Estimated new cases and deaths from anal, anal canal, and anorectal cancer in the United States in 2024:[1]
The two major prognostic factors for anal cancer are tumor size and nodal status. Primary tumors smaller than 2 cm have a better prognosis.[2] Nodal drainage of the anus follows the inguinal vein. The initial evaluation of a patient with anal cancer will include a careful clinical examination of the inguinal region and biopsy of any palpable lymph nodes. For more information, see the American Joint Committee on Cancer Stage Groupings and TNM Definitions section.
Anal cancer is usually curable. At presentation, most patients have T1 or T2 disease (≤5 cm), and fewer than 20% of patients have node-positive disease. The 5-year survival rate for these early-stage patients exceeds 85%.[3,4] Even in patients with node-positive disease, 5-year survival rates exceed 50% in the absence of invasion into adjacent organs or distant metastases.[5]
Overall, the risk of anal cancer is rising due to increased incidence of human papillomavirus (HPV) infection.[6,7] Ninety-five percent of anal cancers are HPV related, with the highest risk for serotypes 16 and 18. Involvement of HPV can be pathologically correlated with P16+ staining.[8] Patients with HIV have a higher risk of HPV coinfection, and consequently have a higher risk of anal cancer.
Data suggest that certain sexual practices, such as receptive anal intercourse or a high lifetime number of sexual partners, portend an increased risk of anal cancer. These practices may have led to an increase in the number of individuals at risk of infection with HPV.[6]
Squamous cell (epidermoid) carcinomas make up most primary anal cancers. Historically, a subset of tumors arising from the epithelial transitional zone were categorized as cloacogenic or basaloid tumors. However, these tumors are now recognized as nonkeratinizing squamous cell cancers and are similarly associated with human papillomavirus.[1,2]
Lesions in the hair-bearing skin distal to the squamous mucocutaneous junction are defined as perianal cancers. These are typically treated the same as anal canal cancers, although local therapy alone can be considered for discrete skin lesions with significant separation from the anal verge.
Adenocarcinomas starting in anal glands or fistulae formation are rare and generally have clinical features that are similar to rectal adenocarcinoma. For more information, see the Clinical Features section in Rectal Cancer Treatment.
Treatment of anal melanoma is not included in this summary.
The anal canal extends from the rectum to the perianal skin and is lined by a mucous membrane that covers the internal sphincter. Tumors of the anal margin (below the anal verge and involving the perianal hair-bearing skin) are classified with skin tumors.
The following is a staging system for anal canal cancer that has been described by the AJCC and the International Union Against Cancer.[1] The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define anal cancer.
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 275–84. | ||
| 0 | Tis, N0, M0 | Tis = High-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II–III, high-grade anal intraepithelial neoplasia). |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 275–84. | ||
| I | T1, N0, M0 | T1 = Tumor ≤2 cm. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 275–84. | ||
| IIA | T2, N0, M0 | T2 = Tumor >2 cm but ≤5 cm. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| IIB | T3, N0, M0 | T3 = Tumor >5 cm. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 275–84. | ||
| IIIA | T1, N1, M0 | T1 = Tumor ≤2 cm. |
| N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes. | ||
| M0 = No distant metastasis. | ||
| T2, N1, M0 | T2 = Tumor >2 cm but ≤5 cm. | |
| N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes. | ||
| M0 = No distant metastasis. | ||
| IIIB | T4, N0, M0 | T4 = Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| IIIC | T3, N1, M0 | T3 = Tumor >5 cm. |
| N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes. | ||
| M0 = No distant metastasis. | ||
| T4, N1, M0 | T4 = Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder. | |
| N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 275–84. | ||
| IV | Any T, Any N, M1 | TX = Primary tumor not assessed. |
| T0 = No evidence of primary tumor. | ||
| Tis = High-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II–III, high-grade anal intraepithelial neoplasia). | ||
| T1 = Tumor ≤2 cm. | ||
| T2 = Tumor >2 cm but ≤5 cm. | ||
| T3 = Tumor >5 cm. | ||
| T4 = Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder. | ||
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node metastasis. | ||
| N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes. | ||
| –N1a = Metastasis in inguinal, mesorectal, or internal iliac lymph nodes. | ||
| –N1b = Metastasis in external iliac lymph nodes. | ||
| –N1c = Metastasis in external iliac with any N1a nodes. | ||
| M1 = Distant metastasis. | ||
Treatment options for anal cancer are described in Table 6.
| Stage (TNM Staging Criteria) | Treatment Options |
|---|---|
| Stage 0 | Surgery |
| Stages I, II, and III | Local resection |
| External-beam radiation therapy with chemotherapy | |
| Alternative strategies | |
| Radical resection | |
| Stage IV | Palliative surgery |
| Palliative radiation therapy | |
| Palliative chemotherapy (with or without radiation therapy) | |
| Checkpoint inhibitors |
The optimal approach in patients with advanced disease is still under clinical evaluation. Information about ongoing clinical trials is available from the NCI website.
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[1,2] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[1-3] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[4-6] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[7] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[8]
Stage 0 anal cancer is carcinoma in situ. Rarely diagnosed, it is a very early cancer that has not spread below the limiting membrane of the first layer of anal tissue.
Treatment options for stage 0 anal cancer include the following:
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Current sphincter-sparing therapies include wide local excision for small tumors of the perianal skin or anal margin, or definitive chemoradiation therapy (fluorouracil [5-FU] and mitomycin) for cancers of the anal canal. Radical resection is reserved for patients with incomplete responses or recurrent disease.
Continued surveillance with rectal examination every 3 months for the first 2 years and endoscopy with biopsy when indicated after completion of sphincter-preserving therapy is important to monitor for recurrence.
Treatment options for stage I, stage II, and stage III anal cancer include the following:
Because of historically high rates of recurrence with colostomy alone, chemoradiation therapy is the preferred approach for patients with anal cancer in the absence of distant metastases.
Evidence (chemoradiation therapy):
In this prospective trial, 585 patients were randomly assigned to receive 45 Gy of radiation in 20 or 25 fractions with or without 5-FU. The 5-FU was given by continuous infusion (750 mg/m2 for 5 days or 1,000 mg/m2 for 4 days) during the first and final weeks of radiation therapy, along with a single dose of mitomycin (12 mg/m2) on the first day.
Subsequent trials have found capecitabine to be a reasonable replacement for 5-FU in combination with mitomycin and radiation therapy.[4,5]
While the ACT I and EORTC randomized trials established chemoradiation therapy as the preferred approach for nonmetastatic anal cancer, the substantial hematological, renal, and pulmonary toxicity of mitomycin has prompted studies of alternative regimens.
Evidence (chemoradiation therapy [alternative regimens]):
Two large intergroup trials studied the substitution of cisplatin for mitomycin, with differing conclusions.
The best time to assess a complete clinical response after chemoradiation therapy is generally after 26 weeks because delayed responses are seen.[12] Residual disease or subsequent local recurrence require further treatment.
The standard salvage therapy for patients with either gross or microscopic residual disease after chemoradiation therapy has been abdominoperineal resection. Alternatively, patients may be treated with additional salvage chemoradiation therapy, chemotherapy alone, or immunotherapy.[12,13]
The optimal radiation dose in various situations has not been determined. There is insufficient evidence to determine whether the dose should be escalated for patients with T3 to T4 disease or nodal metastases, or potentially de-escalated for patients with early-stage tumors smaller than 1 cm. It is also unclear whether the chemotherapy backbone can be safely omitted for some patients with early-stage tumors, and whether such a strategy would affect the optimal dose of radiation. The roles for newer strategies such as intensity-modulated radiation therapy, proton beam therapy, and brachytherapy have yet to be conclusively determined.[14-16] Based on the National Cancer Database, higher volume radiation oncology centers report improved OS for patients with anal cancer.[17]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for stage IV anal cancer include the following:
These promising findings have led international investigators to use carboplatin and paclitaxel as a new backbone in trials for patients with advanced-stage disease, as well as a potential partner for use with radiation therapy. Other chemotherapy regimens, such as modified docetaxel, cisplatin, and 5-FU, are under clinical evaluation.[3]
Although there is no clear standard of care for patients with metastatic disease, recent studies are uncovering promising new avenues for systemic treatment. Palliation of symptoms from the primary lesion is important. Patients with stage IV disease should strongly consider enrolling in clinical trials.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The tolerance of patients with HIV and anal carcinoma to standard fluorouracil and mitomycin chemoradiation therapy is not well defined.[1,2] In general, patients with HIV are treated similarly to other patients and have similar outcomes, particularly in the era of highly active antiretroviral therapy (HAART). Patients with pretreatment CD4 counts of fewer than 200 cells/μl may have increased acute and late toxic effects.[3,4] Therefore, patients with a history of AIDS-related complications may have difficulty tolerating a standard regimen, necessitating a dose adjustment or omission of mitomycin.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Local recurrences and persistent disease after treatment with radiation therapy and chemotherapy or surgery as the primary treatment may be controlled by using the alternate treatment (surgical resection after radiation and vice versa).[1] Salvage chemoradiation therapy with fluorouracil and cisplatin plus a radiation boost may avoid permanent colostomy in patients with residual tumor after initial nonoperative therapy.[2] Clinical trials are exploring the use of radiation therapy with chemotherapy and radiosensitizers to improve local control.
Preliminary studies in patients with stage IV disease suggest that alternative chemotherapy regimens (such as carboplatin and paclitaxel in the InterACCT trial [NCT02560298]) or immune checkpoint inhibitors (as in NCI9673 [NCT02314169] and KEYNOTE-028 [NCT02054806]) may be beneficial in this setting.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Anal Cancer
Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 1).
Added Capecitabine and Fluorouracil Dosing as a new subsection.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of anal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Anal Cancer Treatment are:
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Anal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/anal/hp/anal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389221]
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