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</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"></div><div class="body"><div class="t">Anal Cancer Treatment (PDQ®): Health Professional Version</div><div class="j">PDQ Cancer Information Summaries [Internet]</div></div><div class="tail"></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 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class="title" itemprop="name">Anal Cancer Treatment (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contribs">PDQ Adult Treatment Editorial Board.</p><p class="fm-aai"><a href="#_NBK65778_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000062898__323">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.</p><p id="CDR0000062898__324">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).</p></div><div id="CDR0000062898__1"><h2 id="_CDR0000062898__1_">General Information About Anal Cancer</h2><div id="CDR0000062898__139"><h3>Incidence and Mortality</h3><p id="CDR0000062898__101">Estimated new cases and deaths from anal, anal canal, and anorectal cancer in the United States in 2024:[<a class="bibr" href="#CDR0000062898_rl_1_1" rid="CDR0000062898_rl_1_1">1</a>]</p><ul id="CDR0000062898__102"><li class="half_rhythm"><div>New cases: 10,540.</div></li><li class="half_rhythm"><div>Deaths: 2,190.</div></li></ul></div><div id="CDR0000062898__301"><h3>Prognosis and Survival</h3><p id="CDR0000062898__349">The two major prognostic factors for anal cancer are tumor size and nodal status. Primary tumors smaller than 2 cm have a better prognosis.[<a class="bibr" href="#CDR0000062898_rl_1_2" rid="CDR0000062898_rl_1_2">2</a>] 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 <a href="#CDR0000062898__138">American Joint Committee on Cancer Stage Groupings and TNM Definitions</a> section.</p><p id="CDR0000062898__2">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%.[<a class="bibr" href="#CDR0000062898_rl_1_3" rid="CDR0000062898_rl_1_3">3</a>,<a class="bibr" href="#CDR0000062898_rl_1_4" rid="CDR0000062898_rl_1_4">4</a>] Even in patients with node-positive disease, 5-year survival rates exceed 50% in the absence of invasion into adjacent organs or distant metastases.[<a class="bibr" href="#CDR0000062898_rl_1_5" rid="CDR0000062898_rl_1_5">5</a>]</p></div><div id="CDR0000062898__302"><h3>Risk Factors</h3><p id="CDR0000062898__4">Overall, the risk of anal cancer is rising due to increased incidence of human papillomavirus (HPV) infection.[<a class="bibr" href="#CDR0000062898_rl_1_6" rid="CDR0000062898_rl_1_6">6</a>,<a class="bibr" href="#CDR0000062898_rl_1_7" rid="CDR0000062898_rl_1_7">7</a>] 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.[<a class="bibr" href="#CDR0000062898_rl_1_8" rid="CDR0000062898_rl_1_8">8</a>]
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Patients with HIV have a higher risk of HPV coinfection, and consequently have a higher risk of anal cancer.</p><p id="CDR0000062898__350">Data suggest that
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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.[<a class="bibr" href="#CDR0000062898_rl_1_6" rid="CDR0000062898_rl_1_6">6</a>]</p></div><div id="CDR0000062898_rl_1"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_1_1">American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. <a href="https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 30, 2024.</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_2">Ajani JA, Winter KA, Gunderson LL, et al.: Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the intergroup trial (RTOG 98-11). Cancer 116 (17): 4007-13, 2010. [<a href="/pmc/articles/PMC3831519/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3831519</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20564111" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20564111</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_3">Klas JV, Rothenberger DA, Wong WD, et al.: Malignant tumors of the anal canal: the spectrum of disease, treatment, and outcomes. Cancer 85 (8): 1686-93, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10223561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10223561</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_4">Touboul E, Schlienger M, Buffat L, et al.: Epidermoid carcinoma of the anal canal. Results of curative-intent radiation therapy in a series of 270 patients. Cancer 73 (6): 1569-79, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8156483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8156483</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_5">Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 275–84.</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_6">Johnson LG, Madeleine MM, Newcomer LM, et al.: Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973-2000. Cancer 101 (2): 281-8, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15241824" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15241824</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_7">Holly EA, Ralston ML, Darragh TM, et al.: Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst 93 (11): 843-9, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11390533" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11390533</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_1_8">Ryan DP, Compton CC, Mayer RJ: Carcinoma of the anal canal. N Engl J Med 342 (11): 792-800, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10717015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10717015</span></a>]</div></li></ol></div></div><div id="CDR0000062898__5"><h2 id="_CDR0000062898__5_">Cellular Classification of Anal Cancer</h2><p id="CDR0000062898__6">Squamous cell (epidermoid) carcinomas make up most primary
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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.[<a class="bibr" href="#CDR0000062898_rl_5_1" rid="CDR0000062898_rl_5_1">1</a>,<a class="bibr" href="#CDR0000062898_rl_5_2" rid="CDR0000062898_rl_5_2">2</a>]
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</p><p id="CDR0000062898__351">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.</p><p id="CDR0000062898__352">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 <a href="/books/n/pdqcis/CDR0000062726/?report=reader#CDR0000062726__279">Clinical Features</a> section in Rectal Cancer Treatment.</p><p id="CDR0000062898__353">Treatment of anal melanoma is not included in this summary.</p><div id="CDR0000062898_rl_5"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_5_1">Palefsky JM, Holly EA, Gonzales J, et al.: Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 51 (3): 1014-9, 1991. [<a href="https://pubmed.ncbi.nlm.nih.gov/1846314" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1846314</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_5_2">Pirog EC, Quint KD, Yantiss RK: P16/CDKN2A and Ki-67 enhance the detection of anal intraepithelial neoplasia and condyloma and correlate with human papillomavirus detection by polymerase chain reaction. Am J Surg Pathol 34 (10): 1449-55, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20871219" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20871219</span></a>]</div></li></ol></div></div><div id="CDR0000062898__7"><h2 id="_CDR0000062898__7_">Stage Information for Anal Cancer</h2><p id="CDR0000062898__8">The anal canal extends from the rectum to the perianal skin and is lined by a
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mucous membrane that covers the internal sphincter. Tumors of the anal margin (below the anal verge and involving the perianal
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hair-bearing skin) are classified with skin tumors.
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</p><div id="CDR0000062898__138"><h3>American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions</h3><p id="CDR0000062898__133">The following is a staging
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system for anal canal cancer that has been described by the AJCC and the International Union Against Cancer.[<a class="bibr" href="#CDR0000062898_rl_7_1" rid="CDR0000062898_rl_7_1">1</a>] The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define anal cancer.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000062898330"><a href="/books/NBK65778/table/CDR0000062898__330/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000062898330"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000062898__330"><a href="/books/NBK65778/table/CDR0000062898__330/?report=objectonly" target="object" rid-ob="figobCDR0000062898330">Table</a></h4><p class="float-caption no_bottom_margin">Table 1. Definitions of TNM Stage 0<sup>a</sup>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000062898331"><a href="/books/NBK65778/table/CDR0000062898__331/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000062898331"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000062898__331"><a href="/books/NBK65778/table/CDR0000062898__331/?report=objectonly" target="object" rid-ob="figobCDR0000062898331">Table</a></h4><p class="float-caption no_bottom_margin">Table 2. Definitions of TNM Stage I<sup>a</sup>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000062898333"><a href="/books/NBK65778/table/CDR0000062898__333/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000062898333"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000062898__333"><a href="/books/NBK65778/table/CDR0000062898__333/?report=objectonly" target="object" rid-ob="figobCDR0000062898333">Table</a></h4><p class="float-caption no_bottom_margin">Table 3. Definitions of TNM Stages IIA and IIB<sup>a</sup>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000062898332"><a href="/books/NBK65778/table/CDR0000062898__332/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000062898332"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000062898__332"><a href="/books/NBK65778/table/CDR0000062898__332/?report=objectonly" target="object" rid-ob="figobCDR0000062898332">Table</a></h4><p class="float-caption no_bottom_margin">Table 4. Definitions of TNM Stages IIIA, IIIB, and IIIC<sup>a</sup>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000062898337"><a href="/books/NBK65778/table/CDR0000062898__337/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000062898337"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000062898__337"><a href="/books/NBK65778/table/CDR0000062898__337/?report=objectonly" target="object" rid-ob="figobCDR0000062898337">Table</a></h4><p class="float-caption no_bottom_margin">Table 5. Definitions of Stage IV<sup>a</sup>. </p></div></div></div><div id="CDR0000062898_rl_7"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_7_1">Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 275–84.</div></li></ol></div></div><div id="CDR0000062898__36"><h2 id="_CDR0000062898__36_">Treatment Option Overview</h2><p id="CDR0000062898__429">Treatment options for anal cancer are described in <a href="/books/NBK65778/table/CDR0000062898__430/?report=objectonly" target="object" rid-ob="figobCDR0000062898430">Table 6</a>.
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</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000062898430"><a href="/books/NBK65778/table/CDR0000062898__430/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000062898430"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000062898__430"><a href="/books/NBK65778/table/CDR0000062898__430/?report=objectonly" target="object" rid-ob="figobCDR0000062898430">Table</a></h4><p class="float-caption no_bottom_margin">Table 6. Treatment Options for Anal Cancer. </p></div></div><p id="CDR0000062898__38">The optimal approach in patients with advanced disease is still under clinical evaluation. Information about ongoing clinical trials is available from the <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><div id="CDR0000062898__444"><h3>Capecitabine and Fluorouracil Dosing</h3><p id="CDR0000062898__sm_CDR0000813769_4"><div class="milestone-start" id="CDR0000062898__sm_CDR0000813769_3"></div>The <i>DPYD</i> 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 <i>DPYD</i>, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[<a class="bibr" href="#CDR0000062898_rl_36_1" rid="CDR0000062898_rl_36_1">1</a>,<a class="bibr" href="#CDR0000062898_rl_36_2" rid="CDR0000062898_rl_36_2">2</a>] Patients with the <i>DPYD*2A</i> variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other <i>DPYD</i> variants have been identified, with a range of clinical effects.[<a class="bibr" href="#CDR0000062898_rl_36_1" rid="CDR0000062898_rl_36_1">1</a>-<a class="bibr" href="#CDR0000062898_rl_36_3" rid="CDR0000062898_rl_36_3">3</a>] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's <i>DPYD</i> genotype and number of functioning <i>DPYD</i> alleles.[<a class="bibr" href="#CDR0000062898_rl_36_4" rid="CDR0000062898_rl_36_4">4</a>-<a class="bibr" href="#CDR0000062898_rl_36_6" rid="CDR0000062898_rl_36_6">6</a>] <i>DPYD</i> genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[<a class="bibr" href="#CDR0000062898_rl_36_7" rid="CDR0000062898_rl_36_7">7</a>] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.<div class="milestone-end"></div>[<a class="bibr" href="#CDR0000062898_rl_36_8" rid="CDR0000062898_rl_36_8">8</a>]</p></div><div id="CDR0000062898_rl_36"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_36_1">Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [<a href="/pmc/articles/PMC8649021/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8649021</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34506675" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34506675</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_2">Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/27569869" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27569869</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_3">Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/33410339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33410339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_4">Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [<a href="/pmc/articles/PMC5760397/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5760397</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29152729" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29152729</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_5">Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/30348537" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30348537</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_6">Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [<a href="/pmc/articles/PMC8742388/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8742388</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34996412" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34996412</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_7">Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [<a href="/pmc/articles/PMC10496767/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10496767</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35668003" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35668003</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_36_8">Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [<a href="/pmc/articles/PMC10414691/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10414691</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36821823" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36821823</span></a>]</div></li></ol></div></div><div id="CDR0000062898__42"><h2 id="_CDR0000062898__42_">Treatment of Stage 0 Anal Cancer</h2><div id="CDR0000062898__385"><h3>Treatment Options for Stage 0 Anal Cancer</h3><p id="CDR0000062898__386">Stage 0 anal cancer is carcinoma <i>in situ</i>. Rarely diagnosed, it is a very early
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cancer that has not spread below the limiting membrane of the first layer of
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anal tissue.</p><p id="CDR0000062898__387">Treatment options for <a href="/books/NBK65778/table/CDR0000062898__330/?report=objectonly" target="object" rid-ob="figobCDR0000062898330">stage 0 anal cancer</a> include the following:
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</p><ol id="CDR0000062898__438"><li class="half_rhythm"><div>Surgical resection is used to treat lesions of the perianal area not
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involving the anal sphincter. The surgical approach depends on the location of the lesion in
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the anal canal.</div></li></ol></div><div id="CDR0000062898__TrialSearch_42_sid_5"><h3>Current Clinical Trials</h3><p id="CDR0000062898__TrialSearch_42_22">Use our <a href="https://www.cancer.gov/research/participate/clinical-trials-search/advanced" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> 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. <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div></div><div id="CDR0000062898__45"><h2 id="_CDR0000062898__45_">Treatment of Stages I, II, and III Anal Cancer</h2><div id="CDR0000062898__389"><h3>Treatment Options for Stages I, II, and III Anal Cancer</h3><p id="CDR0000062898__390">Current sphincter-sparing therapies include wide local excision for small
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tumors of the perianal skin or anal margin, or definitive chemoradiation therapy
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(fluorouracil [5-FU] and mitomycin) for cancers of the anal canal. Radical resection is reserved for patients with
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incomplete responses or recurrent disease.
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</p><p id="CDR0000062898__427">Continued surveillance
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with rectal examination every 3 months for the first 2 years and
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endoscopy with biopsy when indicated after completion of sphincter-preserving
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therapy is important to monitor for recurrence.</p><p id="CDR0000062898__391">Treatment options for <a href="/books/NBK65778/table/CDR0000062898__331/?report=objectonly" target="object" rid-ob="figobCDR0000062898331">stage I</a>, <a href="/books/NBK65778/table/CDR0000062898__333/?report=objectonly" target="object" rid-ob="figobCDR0000062898333">stage II</a>, and <a href="/books/NBK65778/table/CDR0000062898__332/?report=objectonly" target="object" rid-ob="figobCDR0000062898332">stage III anal cancer</a> include the following:
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</p><ol id="CDR0000062898__392"><li class="half_rhythm"><div>Small tumors of the perianal skin or anal margin not involving the anal
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sphincter may be adequately treated with local resection.[<a class="bibr" href="#CDR0000062898_rl_45_1" rid="CDR0000062898_rl_45_1">1</a>]</div></li><li class="half_rhythm"><div>The standard of care for all other stage I, II, and III anal cancers in appropriate patients is <a href="#CDR0000062898__396">chemoradiation therapy</a> (external-beam radiation therapy [EBRT] with chemotherapy).<ul id="CDR0000062898__395"><li class="half_rhythm"><div>5-FU + mitomycin + radiation therapy.[<a class="bibr" href="#CDR0000062898_rl_45_2" rid="CDR0000062898_rl_45_2">2</a>,<a class="bibr" href="#CDR0000062898_rl_45_3" rid="CDR0000062898_rl_45_3">3</a>]</div></li><li class="half_rhythm"><div>Capecitabine + mitomycin + radiation therapy.[<a class="bibr" href="#CDR0000062898_rl_45_4" rid="CDR0000062898_rl_45_4">4</a>,<a class="bibr" href="#CDR0000062898_rl_45_5" rid="CDR0000062898_rl_45_5">5</a>]</div></li><li class="half_rhythm"><div>5-FU + cisplatin + radiation therapy.[<a class="bibr" href="#CDR0000062898_rl_45_6" rid="CDR0000062898_rl_45_6">6</a>,<a class="bibr" href="#CDR0000062898_rl_45_7" rid="CDR0000062898_rl_45_7">7</a>]</div></li></ul></div></li><li class="half_rhythm"><div>Alternative strategies such as radiation therapy alone or surgery alone may be considered, depending on the clinical context.</div></li><li class="half_rhythm"><div>Radical resection is reserved for residual or recurrent cancer in the anal
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canal after nonoperative therapy.
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</div></li></ol><div id="CDR0000062898__396"><h4>Chemoradiation therapy</h4><p id="CDR0000062898__397">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.</p><p id="CDR0000062898__398">Evidence (chemoradiation therapy):</p><ol id="CDR0000062898__399"><li class="half_rhythm"><div class="half_rhythm">The Anal Cancer Trial (ACT I) from the United Kingdom Co-ordinating Committee on Cancer Research demonstrated the superiority of chemoradiation with 5-FU and mitomycin over radiation therapy alone with regard to local failure and deaths from anal cancer.[<a class="bibr" href="#CDR0000062898_rl_45_2" rid="CDR0000062898_rl_45_2">2</a>,<a class="bibr" href="#CDR0000062898_rl_45_8" rid="CDR0000062898_rl_45_8">8</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810017/" class="def">Level of evidence A1</a>]</div><div class="half_rhythm">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/m<sup>2</sup> for 5 days or 1,000 mg/m<sup>2</sup> for 4 days) during the first and final weeks of radiation therapy, along with a single dose of mitomycin (12 mg/m<sup>2</sup>) on the first day.<ul id="CDR0000062898__401"><li class="half_rhythm"><div>After a median follow-up of 13.1 years, patients who received chemoradiation therapy had a reduction in local failure (36% vs. 59%; hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.35−0.60; <i>P</i> < .001), risk of death from anal cancer (HR, 0.61; 95% CI, 0.49−0.76; <i>P</i> < .001), and relapse at 12 years (17.7% vs. 29.7%; HR, 0.70; 95% CI, 9.58−0.84; <i>P</i> < .001).[<a class="bibr" href="#CDR0000062898_rl_45_2" rid="CDR0000062898_rl_45_2">2</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810017/" class="def">Level of evidence A1</a>]</div></li><li class="half_rhythm"><div>There was no significant difference in overall survival (OS) in this trial (HR, 0.86; 95% CI, 0.70−1.04; <i>P</i> = .12).</div></li><li class="half_rhythm"><div>An initial 9.1% increase in non–anal cancer deaths was observed in the first 5 years after chemoradiation therapy but was not seen at 10 years.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">A European Organisation for Research and Treatment of Cancer (EORTC) trial prospectively randomly assigned 100 patients with T3 to T4 or N1 to N3 disease to receive 45 Gy of radiation with a 15-Gy or 30-Gy boost with or without 5-FU infusion (750 mg/m<sup>2</sup> for 5 days starting on days 1 and 29) plus mitomycin (15 mg/m<sup>2</sup> on day 1).[<a class="bibr" href="#CDR0000062898_rl_45_3" rid="CDR0000062898_rl_45_3">3</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]<ul id="CDR0000062898__403"><li class="half_rhythm"><div>Outcomes favored chemoradiation therapy with respect to 5-year colostomy-free survival rates (75% vs. 48%; <i>P</i> = .002) and 5-year progression-free survival (PFS) rates (60% vs. 48%; <i>P</i> = .05).</div></li></ul></div></li></ol><p id="CDR0000062898__404">Subsequent trials have found capecitabine to be a reasonable replacement for 5-FU in combination with mitomycin and radiation therapy.[<a class="bibr" href="#CDR0000062898_rl_45_4" rid="CDR0000062898_rl_45_4">4</a>,<a class="bibr" href="#CDR0000062898_rl_45_5" rid="CDR0000062898_rl_45_5">5</a>]</p><p id="CDR0000062898__405">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.</p><p id="CDR0000062898__406">Evidence (chemoradiation therapy [<b>alternative regimens</b>]):</p><ol id="CDR0000062898__407"><li class="half_rhythm"><div class="half_rhythm">A Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group trial of 310 patients studied chemoradiation therapy (5-FU infusion + 45 Gy of radiation) with or without mitomycin.<ul id="CDR0000062898__408"><li class="half_rhythm"><div>After 4-years of follow-up, patients who received mitomycin had an improved colostomy-free survival rate (71% vs. 59%; <i>P</i> = .014) and disease-free survival (DFS) rate (73% vs. 51%; <i>P</i> = .0003).[<a class="bibr" href="#CDR0000062898_rl_45_9" rid="CDR0000062898_rl_45_9">9</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]</div></li></ul></div><div class="half_rhythm">Two large intergroup trials studied the substitution of cisplatin for mitomycin, with differing conclusions. </div></li><li class="half_rhythm"><div class="half_rhythm">In a phase III U.S. Intergroup trial (<a href="https://www.cancer.gov/clinicaltrials/NCT00003596" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">RTOG 9811</a> [<a href="https://clinicaltrials.gov/show/NCT00003596" title="Study NCT00003596" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT00003596</a>]), patients in the cisplatin arm received two cycles of induction 5-FU and cisplatin before receiving concurrent chemoradiation therapy with 5-FU and cisplatin.[<a class="bibr" href="#CDR0000062898_rl_45_6" rid="CDR0000062898_rl_45_6">6</a>]<ul id="CDR0000062898__409"><li class="half_rhythm"><div>Patients who received mitomycin had improved local control and an improved colostomy-free survival rate (90% vs. 81%; <i>P</i> = .02). Subsequent long-term follow-up demonstrated a borderline significant difference in the 5-year colostomy-free survival rate (71.9% vs. 65%; <i>P</i> = .05).[<a class="bibr" href="#CDR0000062898_rl_45_10" rid="CDR0000062898_rl_45_10">10</a>]</div></li><li class="half_rhythm"><div>Long-term follow-up also demonstrated a superior 5-year DFS rate (67.8% vs. 57.8%; <i>P</i> = .006) and OS rate (78.3% vs. 70.7%; <i>P</i> = .074) for patients who received mitomycin.[<a class="bibr" href="#CDR0000062898_rl_45_11" rid="CDR0000062898_rl_45_11">11</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]</div></li><li class="half_rhythm"><div>One potential explanation for the inferiority of cisplatin in this study was the delay in time to radiation therapy during induction chemotherapy.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">In the prospective randomized ACT II trial, 940 patients were assigned in a 2 × 2 factorial design to receive the following: (1) either mitomycin or cisplatin during induction chemoradiation therapy and (2) either maintenance therapy with 5-FU and cisplatin in weeks 11 and 14 or no maintenance therapy.[<a class="bibr" href="#CDR0000062898_rl_45_7" rid="CDR0000062898_rl_45_7">7</a>]<ul id="CDR0000062898__410"><li class="half_rhythm"><div>The complete remission rate was equivalent in patients who received mitomycin or cisplatin after a median follow-up of 5.1 years (90.5% vs. 89.6%; 95% CI, -4.9 to 3.1; <i>P</i> = .64). The 3-year PFS rate was also equivalent in both study groups (73% for mitomycin vs. 72% for cisplatin; HR, 0.95; 95% CI, 0.75−1.19; <i>P</i> = .063).[<a class="bibr" href="#CDR0000062898_rl_45_7" rid="CDR0000062898_rl_45_7">7</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810025/" class="def">Level of evidence B1</a>]</div></li><li class="half_rhythm"><div>There was also no significant effect on 3-year PFS rates among patients who received maintenance therapy or no maintenance therapy (74% vs. 73%; HR, 0.95; 95% CI, 0.75−1.21; <i>P</i> = .70).</div></li><li class="half_rhythm"><div>This study suggests that cisplatin might reasonably substitute for mitomycin in a chemoradiation strategy.</div></li></ul></div></li></ol><p id="CDR0000062898__411">The best time to assess a complete clinical response after chemoradiation therapy is generally after 26 weeks because delayed responses are seen.[<a class="bibr" href="#CDR0000062898_rl_45_12" rid="CDR0000062898_rl_45_12">12</a>] Residual disease or subsequent local recurrence require further treatment.</p><p id="CDR0000062898__412">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.[<a class="bibr" href="#CDR0000062898_rl_45_12" rid="CDR0000062898_rl_45_12">12</a>,<a class="bibr" href="#CDR0000062898_rl_45_13" rid="CDR0000062898_rl_45_13">13</a>]</p><p id="CDR0000062898__413">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.[<a class="bibr" href="#CDR0000062898_rl_45_14" rid="CDR0000062898_rl_45_14">14</a>-<a class="bibr" href="#CDR0000062898_rl_45_16" rid="CDR0000062898_rl_45_16">16</a>] Based on the National Cancer Database, higher volume radiation oncology centers report improved OS for patients with anal cancer.[<a class="bibr" href="#CDR0000062898_rl_45_17" rid="CDR0000062898_rl_45_17">17</a>]</p></div></div><div id="CDR0000062898__TrialSearch_45_sid_6"><h3>Current Clinical Trials</h3><p id="CDR0000062898__TrialSearch_45_22">Use our <a href="https://www.cancer.gov/research/participate/clinical-trials-search/advanced" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> 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. <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062898_rl_45"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_45_1">Enker WE, Heilwell M, Janov AJ, et al.: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Arch Surg 121 (12): 1386-90, 1986. [<a href="https://pubmed.ncbi.nlm.nih.gov/3789909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3789909</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_2">Northover J, Glynne-Jones R, Sebag-Montefiore D, et al.: Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer 102 (7): 1123-8, 2010. [<a href="/pmc/articles/PMC2853094/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2853094</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20354531" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20354531</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_3">Bartelink H, Roelofsen F, Eschwege F, et al.: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15 (5): 2040-9, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9164216" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9164216</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_4">Goodman KA, Julie D, Cercek A, et al.: Capecitabine With Mitomycin Reduces Acute Hematologic Toxicity and Treatment Delays in Patients Undergoing Definitive Chemoradiation Using Intensity Modulated Radiation Therapy for Anal Cancer. Int J Radiat Oncol Biol Phys 98 (5): 1087-1095, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28721892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28721892</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_5">Meulendijks D, Dewit L, Tomasoa NB, et al.: Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer 111 (9): 1726-33, 2014. [<a href="/pmc/articles/PMC4453727/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4453727</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25167226" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25167226</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_6">Ajani JA, Winter KA, Gunderson LL, et al.: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 299 (16): 1914-21, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18430910" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18430910</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_7">James RD, Glynne-Jones R, Meadows HM, et al.: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 14 (6): 516-24, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23578724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23578724</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_8">Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348 (9034): 1049-54, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8874455" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8874455</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_9">Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 14 (9): 2527-39, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8823332" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8823332</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_10">Eng C, Ciombor KK, Cho M, et al.: Anal Cancer: Emerging Standards in a Rare Disease. J Clin Oncol 40 (24): 2774-2788, 2022. [<a href="https://pubmed.ncbi.nlm.nih.gov/35649196" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35649196</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_11">Gunderson LL, Winter KA, Ajani JA, et al.: Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 30 (35): 4344-51, 2012. [<a href="/pmc/articles/PMC3515768/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3515768</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23150707" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23150707</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_12">Pedersen TB, Gocht-Jensen P, Klein MF: 30-day and long-term outcome following salvage surgery for squamous cell carcinoma of the anus. Eur J Surg Oncol 44 (10): 1518-1521, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/30251642" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30251642</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_13">Guerra GR, Kong JC, Bernardi MP, et al.: Salvage Surgery for Locoregional Failure in Anal Squamous Cell Carcinoma. Dis Colon Rectum 61 (2): 179-186, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/29337772" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29337772</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_14">Cordoba A, Escande A, Leroy T, et al.: Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers. Brachytherapy 16 (1): 230-235, 2017 Jan - Feb. [<a href="https://pubmed.ncbi.nlm.nih.gov/27600606" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27600606</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_15">Call JA, Prendergast BM, Jensen LG, et al.: Intensity-modulated Radiation Therapy for Anal Cancer: Results From a Multi-Institutional Retrospective Cohort Study. Am J Clin Oncol 39 (1): 8-12, 2016. [<a href="/pmc/articles/PMC10865428/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10865428</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24401669" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24401669</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_16">Gryc T, Ott O, Putz F, et al.: Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results. Brachytherapy 15 (6): 865-872, 2016 Nov - Dec. [<a href="https://pubmed.ncbi.nlm.nih.gov/27720203" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27720203</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_45_17">Amini A, Jones BL, Ghosh D, et al.: Impact of facility volume on outcomes in patients with squamous cell carcinoma of the anal canal: Analysis of the National Cancer Data Base. Cancer 123 (2): 228-236, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/27571233" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27571233</span></a>]</div></li></ol></div></div><div id="CDR0000062898__73"><h2 id="_CDR0000062898__73_">Treatment of Stage IV Anal Cancer</h2><div id="CDR0000062898__415"><h3>Treatment Options for Stage IV Anal Cancer</h3><p id="CDR0000062898__416">Treatment options for <a href="/books/NBK65778/table/CDR0000062898__337/?report=objectonly" target="object" rid-ob="figobCDR0000062898337">stage IV anal cancer</a> include the following:
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</p><ol id="CDR0000062898__417"><li class="half_rhythm"><div>Palliative surgery.
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</div></li><li class="half_rhythm"><div>Palliative radiation therapy.
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</div></li><li class="half_rhythm"><div> Palliative chemotherapy (with or without radiation therapy).
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<ul id="CDR0000062898__383"><li class="half_rhythm"><div>Cisplatin + infusional fluorouracil (5-FU).[<a class="bibr" href="#CDR0000062898_rl_73_1" rid="CDR0000062898_rl_73_1">1</a>]</div></li><li class="half_rhythm"><div>Carboplatin + weekly paclitaxel.[<a class="bibr" href="#CDR0000062898_rl_73_2" rid="CDR0000062898_rl_73_2">2</a>]</div></li><li class="half_rhythm"><div>Docetaxel + cisplatin + 5-FU.[<a class="bibr" href="#CDR0000062898_rl_73_3" rid="CDR0000062898_rl_73_3">3</a>]</div></li><li class="half_rhythm"><div>Nivolumab.[<a class="bibr" href="#CDR0000062898_rl_73_4" rid="CDR0000062898_rl_73_4">4</a>]</div></li><li class="half_rhythm"><div>Pembrolizumab.[<a class="bibr" href="#CDR0000062898_rl_73_5" rid="CDR0000062898_rl_73_5">5</a>]</div></li></ul></div></li><li class="half_rhythm"><div>Checkpoint inhibitors.</div></li></ol><div id="CDR0000062898__418"><h4>Advanced-stage therapy</h4><ol id="CDR0000062898__420"><li class="half_rhythm"><div class="half_rhythm">In the multicenter, randomized, phase II International Advanced Anal Cancer <a href="https://www.cancer.gov/clinicaltrials/NCT02560298" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">InterAACT</a> trial (<a href="https://clinicaltrials.gov/show/NCT02560298" title="Study NCT02560298" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02560298</a>), carboplatin (area under the curve 5) and weekly paclitaxel was compared with standard infusional 5-FU and bolus cisplatin in patients with advanced-stage anal cancer.[<a class="bibr" href="#CDR0000062898_rl_73_2" rid="CDR0000062898_rl_73_2">2</a>]<ul id="CDR0000062898__421"><li class="half_rhythm"><div>With a median follow-up of 25.3 months, the median overall survival (OS) with carboplatin and paclitaxel was improved compared with cisplatin and 5-FU (20 months vs. 12.3 months; hazard ratio [HR], 2.0; <i>P</i> = .014).[<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810017/" class="def">Level of evidence A1</a>]</div></li><li class="half_rhythm"><div>Serious adverse events were more common in patients treated with cisplatin plus 5-FU (62% vs. 36%; <i>P</i> = .016).</div></li></ul></div><div class="half_rhythm">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.[<a class="bibr" href="#CDR0000062898_rl_73_3" rid="CDR0000062898_rl_73_3">3</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">The checkpoint inhibitors have also shown activity for patients with metastatic disease. The phase II <a href="https://www.cancer.gov/clinicaltrials/NCT02314169" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI96773</a> trial (<a href="https://clinicaltrials.gov/show/NCT02314169" title="Study NCT02314169" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02314169</a>) of single-agent nivolumab (3 mg/kg every 2 weeks) enrolled 37 patients.[<a class="bibr" href="#CDR0000062898_rl_73_4" rid="CDR0000062898_rl_73_4">4</a>]<ul id="CDR0000062898__423"><li class="half_rhythm"><div>The overall response rate was 24%, including two complete responses.[<a class="bibr" href="#CDR0000062898_rl_73_4" rid="CDR0000062898_rl_73_4">4</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810039/" class="def">Level of evidence C3</a>]</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">The phase Ib <a href="https://www.cancer.gov/clinicaltrials/NCT02054806" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">KEYNOTE-028</a> trial (<a href="https://clinicaltrials.gov/show/NCT02054806" title="Study NCT02054806" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02054806</a>) for patients with advanced tumors with programmed death ligand-1 of at least 1% enrolled a cohort of 24 patients with anal squamous cell carcinoma.[<a class="bibr" href="#CDR0000062898_rl_73_5" rid="CDR0000062898_rl_73_5">5</a>]<ul id="CDR0000062898__424"><li class="half_rhythm"><div>The overall response rate was 17%, and an additional stable disease rate was 42%.[<a class="bibr" href="#CDR0000062898_rl_73_5" rid="CDR0000062898_rl_73_5">5</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810039/" class="def">Level of evidence C3</a>]</div></li></ul></div></li></ol><p id="CDR0000062898__74">Although there is no clear standard of care for patients with metastatic disease, recent studies are uncovering promising new avenues for systemic treatment.
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Palliation of symptoms from the primary lesion is important. Patients with stage IV disease should strongly consider enrolling in clinical trials.
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</p></div></div><div id="CDR0000062898__TrialSearch_73_sid_7"><h3>Current Clinical Trials</h3><p id="CDR0000062898__TrialSearch_73_22">Use our <a href="https://www.cancer.gov/research/participate/clinical-trials-search/advanced" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> 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. <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062898_rl_73"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_73_1">James RD, Glynne-Jones R, Meadows HM, et al.: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 14 (6): 516-24, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23578724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23578724</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_73_2">Rao S, Sclafani F, Eng C, et al.: International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol 38 (22): 2510-2518, 2020. [<a href="/pmc/articles/PMC7406334/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7406334</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32530769" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32530769</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_73_3">Kim S, François E, André T, et al.: Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol 19 (8): 1094-1106, 2018. [<a href="https://pubmed.ncbi.nlm.nih.gov/30042063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30042063</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_73_4">Morris VK, Salem ME, Nimeiri H, et al.: Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol 18 (4): 446-453, 2017. [<a href="/pmc/articles/PMC5809128/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5809128</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28223062" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28223062</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_73_5">Ott PA, Piha-Paul SA, Munster P, et al.: Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 28 (5): 1036-1041, 2017. [<a href="/pmc/articles/PMC5406758/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5406758</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28453692" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28453692</span></a>]</div></li></ol></div></div><div id="CDR0000062898__425"><h2 id="_CDR0000062898__425_">Treatment of HIV and Anal Cancer</h2><p id="CDR0000062898__426">The tolerance of patients with HIV and anal
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carcinoma to standard fluorouracil and mitomycin chemoradiation therapy is not well
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defined.[<a class="bibr" href="#CDR0000062898_rl_425_1" rid="CDR0000062898_rl_425_1">1</a>,<a class="bibr" href="#CDR0000062898_rl_425_2" rid="CDR0000062898_rl_425_2">2</a>] 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
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have increased acute and late toxic effects.[<a class="bibr" href="#CDR0000062898_rl_425_3" rid="CDR0000062898_rl_425_3">3</a>,<a class="bibr" href="#CDR0000062898_rl_425_4" rid="CDR0000062898_rl_425_4">4</a>]
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Therefore, patients with a history of AIDS-related complications may have difficulty tolerating a standard regimen, necessitating a dose adjustment or omission of mitomycin.</p><div id="CDR0000062898__TrialSearch_425_sid_8"><h3>Current Clinical Trials</h3><p id="CDR0000062898__TrialSearch_425_22">Use our <a href="https://www.cancer.gov/research/participate/clinical-trials-search/advanced" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> 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. <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062898_rl_425"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_425_1">Holland JM, Swift PS: Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 193 (1): 251-4, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8090901" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8090901</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_425_2">Peddada AV, Smith DE, Rao AR, et al.: Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 37 (5): 1101-5, 1997. [<a href="https://pubmed.ncbi.nlm.nih.gov/9169819" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9169819</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_425_3">Hoffman R, Welton ML, Klencke B, et al.: The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 44 (1): 127-31, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10219805" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10219805</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_425_4">Place RJ, Gregorcyk SG, Huber PJ, et al.: Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum 44 (4): 506-12, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11330577" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11330577</span></a>]</div></li></ol></div></div><div id="CDR0000062898__80"><h2 id="_CDR0000062898__80_">Treatment of Recurrent Anal Cancer</h2><p id="CDR0000062898__81">Local recurrences and persistent disease after treatment with radiation therapy and chemotherapy or
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surgery as the primary treatment may be controlled by using the alternate
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treatment (surgical resection after radiation and vice versa).[<a class="bibr" href="#CDR0000062898_rl_80_1" rid="CDR0000062898_rl_80_1">1</a>] Salvage chemoradiation therapy with fluorouracil and cisplatin plus a radiation boost may avoid permanent colostomy in patients with residual tumor after initial nonoperative therapy.[<a class="bibr" href="#CDR0000062898_rl_80_2" rid="CDR0000062898_rl_80_2">2</a>] Clinical
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trials are exploring the use of radiation therapy with chemotherapy and
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radiosensitizers to improve local control.
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</p><p id="CDR0000062898__384">Preliminary studies in patients with stage IV disease suggest that alternative chemotherapy regimens (such as carboplatin and paclitaxel in the <a href="https://www.cancer.gov/clinicaltrials/NCT02560298" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">InterACCT</a> trial [<a href="https://clinicaltrials.gov/show/NCT02560298" title="Study NCT02560298" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02560298</a>]) or immune checkpoint inhibitors (as in <a href="https://www.cancer.gov/clinicaltrials/NCT02314169" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI9673</a> [<a href="https://clinicaltrials.gov/show/NCT02314169" title="Study NCT02314169" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02314169</a>] and <a href="https://www.cancer.gov/clinicaltrials/NCT02054806" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">KEYNOTE-028</a> [<a href="https://clinicaltrials.gov/show/NCT02054806" title="Study NCT02054806" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02054806</a>]) may be beneficial in this setting.</p><div id="CDR0000062898__TrialSearch_80_sid_9"><h3>Current Clinical Trials</h3><p id="CDR0000062898__TrialSearch_80_22">Use our <a href="https://www.cancer.gov/research/participate/clinical-trials-search/advanced" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">advanced clinical trial search</a> 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. <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">General information</a> about clinical trials is also available.</p></div><div id="CDR0000062898_rl_80"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000062898_rl_80_1">Longo WE, Vernava AM, Wade TP, et al.: Recurrent squamous cell carcinoma of the anal canal. Predictors of initial treatment failure and results of salvage therapy. Ann Surg 220 (1): 40-9, 1994. [<a href="/pmc/articles/PMC1234285/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1234285</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8024357" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8024357</span></a>]</div></li><li><div class="bk_ref" id="CDR0000062898_rl_80_2">Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 14 (9): 2527-39, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8823332" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8823332</span></a>]</div></li></ol></div></div><div id="CDR0000062898__89"><h2 id="_CDR0000062898__89_">Latest Updates to This Summary (01/19/2024)</h2><p id="CDR0000062898__90">The PDQ cancer information summaries are reviewed regularly and updated as
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new information becomes available. This section describes the latest
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changes made to this summary as of the date above.
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</p><p id="CDR0000062898__440">
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<b>
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<a href="#CDR0000062898__1">General Information About Anal Cancer</a>
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</b>
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</p><p id="CDR0000062898__442">Updated <a href="#CDR0000062898__101">statistics</a> with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 1).</p><p id="CDR0000062898__445">
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<b>
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<a href="#CDR0000062898__36">Treatment Option Overview</a>
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</b>
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</p><p id="CDR0000062898__446">Added <a href="#CDR0000062898__444">Capecitabine and Fluorouracil Dosing</a> as a new subsection.</p><p id="CDR0000062898__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/adult-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Adult Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000062898__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® Cancer Information for Health Professionals</a> pages.
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</p></div><div id="CDR0000062898__AboutThis_1"><h2 id="_CDR0000062898__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000062898__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000062898__AboutThis_3">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.</p></div><div id="CDR0000062898__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000062898__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/adult-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Adult Treatment Editorial Board</a>, 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).</p><p id="CDR0000062898__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000062898__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000062898__AboutThis_7">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.</p><p>The lead reviewers for Anal Cancer Treatment are:</p><ul><li class="half_rhythm"><div>Amit Chowdhry, MD, PhD (University of Rochester Medical Center)</div></li><li class="half_rhythm"><div>Valerie Lee, MD (Johns Hopkins University)</div></li><li class="half_rhythm"><div>Leon Pappas, MD, PhD (Dana-Farber Cancer Institute)</div></li><li class="half_rhythm"><div>Ari Seifter, MD (University of Illinois at Chicago)</div></li></ul><p id="CDR0000062898__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000062898__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000062898__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a <a href="/books/n/pdqcis/CDR0000062796/?report=reader">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000062898__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000062898__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000062898__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000062898__AboutThis_15">PDQ® Adult Treatment Editorial Board. PDQ Anal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/types/anal/hp/anal-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/types/anal/hp/anal-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389221]</p><p id="CDR0000062898__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000062898__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000062898__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000062898__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000062898__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div><div class="fm-sec"><h2 id="_NBK65778_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">PDQ Adult Treatment Editorial Board</span>.</p><h3>Publication History</h3><p class="small">Published online: January 19, 2024.</p><h3>Version History</h3><ul class="simple-list" style="padding:0"><li><span class="bk_col_itm">NBK65778.15</span> January 19, 2024 (Displayed Version)</li><li><span class="bk_col_itm"><a href="/books/NBK65778.14/?report=reader">NBK65778.14</a></span> January 13, 2023</li><li><span class="bk_col_itm"><a href="/books/NBK65778.13/?report=reader">NBK65778.13</a></span> November 4, 2022</li><li><span class="bk_col_itm"><a href="/books/NBK65778.12/?report=reader">NBK65778.12</a></span> January 20, 2022</li><li><span class="bk_col_itm"><a href="/books/NBK65778.11/?report=reader">NBK65778.11</a></span> June 3, 2021</li><li><span class="bk_col_itm"><a href="/books/NBK65778.10/?report=reader">NBK65778.10</a></span> January 15, 2021</li><li><span class="bk_col_itm"><a href="/books/NBK65778.9/?report=reader">NBK65778.9</a></span> January 22, 2020</li><li><span class="bk_col_itm"><a href="/books/NBK65778.8/?report=reader">NBK65778.8</a></span> August 16, 2019</li><li><span class="bk_col_itm"><a href="/books/NBK65778.7/?report=reader">NBK65778.7</a></span> January 29, 2019</li><li><span class="bk_col_itm"><a href="/books/NBK65778.6/?report=reader">NBK65778.6</a></span> October 24, 2018</li><li><span class="bk_col_itm"><a href="/books/NBK65778.5/?report=reader">NBK65778.5</a></span> February 1, 2018</li><li><span class="bk_col_itm"><a href="/books/NBK65778.4/?report=reader">NBK65778.4</a></span> January 24, 2018</li><li><span class="bk_col_itm"><a href="/books/NBK65778.3/?report=reader">NBK65778.3</a></span> January 31, 2017</li><li><span class="bk_col_itm"><a href="/books/NBK65778.2/?report=reader">NBK65778.2</a></span> February 4, 2016</li><li><span class="bk_col_itm"><a href="/books/NBK65778.1/?report=reader">NBK65778.1</a></span> July 7, 2015</li></ul><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>PDQ Adult Treatment Editorial Board. Anal Cancer Treatment (PDQ®): Health Professional Version. 2024 Jan 19. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article><article data-type="table-wrap" id="figobCDR0000062898330"><div id="CDR0000062898__330" class="table"><h3><span class="title">Table 1. Definitions of TNM Stage 0<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65778/table/CDR0000062898__330/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062898__330_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th></tr></thead><tbody><tr><td colspan="1" rowspan="3" style="vertical-align:top;">0</td><td colspan="1" rowspan="3" style="vertical-align:top;">Tis, N0, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tis = High-grade squamous intraepithelial lesion (previously termed carcinoma <i>in situ</i>, Bowen disease, anal intraepithelial neoplasia II–III, high-grade anal intraepithelial neoplasia).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No regional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp. 275–84.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobCDR0000062898331"><div id="CDR0000062898__331" class="table"><h3><span class="title">Table 2. Definitions of TNM Stage I<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65778/table/CDR0000062898__331/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062898__331_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th></tr></thead><tbody><tr><td colspan="1" rowspan="3" style="vertical-align:top;">I</td><td colspan="1" rowspan="3" style="vertical-align:top;">T1, N0, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No regional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp. 275–84.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobCDR0000062898333"><div id="CDR0000062898__333" class="table"><h3><span class="title">Table 3. Definitions of TNM Stages IIA and IIB<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65778/table/CDR0000062898__333/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062898__333_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th></tr></thead><tbody><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IIA</td><td colspan="1" rowspan="3" style="vertical-align:top;">T2, N0, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤5 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No regional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IIB</td><td colspan="1" rowspan="3" style="vertical-align:top;">T3, N0, M0 </td><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >5 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No regional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp. 275–84.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobCDR0000062898332"><div id="CDR0000062898__332" class="table"><h3><span class="title">Table 4. Definitions of TNM Stages IIIA, IIIB, and IIIC<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65778/table/CDR0000062898__332/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062898__332_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th></tr></thead><tbody><tr><td colspan="1" rowspan="6" style="vertical-align:top;">IIIA</td><td colspan="1" rowspan="3" style="vertical-align:top;">T1, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">T2, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤5 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">IIIB</td><td colspan="1" rowspan="3" style="vertical-align:top;">T4, N0, M0 </td><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No regional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="6" style="vertical-align:top;">IIIC</td><td colspan="1" rowspan="3" style="vertical-align:top;">T3, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >5 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr><tr><td colspan="1" rowspan="3" style="vertical-align:top;">T4, N1, M0</td><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M0 = No distant metastasis.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp. 275–84.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobCDR0000062898337"><div id="CDR0000062898__337" class="table"><h3><span class="title">Table 5. Definitions of Stage IV<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65778/table/CDR0000062898__337/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062898__337_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Stage</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">TNM</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Description</th></tr></thead><tbody><tr><td colspan="1" rowspan="14" style="vertical-align:top;">IV</td><td colspan="1" rowspan="14" style="vertical-align:top;">Any T, Any N, M1</td><td colspan="1" rowspan="1" style="vertical-align:top;">TX = Primary tumor not assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T0 = No evidence of primary tumor.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Tis = High-grade squamous intraepithelial lesion (previously termed carcinoma <i>in situ</i>, Bowen disease, anal intraepithelial neoplasia II–III, high-grade anal intraepithelial neoplasia).</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T1 = Tumor ≤2 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T2 = Tumor >2 cm but ≤5 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T3 = Tumor >5 cm.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">T4 = Tumor of any size invading adjacent organ(s), such as the vagina, urethra, or bladder.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NX = Regional lymph nodes cannot be assessed.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N0 = No regional lymph node metastasis.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">N1 = Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1a = Metastasis in inguinal, mesorectal, or internal iliac lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1b = Metastasis in external iliac lymph nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">–N1c = Metastasis in external iliac with any N1a nodes.</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">M1 = Distant metastasis.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">T = primary tumor; N = regional lymph node; M = distant metastasis.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Reprinted with permission from AJCC: Anus. In: Amin MB, Edge SB, Greene FL, et al., eds.: <i>AJCC Cancer Staging Manual</i>. 8th ed. New York, NY: Springer, 2017, pp. 275–84.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobCDR0000062898430"><div id="CDR0000062898__430" class="table"><h3><span class="title">Table 6. Treatment Options for Anal Cancer</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK65778/table/CDR0000062898__430/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000062898__430_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Stage (<a href="#CDR0000062898__138">TNM Staging Criteria</a>)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Treatment Options</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Stage 0</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="#CDR0000062898__387">Surgery</a>
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</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;">Stages I, II, and III</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__392">Local resection</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__392">External-beam radiation therapy with chemotherapy</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__392">Alternative strategies</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__392">Radical resection</a>
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</td></tr><tr><td colspan="1" rowspan="4" style="vertical-align:top;">Stage IV</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__417">Palliative surgery</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__417">Palliative radiation therapy</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__417">Palliative chemotherapy (with or without radiation therapy)</a>
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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<a href="/books/NBK65778/?report=reader#CDR0000062898__417">Checkpoint inhibitors</a>
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