical outcomes
HPV/p16 testing
HPV- and/or p16-positivity are prognostic for improved overall survival in patients with anal carcinoma; in a retrospective study of 143 tumor samples, p16-positivity was an independent prognostic factor for OS (HR, 0.07; 95% CI, 0.01–0.61; P = .016); high-risk HPV DNA detected in 84% of anal cancer specimens in one study
MSI/MMR testing
MSI is uncommon in anal cancer; however, responses to PD-1/PD-L1 inhibitors occur in 20% to 24% of patients regardless of MSI status; anal cancers may respond due to high PD-L1 expression and/or high tumor mutational load despite being microsatellite stable
DPYD testing
FDA added a Boxed warning to the capecitabine label recommending testing for DPYD genetic variants prior to initiating capecitabine unless immediate treatment is necessary
StagingClick to collapse
AJCC Cancer Staging System, 9th Edition (2022)
T Categories
| Stage | Description |
|---|---|
| TX | Primary tumor not assessed |
| T0 | No evidence of primary tumor |
| T1 | Tumor less than or equal to 2 cm in greatest dimension |
| T2 | Tumor greater than 2 cm but less than or equal to 5 cm in greatest dimension |
| T3 | Tumor greater than 5 cm in greatest dimension |
| T4 | Tumor of any size invades adjacent organ(s), such as the vagina, urethra, or bladder |
N Categories
| Stage | Description |
|---|---|
| NX | Regional lymph nodes cannot be assessed |
| N0 | No tumor involvement of regional lymph node(s) |
| N1 | Tumor involvement of regional lymph node(s) |
| N1a | Tumor involvement of inguinal, mesorectal, superior rectal, internal iliac, or obturator lymph node(s) |
| N1b | Tumor involvement of external iliac lymph node(s) |
| N1c | Tumor involvement of N1b (external iliac) with any N1a node(s) |
M Categories
| Stage | Description |
|---|---|
| cM0 | No distant metastasis |
| cM1 | Distant metastasis |
| pM1 | Microscopic confirmation of distant metastasis |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage I | T1, N0, M0 | Small tumor (≤2 cm) limited to the anal canal without lymph node involvement or distant metastasis | Localized disease: 80% five-year survival (SEER data 1999-2006) | Curative; for anal canal: chemoRT; for perianal: local excision if well/moderately differentiated T1N0 or select T2N0 not involving sphincter |
| Stage IIA | T2, N0, M0 | Tumor >2 cm but ≤5 cm without lymph node involvement or distant metastasis | Localized disease: 80% five-year survival | Curative; chemoRT for anal canal; for perianal: local excision if select T2N0 not involving sphincter, otherwise chemoRT |
| Stage IIB | T1–T2, N1, M0 | Small to moderate tumor with regional lymph node involvement but no distant metastasis | Regional disease: 60% five-year survival | Curative; chemoRT |
| Stage IIIA | T3, N0–N1, M0 | Large tumor (>5 cm) with or without regional lymph node involvement, no distant metastasis | Regional disease: 60% five-year survival | Curative; chemoRT |
| Stage IIIB | T4, N0, M0 | Tumor invading adjacent organs (vagina, urethra, bladder) without regional lymph node involvement or distant metastasis | Regional disease: 60% five-year survival; worst prognosis among node-negative groups | Curative; chemoRT |
| Stage IIIC | T4, N1, M0 | Tumor invading adjacent organs with regional lymph node involvement, no distant metastasis | Regional disease: 60% five-year survival; worst prognosis category | Curative; chemoRT |
| Stage IV | Any T, Any N, M1 | Any primary tumor with distant metastasis | Distant metastasis: 30.5% five-year survival | Palliative; systemic therapy; chemoRT to primary site may be considered for local control |
Staging Pearls
- The AJCC 9th edition removed the former N2 and N3 categories by locations of positive nodes and introduced new categories N1a, N1b, and N1c based on specific nodal regions
- N1a represents metastasis in inguinal, mesorectal, superior rectal, internal iliac, or obturator nodes; N1b represents external iliac nodes; N1c represents external iliac with any N1a nodes
- Both anal canal and perianal tumors use the AJCC anus staging system (previously perianal cancer used the skin cancer staging system)
- Prognosis is related to tumor size and lymph node metastases; male sex, positive lymph nodes, and tumor size >5 cm are independently prognostic for worse OS
- The same staging system applies to both anal canal and perianal cancers to avoid undertreatment of perianal cancers that may involve the anal canal
- T stage is primarily determined through clinical examination (DRE, anoscopy) rather than pathologic staging since primary treatment does not involve surgical excision
- Para-aortic lymph nodes that can be included in a radiation field may be treated with definitive chemoRT, although only limited retrospective data support this use
- Distal anal cancers present with a higher incidence of inguinal node metastases, but inguinal node metastases can occur in proximal anal cancer as well since lymphatic drainage systems are not isolated from each other
- Five-year survival by stage: localized 80%, regional 60%, distant 30.5%
Management PrinciplesClick to collapse
Anal carcinoma is primarily managed with concurrent chemoradiation (chemoRT), a paradigm established after Nigro and colleagues observed complete tumor regression with preoperative 5-fluorouracil (5-FU)–based concurrent chemotherapy and radiation in 1974 [122]. Prior to this, patients with invasive anal carcinoma were routinely treated with abdominoperineal resection (APR); however, local recurrence rates were high, 5-year survival was only 40% to 70%, and morbidity with permanent colostomy was considerable [15]. The current treatment philosophy is organ-preserving: definitive chemoRT achieves cure in the majority of patients while avoiding permanent colostomy. All recommendations are category 2A unless otherwise indicated, reflecting uniform NCCN consensus based on lower-level evidence. Clinical trial participation is encouraged when applicable and available [NCCN]. The NCCN Guidelines Panel believes that a multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary for treating individuals with anal carcinoma [MS-23]. Surgery (APR) is reserved for biopsy-proven recurrent or persistent disease following primary treatment, or for the small subset of very early lesions amenable to local excision. Systemic therapy is the backbone of treatment for metastatic disease, with recent evidence supporting the addition of immune checkpoint inhibitors to first-line chemotherapy [234].
Curative
Non-metastatic anal canal cancer (stage I–III, including positive para-aortic lymph nodes that can be included in the radiation field)
Concurrent chemoRT with mitomycin/5-FU, mitomycin/capecitabine, or cisplatin/5-FU (category 2B) [ANAL-1, ANAL-B 1 of 5]
Curative
T1N0 well or moderately differentiated or select T2N0 perianal cancer not involving the sphincter
Local excision with 1-cm margins; if margins adequate, observe; if margins inadequate, re-excision preferred or consider local RT ± chemotherapy [ANAL-2, ANAL-A]
Curative
T1N0 poorly differentiated or T2–T4 N0 or any T N+ perianal cancer
Local excision → re-excision (preferred) if inadequate margins, or consider local RT ± chemotherapy; OR definitive chemoRT as for anal canal cancer [ANAL-2]
Palliative
Metastatic anal carcinoma (any subsite)
First-line systemic therapy (preferred: carboplatin/paclitaxel + retifanlimab-dlwr); chemo/RT to the primary site may be considered for local control of symptomatic bulky primary [ANAL-1, ANAL-B 2 of 5, ANAL-C 4 of 6]
Salvage
Locally recurrent or persistent disease after prior chemoRT
APR with colostomy; immunotherapy (nivolumab, pembrolizumab, retifanlimab-dlwr, cemiplimab-rwlc, dostarlimab-gxly, tislelizumab-jsgr, toripalimab-tpzi, or penpulimab-kcqx) (category 2B) may be considered before proceeding to APR based on institutional experience [ANAL-3, ANAL-4]
A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary for treating individuals with anal carcinoma [MS-23]. The oncologist and primary care provider should have defined roles in the surveillance period, with roles communicated to the patient [MS-23]. Modifications to cancer treatment should not be made solely based on HIV status; additional considerations for people with HIV (PWH) who have anal cancer are outlined in the NCCN Guidelines for Cancer in People with HIV, including the use of normal tissue-sparing radiation techniques, the consideration of non-malignant causes for lymphadenopathy, and the need for more frequent post-treatment surveillance anoscopy [ANAL-1 footnote i, MS-16].
The Panel notes that poor performance status in PWH and anal cancer may be from HIV, cancer, or other causes. The reason for poor performance status should be considered when making treatment decisions. Treatment with antiretroviral therapy (ART) may improve poor performance status related to HIV [MS-16]. For individuals with anal cancer who are not candidates for intensive therapy, the optimal chemotherapy regimen remains uncertain. Some NCCN Panel members have used a combination of weekly cisplatin and daily 5-FU on days of radiation for chemoRT in localized anal cancer. Other potential strategies may include capecitabine plus RT or RT alone (without chemotherapy). However, due to a lack of data supporting this approach and differing strategies among Panel members, recommendations have not yet been defined. Use of a geriatric assessment to guide management and elicitation of the patient's goals and objectives with regard to their cancer diagnosis is critical to inform shared decision-making [MS-15, MS-16].
Management PathwaysClick to collapse
Branching: Anatomic site (anal canal), Clinical stage, Nodal involvement (including para-aortic nodes that can be included in radiation field)
Branching: Anatomic site (perianal), T stage, Nodal status, Histologic grade, Sphincter involvement, Surgical margin status
Branching: Anatomic site (perianal), Histologic grade (poorly differentiated), T stage (T2–T4), Nodal status (N+), Para-aortic node involvement
Branching: Disease status (metastatic), Prior therapy (treatment-naïve), HIV status, Performance status
Branching: Prior immunotherapy received or not, Prior chemotherapy agents received, Response to first-line therapy
Branching: Response assessment at 8–12 weeks, Clinical stage at diagnosis (I–III), DRE and clinical evaluation
Branching: Clinical response at 8–12 weeks, Progression on serial exams vs regression/no progression, Duration of follow-up (up to 6 months)
Branching: Site of recurrence (primary site vs inguinal nodes), Prior radiation to the groin, Surgical candidacy, Metastatic workup
Branching: Synchronous local and metastatic disease, Performance status, Extent of metastatic disease
Pretreatment EvaluationClick to collapse
Clinical Examination
Pathology
Imaging
Laboratory Testing
Specialist Consultations
Functional Assessments
SurgeryClick to collapse
Surgery plays a limited but critical role in the management of anal carcinoma. The primary treatment for most anal canal cancers is organ-preserving concurrent chemoRT; surgery is reserved for (1) very early perianal lesions amenable to local excision, (2) biopsy-proven recurrent or persistent disease after primary chemoRT (APR), and (3) inguinal node recurrence (groin dissection) [MS-15, MS-19]. Radical surgery (APR) is the primary treatment for local recurrence/persistence following failed chemoRT [ANAL-A].
Local excision is used for SISCCA and select early perianal cancers with histologically negative margins [ANAL-A]
For SISCCA, local excision alone with a structured surveillance plan may represent adequate treatment in carefully selected patients followed by an experienced provider and/or team [ANAL-A, MS-16]
APR for anal cancer may require wider lateral perianal margins than are required for rectal cancer [ANAL-A, MS-19]
General principles for APR are similar to those for distal rectal cancer and include the incorporation of total mesorectal excision (TME) [ANAL-A, MS-19]
Reconstructive tissue flaps (vertical rectus or local myocutaneous flaps) should be considered due to poor perineal wound healing following prior RT [ANAL-A, MS-19; 227, 228]
For patients who have already received groin radiation, consider an inguinal node dissection [ANAL-A]
Groin dissection can be done with or without APR depending on whether disease is isolated to the groin or is in conjunction with recurrence/persistence at the primary site [ANAL-A, MS-19]
Procedures
Local Excision (for SISCCA)
Local Excision (for Perianal Cancer)
Abdominoperineal Resection (APR)
Inguinal Node Dissection
Radiation TherapyClick to collapse
Radiation therapy (RT) is a central component of definitive treatment for non-metastatic anal carcinoma, delivered concurrently with chemotherapy (chemoRT). The consensus of the NCCN Panel is that intensity-modulated RT (IMRT) is preferred over 3D conformal RT (3D-CRT) [ANAL-C 1 of 6, 193]. RT is also used for palliation of symptomatic recurrent or metastatic disease, and for oligometastatic disease (SBRT may be considered) [ANAL-C 1 of 6].
Principles
- IMRT is preferred over 3D-CRT and requires expertise and careful target design to avoid reduction in local control by 'marginal miss' [ANAL-C 1 of 6, 3]
- Image-guided RT (IGRT) with kilovoltage (kV) imaging or cone beam CT imaging should be routinely used during treatment with IMRT and SBRT [ANAL-C 1 of 6]
- Consider SBRT for patients with oligometastatic disease [ANAL-C 1 of 6]
- Avoid extension of overall chemoRT treatment time to improve progression-free survival [ANAL-C 5 of 6]
- Fusion of MRI pelvis and/or FDG-PET/CT or FDG-PET/MRI with the simulation CT is recommended in defining local and regional target structures [ANAL-C 1 of 6]
- Displacement of the external genitalia from the radiation field should be considered to minimize treatment dose [ANAL-C 1 of 6]
- Patients are instructed to maintain a full bladder and, if possible, a rectum empty of stool and gas for simulation and treatment [ANAL-C 1 of 6]
- A radiopaque marker should be placed at the anal verge and perianal skin involvement can be outlined with radio-opaque markers [ANAL-C 1 of 6]
- The pelvic and inguinal nodes should be routinely treated in all patients [ANAL-C 2 of 6]
- For patients with cT3/4 anal cancer, consider selective dose escalation to 53.2–59.4 Gy in 28–33 fractions [ANAL-C 3 of 6]
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Standard Shrinking Field Technique (RTOG 98-11 based) | 50.4–59.4 Gy | 1.8–2.0 Gy | 28–33 | 5 days per week | Standard treatment for non-metastatic anal canal cancer. Low-risk elective nodal PTV: 30.6 Gy in 1.8 Gy fractions. High-risk elective nodal PTV: additional 14.4 Gy (total 45 Gy). Gross disease PTV: additional 5.4–14.4 Gy (total 50.4–59.4 Gy) [ANAL-C 3 of 6] |
| RTOG 0529 Simultaneous Integrated Boost (SIB) | See table | 1.5–1.8 Gy | 28–30 | 5 days per week | Dose-painted IMRT with SIB technique. T1,N0: Primary 50.4 Gy/28 fx at 1.8 Gy/fx, Nodal 42 Gy/28 fx at 1.5 Gy/fx. T2,N0: same as T1,N0. T3–4,N0: Primary 54 Gy/30 fx at 1.8 Gy/fx, Nodal 45 Gy/30 fx at 1.5 Gy/fx. T any,N+(≤3 cm): Primary 54 Gy/30 fx at 1.8 Gy/fx, Involved nodal 50.4 Gy/30 fx at 1.68 Gy/fx, Nodal 45 Gy/30 fx at 1.5 Gy/fx. T any,N+(>3 cm): Primary 54 Gy/30 fx at 1.8 Gy/fx, Involved nodal 54 Gy/30 fx at 1.8 Gy/fx, Nodal 45 Gy/30 fx at 1.5 Gy/fx [ANAL-C 3 of 6, Table 1] |
| Selective Dose Escalation for cT3/4 | 53.2–59.4 Gy | 1.8–2.0 Gy | 28–33 | 5 days per week | For patients with cT3/4 anal cancer, consider selective dose escalation [ANAL-C 3 of 6] |
| Palliative RT | 20–30 Gy | N/A | 5–10 | Daily fractions | Pure palliation for recurrent disease in previously irradiated fields. RT technique and doses are dependent on dosing and technique of prior treatment [ANAL-C 4 of 6] |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| IMRT with Concurrent 5-FU/Mitomycin | Per RTOG 0529 or standard shrinking field technique | Fluorouracil 1000 mg/m2/day continuous infusion Days 1–4 and 29–32 + Mitomycin 10 mg/m2 IV bolus Days 1 and 29 (capped at 20 mg) or Mitomycin 12 mg/m2 IV bolus Day 1 (capped at 20 mg) | Primary treatment of non-metastatic anal canal cancer | RTOG 0529: Grade 2+ hematologic events reduced (73% vs 85%; P = .032), grade 3+ GI events reduced (21% vs 36%; P = .008), grade 3+ dermatologic events reduced (23% vs 49%; P < .0001) [189]. Long-term: 8-year OS 62%, 8-year DFS 62% [190]. | Grade 2+ combined acute adverse event rate was 77%. Grade ≥2 non-hematologic late toxicities rate was 15% [189, 190]. |
| IMRT with Concurrent Capecitabine/Mitomycin | Per RTOG 0529 or standard shrinking field technique | Capecitabine 825 mg/m2 PO BID Monday–Friday on days of radiation treatment only + Mitomycin 10 mg/m2 IV bolus Days 1 and 29 (capped at 20 mg) or Mitomycin 12 mg/m2 IV bolus Day 1 (capped at 20 mg) | Primary treatment of non-metastatic anal canal cancer; alternative to 5-FU/mitomycin | Phase II study found 6-month locoregional control rate of 86% (95% CI, 0.72–0.94) [142]. Retrospective study showed significantly lower grade 3/4 hematologic toxicities with capecitabine vs 5-FU [139]. | Grade 3/4 hematologic toxicities significantly lower compared to 5-FU-based regimen [139] |
| IMRT with Concurrent Cisplatin/5-FU | Per standard technique | Cisplatin 75 mg/m2 IV Day 1 + continuous infusion Fluorouracil 1000 mg/m2/day IV Days 1–4, repeat every 4 weeks | Primary treatment of non-metastatic anal canal cancer (category 2B) | ACT II trial demonstrated equivalence of cisplatin and mitomycin in chemoRT regimens [143]. RTOG 98-11 showed inferior 5-year DFS (57.8% vs 67.8%; P = .006) and 5-year OS (70.7% vs 78.3%; P = .026) for cisplatin-based regimen [100, 144]. | Higher toxicity compared to mitomycin-based regimen in RTOG 98-11 [100, 144] |
Systemic TherapyClick to collapse
Systemic therapy serves two roles in anal carcinoma: (1) concurrent chemotherapy with radiation for non-metastatic disease, and (2) palliative systemic therapy for metastatic disease. For localized disease, mitomycin/5-FU or mitomycin/capecitabine with concurrent RT are preferred regimens, with cisplatin/5-FU as a category 2B alternative [ANAL-B 1 of 5]. For metastatic disease, carboplatin/paclitaxel plus the PD-1 inhibitor retifanlimab-dlwr is the preferred first-line regimen based on the phase 3 POD1UM-303/InterAACT2 trial showing improved PFS (9.30 vs 7.39 months; HR = 0.63; P = .0006) [234, ANAL-B 2 of 5]. PD-1/PD-L1 inhibitors are preferred options for second-line and subsequent therapy [ANAL-B 2 of 5, MS-21, MS-22].
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Post-Chemoradiation Response Assessment and Follow-Up
Timing
Patients are re-evaluated by DRE between 8 and 12 weeks after completion of chemoRT [ANAL-3, MS-18].
Imaging Recommendations
-
FDG-PET/CT is not indicated in routine surveillance [ANAL-3, ANAL-4]
-
C/A/P CT with contrast or chest CT without contrast and abdomen/pelvis MRI with contrast annually for 3 years (stage II–III) [ANAL-3]
-
DRE every 3–6 months for 5 years [ANAL-3]
-
Inguinal node palpation every 3–6 months for 5 years [ANAL-3]
-
Anoscopy every 6–12 months × 3 years [ANAL-3]
Biopsy Or Salvage Logic
-
Evidence of progression found on DRE should be followed by biopsy as well as restaging with CT and/or FDG-PET/CT imaging [MS-19, ANAL-4]
-
Use imaging studies as per initial workup for restaging [ANAL-4 footnote s]
-
The Panel recommends against the use of FDG-PET/CT imaging as part of the reevaluation strategy for persistent disease due to concerns for false-positivity from local inflammation from RT leading to unnecessary surgeries [MS-18]
-
Patients with biopsy-proven locally progressive disease are candidates for radical surgery with an APR and colostomy [MS-19]
SurveillanceClick to collapse
Clinical Follow Up Schedule
- Post-primary chemoradiation (complete remission):
- - Digital rectal examination (DRE) every 3-6 months for 5 years.
- - Inguinal lymph node palpation every 3-6 months for 5 years.
- - Anoscopy every 6-12 months for 3 years.
- Post-APR for recurrence/persistence:
- - DRE and inguinal node palpation every 3-6 months for 5 years.
- - Anoscopy every 6-12 months for 3 years (consider if anal canal not removed).
Imaging Strategy
- For stage II-III disease after primary treatment:
- - Annual chest/abdomen/pelvis CT with contrast OR chest CT without contrast and abdomen/pelvis MRI with contrast for 3 years.
- For post-APR or following treatment of recurrence:
- - Annual chest/abdomen/pelvis CT with contrast OR chest CT without contrast and abdomen/pelvis MRI with contrast for 3 years.
- FDG-PET/CT is NOT routinely indicated for surveillance due to concerns for false-positivity from post-treatment inflammation.
Laboratory Monitoring
- No specific serum tumor markers are routinely recommended for surveillance.
- HIV testing: If HIV status is unknown at diagnosis, testing is recommended. For known HIV-positive patients, management should follow NCCN Guidelines for Cancer in People with HIV.
Supportive Follow Up
- Fertility counseling and discussion of long-term effects of treatment (sexual function, bowel/bladder function).
- Referral to pelvic floor rehabilitation if needed for bowel or urinary dysfunction.
- Ostomy care coordination and support group referral if applicable.
- Bone density monitoring as indicated for post-RT patients.
- Smoking cessation counseling per NCCN Guidelines for Smoking Cessation.
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Locoregional recurrence | Biopsy-proven recurrence is treated with salvage abdominoperineal resection (APR). For isolated inguinal node recurrence, inguinal node dissection is recommended. Palliative RT or systemic therapy can be considered for symptomatic control. |
| Distant metastasis (most common sites: liver, lung, extrapelvic nodes) | Treated with systemic therapy. Palliative RT to the primary site can be considered for local control following upfront chemotherapy. |
Supportive CareClick to collapse
Supportive care is integral throughout the treatment and survivorship continuum, aiming to manage treatment toxicities, preserve function, and optimize quality of life. A multidisciplinary approach involving oncology, surgery, radiation, gastroenterology, urology, gynecology, and supportive care specialists is essential.
Nutritional status should be monitored, as pelvic radiotherapy can cause malabsorption and diarrhea. Diet manipulation (e.g., low-fiber for diarrhea, bulk-forming agents for incontinence) and potential referral to a nutritionist are recommended. Role of nutritional intervention in managing gastrointestinal symptoms post-pelvic RT is noted.
Antiemetics are used based on the emetogenic potential of the chemotherapy regimen. Platinum-based (cisplatin) and mitomycin regimens are moderately to highly emetogenic and require prophylaxis per antiemetic guidelines.
Growth factor support (G-CSF) may be considered for regimens with high risk of febrile neutropenia or for patients with prior episodes of severe neutropenia.
VTE prophylaxis should be considered per institutional guidelines for hospitalized patients or those with additional risk factors.
Pain should be assessed and managed appropriately. This may include analgesics for acute treatment-related pain (e.g., proctitis) and management of chronic pain syndromes.
Distress screening using tools like the NCCN Distress Thermometer is recommended at diagnosis and during follow-up. Support for issues related to body image changes, sexual dysfunction, ostomy management, and fear of recurrence should be provided. Referral to social work, psychology, or support groups is beneficial.
Dental evaluation prior to chemoradiation is recommended to address potential oral complications, especially with regimens affecting mucosal integrity.
PrognosisClick to collapse
Anal carcinoma prognosis is variable and stage-dependent, with a generally favorable outlook for localized disease but poorer outcomes for advanced or metastatic presentations. The prognosis is influenced by primary tumor size, lymph node status, HIV status, and HPV/p16 expression. Achieving a complete clinical response after primary chemoradiation is the strongest predictor of favorable long-term outcomes.
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Localized (SEER 1999-2006 data) | 80% | Approximately 50% of anal carcinomas are localized at diagnosis. |
| Regional Lymph Node Metastasis | 60% | About 29% of patients present with regional nodal disease. |
| Distant Metastatic Disease | 30.5% | Approximately 12% of patients present with metastatic disease. |
Prognostic Factors
- Tumor size: Larger tumor size (>5 cm) is an independent adverse prognostic factor for overall survival (OS) and colostomy rate.
- Nodal status: Positive lymph nodes are associated with worse disease-free survival (DFS) and OS. Among node-positive patients, survival is related more to T-stage than nodal burden, with 5-year survival rates of 72.7% and 39.9% for T1-T2 vs. T3-T4 tumors.
- Sex: Male sex is an independent prognostic factor for worse DFS and OS.
- HPV/p16 status: HPV- and/or p16-positivity are associated with improved OS (p16-positive: HR, 0.07; 95% CI, 0.01–0.61; P = .016).
- Response to therapy: Complete clinical response (CCR) at 26 weeks post-treatment is strongly associated with superior 5-year survival. Persistent disease may continue to regress up to 6 months post-chemoradiation.
- HIV status: While most studies show similar efficacy of chemoradiation in HIV-positive vs. negative patients, some data suggest a greater risk of grade ≥3 cutaneous toxicities (RR = 1.34) and worse 3-year DFS (RR = 1.32) and OS (RR = 1.77) in people living with HIV.
Follow UpClick to collapse
Post Curative Treatment
Following curative-intent chemoradiation, patients are evaluated 8-12 weeks post-treatment with DRE to assess response. Based on the ACT-II study, patients with persistent disease (not complete response) without progression may be observed for up to 6 months, as continued regression can occur. Re-evaluation is performed every 4 weeks until progression or regression/no progression is confirmed. For complete remission, transition to a structured surveillance program is initiated.
Surveillance Rationale
The goal of surveillance is to detect recurrence early, when additional curative-intent treatment (e.g., salvage surgery, re-irradiation) may still be possible. Late recurrences can occur, warranting long-term monitoring. The intensity of surveillance is highest in the first 3-5 years, corresponding to the peak risk period for recurrence.
Late Effects Screening
- Bowel function: Screen for chronic diarrhea, incontinence, urgency, stool clustering, and cramping.
- Urogenital dysfunction: Screen for sexual dysfunction (erectile dysfunction, dyspareunia, vaginal stenosis, dryness), urinary incontinence, frequency, and urgency.
- Bone health: Consider bone density monitoring for patients who received pelvic RT, given increased fracture risk.
- Second primary cancers: Encourage age- and gender-appropriate cancer screenings (e.g., cervical, breast, colorectal).
- Psychosocial and functional: Screen for distress, fatigue, and impacts on quality of life.
Recurrence Patterns
Recurrence patterns are often locoregional (10-30% locoregional failure rate after primary chemoradiation). Higher T and N stage are associated with higher recurrence rates. Most recurrences occur within the first 3 years, but late recurrences are possible. Metastatic recurrence most commonly involves the liver, lungs, and extrapelvic lymph nodes.
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| EORTC 22861 | European Organization for Research and Treatment of Cancer Trial 22861 | 1997 | 103 | Concurrent chemoradiation (5-FU + mitomycin + RT) | Radiation therapy alone | Locally advanced anal carcinoma | 5-year locoregional control | Chemoradiation superior: 18% higher locoregional control rate and 32% longer colostomy-free interval at 5 years. | No significant difference in OS at 5 years. | Established chemoradiation as superior to radiation alone for locally advanced anal cancer. | Journal of Clinical Oncology |
| ACT I (UKCCCR) | UK Coordinating Committee on Cancer Research Anal Cancer Trial I | 1996 | 585 | Chemoradiation (5-FU + mitomycin + RT) | Radiation therapy alone | Locally advanced anal carcinoma | Locoregional failure | Chemoradiation superior for local control (RR, 0.54; 95% CI, 0.42–0.69; P < .0001). 13-year follow-up showed OS benefit (HR, 0.67; 95% CI, 0.51–0.88; P = .004). | Improved colostomy-free survival. | Confirmed chemoradiation as standard of care over radiation alone. | The Lancet |
| RTOG 98-11 | Radiation Therapy Oncology Group 98-11 | 2008 | 682 | Induction 5-FU/cisplatin followed by concurrent chemoRT (5-FU/cisplatin) | Concurrent chemoRT (5-FU/mitomycin) | Locally advanced anal carcinoma | 5-year disease-free survival (DFS) | 5-FU/mitomycin superior: 5-year DFS 67.8% vs. 57.8% (P = .006). 5-year OS also superior (78.3% vs. 70.7%; P = .026). | 5-year colostomy-free survival trended better with mitomycin (71.9% vs. 65.0%; P = .05). | Established 5-FU/mitomycin as the standard concurrent chemotherapy regimen over 5-FU/cisplatin. Suggested induction chemotherapy is detrimental. | Journal of Clinical Oncology |
| ACT II | Anal Cancer Trial II | 2013 | 940 | Two factorial: 1) Cisplatin-based vs. Mitomycin-based chemoRT; 2) Maintenance chemo (5-FU/cisplatin) vs. no maintenance | See intervention | Anal squamous cell carcinoma | Complete response rate (chemoRT comparison); Progression-free survival (maintenance comparison) | No difference between cisplatin and mitomycin arms. No benefit for maintenance chemotherapy. | No difference in colostomy rates. 72% of patients without complete response at 11 weeks achieved it by 26 weeks. | Cisplatin is an acceptable alternative to mitomycin. Maintenance chemotherapy is not recommended. Established that persistent disease can regress for up to 6 months. | The Lancet Oncology |
| RTOG 0529 | Radiation Therapy Oncology Group 0529 | 2013 | 52 | Dose-painted IMRT with concurrent 5-FU/mitomycin | Historical control (3D-CRT from RTOG 98-11) | Anal carcinoma treated with IMRT | Grade ≥2 combined acute genitourinary and gastrointestinal adverse events | Did not meet primary endpoint (77% vs. 77%). However, significant reductions in grade ≥2 hematologic (73% vs. 85%; P = .032), grade ≥3 GI (21% vs. 36%; P = .008), and grade ≥3 dermatologic (23% vs. 49%; P < .0001) toxicities. | Long-term: 4-year OS 85.5%, 8-year OS 68%, 8-year DFS 62%. | Demonstrated reduced acute toxicity with IMRT, leading to its preferred status over 3D-CRT for anal cancer treatment. | International Journal of Radiation Oncology, Biology, Physics |
| InterAACT | International Rare Cancers Initiative Multicenter Randomized Phase II Trial | 2020 | 91 | Carboplatin + paclitaxel | Cisplatin + 5-FU | Advanced/metastatic anal squamous cell carcinoma, first-line | Response rate | Similar response rates (59% vs. 57%). Carboplatin/paclitaxel had lower grade ≥3 toxicity (71% vs. 76%) and fewer serious adverse events (36% vs. 62%; P = .016). | Median PFS 8.1 vs. 5.7 months. Median OS 20 vs. 12.3 months (HR, 2.0; 95% CI, 1.15–3.47; P = .014). | Established carboplatin/paclitaxel as a less toxic and potentially more effective first-line regimen than cisplatin/5-FU for metastatic anal cancer. | Journal of Clinical Oncology |
| POD1UM-303/InterAACT2 | Phase 3 study of retifanlimab with carboplatin-paclitaxel in patients with inoperable locally recurrent or metastatic SCAC | 2024 | 315 | Carboplatin/paclitaxel + retifanlimab-dlwr | Carboplatin/paclitaxel + placebo | First-line metastatic/inoperable locally recurrent anal squamous cell carcinoma | Progression-free survival (PFS) | PFS improved: median 9.30 months (95% CI, 7.5–11.3) vs. 7.39 months (95% CI, 7.1–7.7); HR = 0.63; P = .0006. | OS trended favorable: 29.2 months vs. 23.0 months. | Established carboplatin/paclitaxel + retifanlimab as the new preferred first-line regimen for metastatic anal cancer. | Annals of Oncology (abstract) |
| KEYNOTE-158 | Pembrolizumab in patients with previously treated advanced anal squamous cell carcinoma | 2022 | 112 (cohort A) | Pembrolizumab | None (single-arm) | Previously treated advanced anal squamous cell carcinoma | Objective response rate (ORR) | ORR 11% (95% CI, 6–18). Higher in PD-L1-positive (15%) vs. PD-L1-negative (3%). | Disease control rate 58%. | Supported use of pembrolizumab in second-line metastatic anal cancer, regardless of PD-L1 status. | The Lancet Gastroenterology & Hepatology |
| NCI9673 | Nivolumab for previously treated unresectable metastatic anal cancer | 2017 | 37 | Nivolumab | None (single-arm) | Refractory metastatic anal cancer | Response rate | Response rate 24% (95% CI, 15–33). Two complete responses. | Manageable toxicity (13% grade 3 AEs). | Provided early evidence for checkpoint inhibitor activity in anal cancer, leading to inclusion of nivolumab as a second-line option. | The Lancet Oncology |
| ANCHOR | Anal Cancer HSIL Outcomes Research | 2022 | 4459 | Topical or ablative treatment of HSIL | Active monitoring with HRA every 6 months | People living with HIV with anal high-grade squamous intraepithelial lesions (HSIL) | Incident anal cancer | Treatment reduced progression to anal cancer by 57% (95% CI, 6–80; P = .03). 9 vs. 21 cancer cases in treatment vs. monitoring groups. | Progression rate from HSIL to cancer was 402/100,000 person-years with monitoring. | Provides high-level evidence supporting treatment of anal HSIL to prevent anal cancer in high-risk populations. | New England Journal of Medicine |
Clinical PearlsClick to collapse
- Pearl 1: The superior border of the functional anal canal (anorectal ring) separates it from the rectum. Tumors that cannot be entirely seen when buttocks are pressed are anal canal cancers; those that can be visualized are perianal cancers.
- Pearl 2: Concurrent chemoradiation is the standard of care for locoregional anal carcinoma, avoiding the morbidity of a permanent colostomy associated with primary APR.
- Pearl 3: Mitomycin is a critical component of the concurrent chemoradiation regimen. The phase III Intergroup study showed a lower colostomy rate (9% vs. 22%) and higher 4-year DFS (73% vs. 51%) with mitomycin/5-FU vs. 5-FU alone.
- Pearl 4: The ACT-II trial showed no benefit of maintenance chemotherapy or replacement of mitomycin with cisplatin in the chemoRT regimen. Importantly, it also demonstrated that persistent disease may continue to regress up to 26 weeks from treatment start.
- Pearl 5: IMRT is preferred over 3D conformal RT to reduce acute toxicities (especially dermatologic and gastrointestinal) without compromising local control, as demonstrated in RTOG 0529.
- Pearl 6: The POD1UM-303/InterAACT2 trial established carboplatin/paclitaxel + retifanlimab as the new preferred first-line regimen for metastatic anal cancer, showing improved PFS over chemotherapy alone.
- Pearl 7: HPV vaccination is recommended for prevention of anal HPV infection and related lesions. The 9-valent vaccine (Gardasil 9) is now the standard, with demonstrated efficacy in preventing HPV-6/11/16/18-related disease.
- Pearl 8: For patients with persistent disease post-chemoradiation without progression, observation for up to 6 months is appropriate, as complete responses can still be achieved, potentially avoiding an APR.
Special SituationsClick to collapse
People with HIV/AIDS
Persistent Disease After Chemoradiation
Locoregional Recurrence
Metastatic Anal Cancer
Superficially Invasive Squamous Cell Carcinoma (SISCCA)
Perianal Cancer (T1, N0, Well/Moderately Differentiated)
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Anal Carcinoma
NCCN Guidelines for Cancer in People with HIV
NCCN Guidelines for Survivorship
NCCN Guidelines for Distress Management
NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities
NCCN Guidelines for Colon Cancer
Consensus Guidelines for Anal Cancer Screening
AJCC Cancer Staging Manual, 9th Edition
Protective FactorsClick to collapse
- HPV vaccination (quadrivalent or 9-valent vaccine). A substudy showed 77.5% observed efficacy for the quadrivalent vaccine in preventing high-grade anal intraepithelial neoplasia in men who have sex with men [MS-5].
- Antiretroviral therapy (ART) for HIV: Some evidence suggests prolonged ART (>24 months) may be associated with a decrease in the incidence of high-grade anal intraepithelial neoplasia [MS-4].