NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY

Anal Carcinoma, Version 2.2023

Al B. Benson III, MD1,*; Alan P. Venook, MD2,*; Mahmoud M. Al-Hawary, MD3; Nilofer Azad, MD4; Yi-Jen Chen, MD, PhD5;
Kristen K. Ciombor, MD6; Stacey Cohen, MD7,*; Harry S. Cooper, MD8; Dustin Deming, MD9,*;
Ignacio Garrido-Laguna, MD, PhD10; Jean L. Grem, MD11; J. Randolph Hecht, MD12; Sarah Hoffe, MD13;
Joleen Hubbard, MD14; Steven Hunt, MD15; Hisham Hussan, MD16; William Jeck, MD17; Kimberly L. Johung, MD, PhD18;
Nora Joseph, MD3; Natalie Kirilcuk, MD19; Smitha Krishnamurthi, MD20; Jennifer Maratt, MD21; Wells A. Messersmith, MD22;
Jeffrey Meyerhardt, MD, MPH23; Eric D. Miller, MD, PhD24,*; Mary F. Mulcahy, MD1; Steven Nurkin, MD, MS25;
Michael J. Overman, MD26,*; Aparna Parikh, MD27; Hitendra Patel, MD28; Katrina Pedersen, MD, MS15,*;
Leonard Saltz, MD29; Charles Schneider, MD30; David Shibata, MD31,*; John M. Skibber, MD26;
Constantinos T. Sofocleous, MD, PhD29; Eden Stotsky-Himelfarb, BSN, RN4; Anna Tavakkoli, MD, MSc32;
Christopher G. Willett, MD17; Grant Williams, MD, MSPH33,*; Frankie Algieri34;
Lisa Gurski, PhD34; and Katie Stehman, PA-C, MMS34

ABSTRACT NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform
NCCN consensus that the intervention is appropriate.
This discussion summarizes the NCCN Clinical Practice Guidelines for
Category 2A: Based upon lower-level evidence, there is uniform
managing squamous cell anal carcinoma, which represents the most
NCCN consensus that the intervention is appropriate.
common histologic form of the disease. A multidisciplinary approach in-
cluding physicians from gastroenterology, medical oncology, surgical Category 2B: Based upon lower-level evidence, there is NCCN
oncology, radiation oncology, and radiology is necessary. Primary treat- consensus that the intervention is appropriate.
ment of perianal cancer and anal canal cancer are similar and include Category 3: Based upon any level of evidence, there is major
chemoradiation in most cases. Follow-up clinical evaluations are rec- NCCN disagreement that the intervention is appropriate.
ommended for all patients with anal carcinoma because additional All recommendations are category 2A unless otherwise noted.
curative-intent treatment is possible. Biopsy-proven evidence of locally
recurrent or persistent disease after primary treatment may require sur- Clinical trials: NCCN believes that the best management of
gical treatment. Systemic therapy is generally recommended for extrap- any patient with cancer is in a clinical trial. Participation in
elvic metastatic disease. Recent updates to the NCCN Guidelines for clinical trials is especially encouraged.
Anal Carcinoma include staging classification updates based on the 9th
edition of the AJCC Staging System and updates to the systemic ther- PLEASE NOTE
apy recommendations based on new data that better define optimal The NCCN Clinical Practice Guidelines in Oncology (NCCN
treatment of patients with metastatic anal carcinoma. Guidelines®) are a statement of evidence and consensus of the
authors regarding their views of currently accepted approaches
J Natl Compr Canc Netw 2023;21(6):653–677
to treatment. Any clinician seeking to apply or consult the NCCN
doi: 10.6004/jnccn.2023.0030
Guidelines is expected to use independent medical judgment in
the context of individual clinical circumstances to determine any
patient’s care or treatment. The National Comprehensive Cancer
Network® (NCCN®) makes no representations or warranties of
1
Robert H. Lurie Comprehensive Cancer Center of Northwestern University; any kind regarding their content, use, or application and disclaims
2
UCSF Helen Diller Family Comprehensive Cancer Center; 3University of Michigan any responsibility for their application or use in any way.
Rogel Cancer Center; 4The Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins; 5City of Hope National Medical Center; 6Vanderbilt-Ingram The complete NCCN Guidelines for Anal Carcinoma are not
Cancer Center; 7Fred Hutchinson Cancer Center; 8Fox Chase Cancer Center; printed in this issue of JNCCN but can be accessed online at
9
University of Wisconsin Carbone Cancer Center; 10Huntsman Cancer Institute at [Link].
the University of Utah; 11Fred & Pamela Buffett Cancer Center; 12UCLA Jonsson © 2023 National Comprehensive Cancer Network® (NCCN®).
Comprehensive Cancer Center; 13Moffitt Cancer Center; 14Mayo Clinic Cancer All rights reserved. The NCCN Guidelines and the illustrations
Center; 15Siteman Cancer Center at Barnes-Jewish Hospital and Washington herein may not be reproduced in any form without the express
University School of Medicine; 16UC Davis Comprehensive Cancer Center; 17Duke written permission of NCCN.
Cancer Institute; 18Yale Cancer Center/Smilow Cancer Hospital; 19Stanford Cancer
Institute; 20Case Comprehensive Cancer Center/University Hospitals Seidman Disclosures for the NCCN Anal Carcinoma Panel
Cancer Center and Cleveland Clinic Taussig Cancer Institute; 21Indiana University
Melvin and Bren Simon Comprehensive Cancer Center; 22University of Colorado At the beginning of each NCCN Guidelines Panel meeting, panel
Cancer Center; 23Dana-Farber Brigham and Women’s Cancer Center; 24The Ohio members review all potential conflicts of interest. NCCN, in
State University Comprehensive Cancer Center - James Cancer Hospital and keeping with its commitment to public transparency, publishes
Solove Research Institute; 25Roswell Park Comprehensive Cancer Center; these disclosures for panel members, staff, and NCCN itself.
26
The University of Texas MD Anderson Cancer Center; 27Massachusetts General Individual disclosures for the NCCN Anal Carcinoma Panel
Hospital Cancer Center; 28UC San Diego Moores Cancer Center; 29Memorial Sloan members can be found on page 677. (The most recent version
Kettering CancerCenter; 30Abramson Cancer Center at the University of Pennsylvania; of these guidelines and accompanying disclosures are available
31
The University of Tennessee Health Science Center; 32UT Southwestern at [Link].)
Simmons Comprehensive Cancer Center; 33O’Neal Comprehensive Cancer
Center at UAB; and 34National Comprehensive Cancer Network The complete and most recent version of these guidelines is
available free of charge at [Link].
*Discussion Writing Committee Member.

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 NCCN GUIDELINES® Anal Carcinoma, Version 2.2023

Overview This discussion summarizes the NCCN Clinical Prac-

An estimated 9,760 new cases (3,180 male and 6,580 fe- tice Guidelines for managing squamous cell anal carci-
male) of anal cancer involving the anus, anal canal, or ano- noma, which represents the most common histologic
rectum will occur in the United States in 2023, accounting form of the disease. Other groups have also published
for approximately 2.8% of digestive system cancers.1 Ex- guidelines for the management of anal squamous cell
perts project that 1,870 deaths due to anal cancer will oc- carcinoma.8–10 Other types of cancers occurring in the
cur in the United States in 2023.1 Although considered to anal region are addressed in other NCCN Guidelines;
be a rare cancer, the incidence rate of invasive anal carci- anal adenocarcinoma and anal melanoma are managed
noma in the United States increased by approximately according to the NCCN Guidelines for Rectal Cancer and
1.9-fold for males and 1.5-fold for females between the pe- the NCCN Guidelines for Melanoma, respectively.
riods of 1973–1979 to 1994–2000 and has continued to in-
crease since that time.2–4 According to an analysis of SEER Risk Factors
data, the incidence of anal squamous carcinoma in- Anal carcinoma is associated with human papillomavirus
creased at a rate of 2.9% per year from 1992 to 2001.5 Sup- (HPV) infection (anal-genital warts); a history of receptive
porting this, an analysis of the US Cancer Statistics dataset anal intercourse or sexually transmitted disease; a history
reported an annual increase of 2.7% between 2001 and of cervical, vulvar, or vaginal cancer; immunosuppres-
2015, with the greatest increases in age groups $50 years,6 sion after solid organ transplantation or HIV infection;
while the National Program of Cancer Registries and SEER hematologic malignancies; certain autoimmune disorders;
programs showed similar trends from 2001 to 2016, with and smoking.11–19
an annual percent change of 2.1 (95% CI, 1.7–2.5) overall, The association between anal carcinoma and persis-
and 2.8 (95% CI, 2.5–3.1) in those $50 years of age.7 In- tent infection with a high-risk form of HPV (eg, HPV-16;
creases in incidence of anal cancer during that time frame HPV-18) is especially strong.12,20,21 For example, a study
were especially noted for women $50 years. Anal cancer of tumor specimens from more than 60 pathology labo-
mortality rates (2001–2016) also rose, with an average in- ratories in Denmark and Sweden showed that high-risk
crease of 3.1% per year.6 HPV DNA was detected in 84% of anal cancer specimens,

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Anal Carcinoma, Version 2.2023 NCCN GUIDELINES®

with HPV-16 detected in 73% of them. In contrast, high- 131 per 100,000 person-years in males who have sex with
risk HPV was not detected in any of the rectal adenocar- males (MSM) with HIV in North America, and in the
cinoma specimens analyzed.12 In addition, results of a range of 3.9 to 30 per 100,000 person-years in females
systematic review of 35 peer-reviewed anal cancer stud- living with HIV.31,32 An analysis of the French Hospital
ies that included HPV DNA testing results published up Database on HIV showed a highly elevated risk of anal
until July 2007 showed the prevalence of HPV-16/18 to cancer in PLWH, including in those who were on therapy
be 72% in patients with invasive anal cancer.21 Popula- and whose CD41T-cell counts were high.33 The data also
tion and registry studies have found similar HPV preva- revealed an increasing incidence of anal cancer in the
lence rates in anal cancer specimens.22,23 A 2012 report PLWH population over time. However, some evidence
from the US CDC estimated that 86%–97% of cancers of suggests that prolonged ART (.24 months) may be asso-
the anus are attributable to HPV infection.24 ciated with a decrease in the incidence of high-grade
Suppression of the immune system by the use of im- anal intraepithelial neoplasia (AIN).34
munosuppressive drugs or HIV infection likely facilitates A meta-analysis of anal cancer incidence across risk
persistence of HPV infection of the anal region.25,26 Stud- groups found that the incidence of anal cancer in solid
ies have shown that people living with HIV (PLWH) have organ transplant recipients increased both by age and
an approximately 15- to 35-fold increased likelihood of years since transplant.19 Incidence rates rose from 0.0
being diagnosed with anal cancer compared with the and 3.1 per 100,000 person-years in men and women
general population.27–30 In PLWH, the standardized inci- .30 years to 13.4 and 25.9 per 100,000 person-years in
dence rate of anal carcinoma per 100,000 person-years in men and women $60 years. Years since transplant ap-
the United States, estimated to be 19.0 in 1992 through peared to identify an even higher risk than age, with an
1995, increased to 78.2 during 2000 through 2003.26 This incidence rate of 24.5 and 29.6 per 100,000 person-years
result likely reflects both the survival benefits of modern in males and females $10 years posttransplant, respec-
antiretroviral therapy (ART) and the lack of an impact of tively. This study also assessed risk in patients with auto-
ART on the progression of anal cancer precursors. The immune diseases and found incidence rates of 10, 6, and
incidence rate of anal cancer has been reported to be 3 per 100,000 person-years for patients with systemic

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lupus erythematosus, ulcerative colitis, and Crohn’s dis- even in people at high risk at this time or state that there
ease, respectively. may be some benefit with anal cytology.51,56 Few guidelines
recommend screening for anal cancer with DRE in PLWH.57
Risk Reduction Guidelines for the treatment of AIN have been devel-
High-grade AIN can be a precursor to anal cancer,35–38 oped by several groups, including the American Society
and treatment of high-grade AIN may prevent the develop- of Colon and Rectal Surgeons (ASCRS).51,56,58,59 Treatment
ment of anal cancer.39 AIN can be identified by cytology, recommendations vary widely because high-level evi-
HPV testing, digital rectal examination (DRE), high-resolu- dence in the field is limited.58 One randomized controlled
tion anoscopy, and/or biopsy.40,41 The spontaneous regres- trial in 246 HIV-positive MSM found that electrocautery
sion rate of high-grade AIN is not known, and estimates was superior to both topical imiquimod and topical fluo-
suggest that the progression rates of AIN to cancer in MSM rouracil in the treatment of AIN overall.60 The subgroup
might be quite low.42–45 However, a prospective cohort with perianal AIN, as opposed to intra-anal AIN, ap-
study of 550 HIV-positive MSM found the rate of conversion peared to show better response to imiquimod. Regardless
of high-grade AIN to anal cancer to be 18% (7/38) at a me- of treatment, recurrence rates were high, and careful
dian follow-up of 2.3 years, despite treatment.38 In this follow-up is likely needed. A large randomized phase III
study, screening led to the identification of high-grade AIN trial compared topical or ablative treatment with active
and/or anal cancer in 8% of the cohort. monitoring in 4,459 PLWH with high-grade AIN.61 With a
Routine screening for AIN in individuals at high risk median follow-up of 25.8 months, 9 cases of anal cancer
such as PLWH or MSM is controversial, because random- were diagnosed in the treatment group compared with
ized controlled trials showing that such screening pro- 21 cases in the active monitoring group. The rate of pro-
grams are efficacious at reducing anal cancer incidence gression to anal cancer was 57% lower with treatment
and mortality are lacking, whereas the potential benefits compared with active monitoring (95% CI, 6–80; P5.03).
are quite large.46–52 Systematic reviews and meta-analyses
have suggested that anal cytology is effective in detection HPV Immunization
of AIN, particularly for individuals at high risk.53–55 Most A quadrivalent HPV vaccine is available and has been
guidelines do not recommend anal cancer screening shown to be effective in preventing persistent cervical

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Anal Carcinoma, Version 2.2023 NCCN GUIDELINES®

infection with HPV-6, -11, -16, or -18 as well as in pre- young people.70 The effect on precancerous anal lesions
venting high-grade cervical intraepithelial neoplasia re- has not yet been reported.
lated to these strains of the virus.62–64 The vaccine has A 9-valent HPV vaccine is also now available, pro-
also been shown to be efficacious in young males at pre- tecting against HPV-6, -11, -16, -18, -31, -33, -45, -52, and
venting genital lesions associated with HPV-6, -11, -16, or -58.71 Targeting the additional strains over the quadriva-
-18 infection.65 A substudy of a larger double-blind study lent vaccine is predicted to prevent an additional 464
assessed the efficacy of the vaccine for the prevention of cases of anal cancer annually.72 This vaccine was com-
AIN and anal cancer related to infection with HPV-6, -11, pared with the quadrivalent vaccine in an international,
-16, or -18 in MSM.66 In this study, 602 healthy MSM randomized phase IIb–III study that included more than
aged 16 to 26 years were randomized to receive the vac- 14,000 female patients.73 The 9-valent vaccine was nonin-
cine or a placebo. Although none of the participants in ei- ferior to the quadrivalent vaccine for antibody response to
ther arm developed anal cancer during the 3-year follow- HPV-6, -11, -16, and -18 and prevented infection and dis-
up period, there were 5 cases of grade 2/3 AIN associated ease related to the other viral strains included in the vac-
with one of the vaccine strains in the vaccine arm and 24 cine. The calculated efficacy of the 9-valent vaccine was
such cases in the placebo arm in the per-protocol popu- 96.7% (95% CI, 80.9–99.8) for the prevention of high-grade
lation, giving an observed efficacy of 77.5% (95% CI, cervical, vulvar, or vaginal disease related to those strains.
39.6–93.3). Since high-grade AIN is known to have the The Advisory Committee on Immunization Practices
ability to progress to anal cancer,35–37 these results sug- (ACIP) recommends routine use of the 9-valent vaccine
gest that use of the quadrivalent HPV vaccine in MSM in children aged 11 and 12 years, as well as catch-up vac-
may reduce the risk of anal cancer in this population. cination for individuals through 26 years of age who have
A bivalent HPV vaccine against HPV-16 and -18 is also not been previously vaccinated.74–77 The American
available.67 In a randomized, double-blind controlled trial Academy of Pediatrics concurs with this vaccination
of female patients in Costa Rica, the vaccine was 83.6% schedule.78 ASCO released a statement regarding HPV
effective against initial anal HPV-16/18 infection (95% CI, vaccination for cancer prevention with the goal of
66.7–92.8).68,69 It has also been shown to be effective at pre- increasing vaccine update.79 In 2018, the FDA expanded
venting high-grade cervical intraepithelial neoplasia in use of the 9-valent vaccine to include individuals aged 27

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through 45 years,80 and the ACIP voted in 2019 to recom- urothelial, and squamous histologic characteristics.14,82
mend vaccination, based on shared clinical decision- The most inferior aspect of the anal canal, approximately
making, for individuals in this age range who are not at the anal verge, corresponds to the area where the mu-
adequately vaccinated. cosa, lined with modified squamous epithelium, transi-
tions to an epidermis-lined anal margin.
Anatomy/Histology The anatomic anal canal begins at the anorectal ring
The anal region is comprised of the anal canal and the and extends to the anal verge (ie, squamous mucocuta-
perianal region, dividing anal cancers into 2 categories. The neous junction with the perianal skin).83
anal canal is the more proximal portion of the anal region. Functionally, the anal canal is defined by the sphincter
The 9th Edition of the AJCC Cancer Staging Manual in- muscles. The superior border of the functional anal canal,
cludes a definition of anal canal cancer as tumors that de- separating it from the rectum, has been defined as the pal-
velop from mucosa that cannot be entirely seen when the pable upper border of the anal sphincter and puborectalis
buttocks are gently pressed.81 The corresponding definition muscles of the anorectal ring. It is approximately 3 to 5 cm
for perianal cancer is tumors that (1) arise within the skin in length, and its inferior border starts at the anal verge, the
distal to or at the squamous mucocutaneous junction; (2) lowermost edge of the sphincter muscles, corresponding to
can be visualized completely when the buttocks are gently the introitus of the anal orifice.14,82,84 The functional defini-
pressed; and (3) are within 5 cm of the anus.81 Various other tion of the anal canal is primarily used in the radical surgical
definitions of the anal canal exist (ie, functional/surgical; treatment of anal cancer and is used in these guidelines to dif-
anatomic; histologic) that are based on particular physical/ ferentiate between treatment options. The anal margin starts
anatomic landmarks or histologic characteristics. at the anal verge and includes the perianal skin over a 5- to 6-
Histologically, the mucosal lining of the anal canal is cm radius from the squamous mucocutaneous junction.82
predominantly formed by squamous epithelium, in con- Tumors can involve both the anal canal and the anal margin.
trast to the mucosa of the rectum, which is lined with
glandular epithelium.14,82 The anal margin, conversely, is Pathology
lined with skin. By the histologic definition, the most su- Most primary cancers of the anal canal are of squamous cell
perior aspect of the anal canal is a 1- to 2-cm zone be- histology.82 The second edition of the WHO classification
tween the anal and rectal epithelium, which has rectal, system of anal carcinoma designated all squamous cell

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carcinoma variants of the anal canal as cloacogenic and keratinizing large-cell types,89 but they are not character-
identified subtypes as large-cell keratinizing, large-cell non- ized in the guidelines according to cell type. The pres-
keratinizing (transitional), or basaloid.85 It has been re- ence of skin appendages (eg, hair follicles, sweat glands)
ported that squamous cell cancers in the more proximal in perianal tumors can distinguish them from anal canal
region of the anal canal are more likely to be nonkeratinizing tumors. However, it is not always possible to distinguish
and less differentiated.14 However, the terms “cloacogenic,” between anal canal and perianal squamous cell carci-
“transitional,” “keratinizing,” and “basaloid” were removed noma since tumors can involve both areas.
from the third and fourth editions of the WHO classification Lymph drainage of anal cancer tumors is dependent
system of anal canal carcinoma,86,87 and all subtypes have on the location of the tumor in the anal region: cancers in
been included under a single generic heading of “squamous the perianal skin and the region of the anal canal distal to
cell carcinoma.”81,86 Reasons for this change include the fol- the dentate line drain mainly to the superficial inguinal
lowing: both cloacogenic (which is sometimes used inter- nodes.81,82 Lymph drainage at and proximal to the dentate
changeably with the term basaloid) and transitional tumors line is directed toward the anorectal, perirectal, and para-
are now considered to be nonkeratinizing tumors; it has vertebral nodes and to some of the nodes of the internal il-
been reported that both keratinizing and nonkeratinizing iac system. More proximal cancers drain to perirectal
tumors have a similar natural history and prognosis86; and a nodes and to nodes of the inferior mesenteric system.
mixture of cell types frequently characterize histologic Therefore, distal anal cancers present with a higher inci-
specimens of squamous cell carcinomas of the anal dence of inguinal node metastases. Because the lymphatic
canal.82,86,88 No distinction between squamous anal canal drainage systems throughout the anal canal are not iso-
tumors on the basis of cell type has been made in these lated from each other, however, inguinal node metastases
guidelines. Other less common anal canal tumors, not can occur in proximal anal cancer as well.82
addressed in these guidelines, include adenocarcinomas in The College of American Pathologists publishes pro-
the rectal mucosa or the anal glands, small cell (anaplastic) tocols for the pathologic examination and reporting of
carcinoma, undifferentiated cancers, and melanomas.82 anal tumors following excision or transabdominal resec-
Perianal squamous cell carcinomas are more likely tion. The most recent updates were made in April 2020
than those of the anal canal to be well-differentiated and and February 2020, respectively.90,91

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Staging N1b, and N1c were defined and then further refined in
The TNM staging system for anal canal cancer developed the 9th edition.81 N1a now represents metastasis in ingui-
by the AJCC is detailed in the guidelines.81 Because cur- nal, mesorectal, superior rectal, internal iliac, or obtura-
rent recommendations for the primary treatment of anal tor nodes. N1b represents metastasis in external iliac
canal cancer do not involve a surgical excision, most tu- nodes. N1c represents metastasis in external iliac with
mors are staged clinically with an emphasis on the size of any N1a nodes. However, initial therapy of anal cancer
the primary tumor as determined by direct examination does not typically involve surgery, and the true lymph
and microscopic confirmation. A tumor biopsy is re- node status may not be determined accurately by clinical
quired. Rectal ultrasound to determine depth of tumor and radiologic evaluation. Fine-needle aspiration biopsy
invasion is not used in the staging of anal cancer (see of inguinal nodes can be considered if tumor metastasis
“Clinical Presentation/Evaluation,” page 660). to these nodes is suspected. In a series of patients with
In the past, these guidelines have used the AJCC anal cancer who underwent an abdominoperineal resec-
TNM skin cancer system for the staging of perianal can- tion (APR), it was noted that pelvic nodal metastases
cer because the 2 types of cancers have a similar biology. were often less than 0.5 cm,97 suggesting that routine ra-
However, the seventh edition of the AJCC Cancer Staging diologic evaluation with CT and PET/CT scan may not be
Manual included substantial changes to the cutaneous reliable in the determination of lymph node involvement
squamous cell carcinoma stagings,92 making them much (discussed in more detail in “Clinical Presentation/
less appropriate for the staging of perianal cancers. Fur- Evaluation,” page 660).
thermore, many perianal cancers have involvement of the
anal canal or have high-grade, precancerous lesions in Prognostic Factors
the anal canal. It is important to look for such anal canal Multivariate analysis of data from the RTOG 98-11 trial
involvement, particularly if conservative management showed that male sex and positive lymph nodes were in-
(simple excision) is being contemplated. Many patients, dependent prognostic factors for DFS in patients with
particularly PLWH, could be significantly undertreated. anal cancer treated with 5-FU and radiation and either
For these reasons, these guidelines use the AJCC anus mitomycin or cisplatin.98 Male sex, positive nodes, and
staging system for both anal canal and perianal tumors. tumor size .5 cm were independently prognostic for
The prognosis of anal carcinoma is related to the size worse OS. A secondary analysis of this trial found that tu-
of the primary tumor and the presence of lymph node me- mor diameter could also be prognostic for colostomy
tastases.14 According to the SEER database,93 between rate and time to colostomy.99 These results are consistent
1999 and 2006, 50% of anal carcinomas were localized at with earlier analyses from the EORTC 22861 trial, which
initial diagnosis; these patients had an 80% 5-year survival found male sex, lymph node involvement, and skin ulcer-
rate. Approximately 29% of patients had anal carcinoma ation to be prognostic for worse survival and local con-
that had already spread to regional lymph nodes at diag- trol.100 Similarly, multivariate analyses of data from the
nosis; these patients had a 60% 5-year survival rate. The ACT I trial also showed that positive lymph nodes and
12% of patients presenting with distant metastasis dem- male sex are prognostic indicators for higher local re-
onstrated a 30.5% 5-year survival rate.93 In a retrospective gional failure, anal cancer death, and lower OS.101
study of 270 patients treated for anal canal cancer with ra- Data suggest that HPV- and/or p16-positivity are prog-
diation therapy (RT) between 1980 and 1996, synchronous nostic for improved OS in patients with anal carci-
inguinal node metastasis was observed in 6.4% of patients noma.102–105 In a retrospective study of 143 tumor samples,
with tumors staged as T1 or T2, and in 16% of patients
p16-positivity was an independent prognostic factor for OS
with T3 or T4 tumors.94 In patients with N2–3 disease, sur-
(hazard ratio [HR], 0.07; 95% CI, 0.01–0.61; P5.016).103
vival was related to T-stage rather than nodal involvement
Another study involving 95 patients found similar results.102
with respective 5-year survival rates of 72.7% and 39.9%
for patients with T1–T2 and T3–T4 tumors; however, the
Management of Anal Carcinoma
number of patients involved in this analysis was small.94
An analysis of more than 600 patients with nonmetastatic Clinical Presentation/Evaluation
anal carcinoma from the RTOG 98-11 trial also found that Approximately 45% of patients with anal carcinoma pre-
the tumor and node categories impacted clinical outcomes sent with rectal bleeding, while approximately 30% have
such as overall survival (OS), disease-free survival (DFS), either pain or the sensation of a rectal mass.14 Following
and colostomy failure, with the worst prognoses for patients confirmation of squamous cell carcinoma by biopsy, the
with T4,N0 and T3–4,N1 disease.95 recommendations of the NCCN Anal Carcinoma Guide-
By the eighth edition of the AJCC Cancer Staging lines Panel for the clinical evaluation of patients with anal
Manual, the former N2 and N3 categories by locations of canal or perianal cancer are very similar (see ANAL-1 and
positive nodes were removed.96 New categories of N1a, ANAL-2, pages 654 and 655).

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The panel recommends a thorough examination/ occurred in 12%–59% of patients based on PET/CT re-
evaluation, including a careful DRE, an anoscopic exami- sults.116,118 The panel does not consider PET/CT to be a re-
nation, and palpation of the inguinal lymph nodes, with placement for a diagnostic CT.
fine-needle aspiration and/or excisional biopsy of nodes According to a systematic review and meta-regression,
found to be enlarged by either clinical or radiologic ex- the proportion of patients who are node-positive by pre-
amination. Evaluation of pelvic lymph nodes with CT or treatment clinical imaging has increased from 15.3%
MRI of the pelvis is also recommended. These methods (95% CI, 10.5–20.1) in 1980 to 37.1% (95% CI, 34.0–41.3) in
can also provide information on whether the tumor in- 2012 (P,.0001), likely resulting from the increased use of
volves other abdominal/pelvic organs; however, assess- more sensitive imaging techniques.119 This increase in
ment of T stage is primarily performed through clinical lymph node positivity was associated with improvements
examination. A CT scan of the abdomen is also recom- in OS for both the lymph-node–positive and the lymph-
mended to assess possible disease dissemination. Be- node–negative groups. Because the proportion of patients
cause veins of the anal region are part of the venous with T3/T4 disease remained constant and therefore
network associated with systemic circulation,82 chest disease is not truly being diagnosed at more advanced
CT scan is performed to evaluate for pulmonary metas- stages over time, the authors attribute the improved OS
tasis. Gynecologic examination, including cervical can- results to the “Will Rogers effect”: The average survival of
cer screening, is suggested due to the association of both groups increases as patients with worse-than-average
anal cancer and HPV.12 A discussion of infertility risks survival in the node-negative group migrate to the node-
and counseling on fertility preservation, if appropriate, positive group, in which their survival is better than aver-
should be performed before the start of treatment. age. Thus, the survival of individuals has not necessarily
HIV testing should be performed if the patient’s HIV improved over time, even though the average survival of
status is unknown, because the risk of anal carcinoma each group has. Using simulated scenarios, the authors
has been reported to be higher in PLWH.16 Furthermore, further conclude that the actual rate of true node-positivity
about 13% of people in the United States who are in- is likely less than 30%, suggesting that it is possible some
fected with HIV are not aware of their infection status,106 patients are being misclassified and overtreated with the
and individuals who are unaware of their HIV-positive increased use of highly sensitive imaging.
status do not receive the clinical care they need to reduce
HIV-related morbidity and mortality and may unknow- Primary Treatment of Non-Metastatic Anal Carcinoma
ingly transmit HIV.107 HIV testing may be particularly im- In the past, patients with invasive anal carcinoma were
portant in patients with cancer, because identification of routinely treated with an APR; however, local recurrence
HIV infection has the potential to improve clinical out- rates were high, 5-year survival was only 40%–70%, and
comes.108 The CDC recommends HIV screening for all the morbidity with a permanent colostomy was consider-
patients in all health care settings unless the patient de- able.14 In 1974, Nigro et al120 observed complete tumor
clines testing (opt-out screening).109 regression in some patients with anal carcinoma treated
PET/CT scanning, or PET/MRI if available, can be with preoperative 5-FU–based concurrent chemotherapy
considered to verify staging before treatment. PET/CT and RT (chemoRT) including either mitomycin or porfir-
scanning has been reported to be useful in the evaluation omycin, suggesting that it might be possible to cure anal
of pelvic nodes, even in patients with anal canal cancer carcinoma without surgery and permanent colostomy.
who have normal-sized lymph nodes on CT imaging.110–115 Subsequent nonrandomized studies using similar regi-
A systematic review and meta-analysis of 7 retrospective mens and varied doses of chemoRT provided support for
and 5 prospective studies calculated pooled estimates of this conclusion.121,122 Results of randomized trials evalu-
sensitivity and specificity for detection of lymph node in- ating the efficacy and safety of administering chemother-
volvement by PET/CT to be 56% (95% CI, 45%–67%) and apy with RT support the use of combined modality
90% (95% CI, 86%–93%), respectively.111 A more recent therapy in the treatment of anal cancer.17 Summaries of
meta-analysis of 17 clinical studies calculated the pooled clinical trials involving patients with anal cancer have
sensitivity and specificity for detection of lymph node in- been presented,123,124 and several key trials are discussed
volvement by PET/CT at 93% and 76%, respectively.116 The subsequently.
use of PET or PET/CT led to upstaging in 5%–38% of pa-
tients and downstaging in 8%–27% of patients. Another Chemotherapy
systematic review and meta-analysis found PET/CT to A phase III study from the EORTC compared the use of
change nodal status and TNM stage in 21% and 41% of pa- chemoRT (5-FU 1 mitomycin) to RT alone in the treat-
tients, respectively.117 PET/CT results can also impact radi- ment of anal carcinoma. Results from this trial showed
ation therapy planning, as systematic reviews and meta- that patients in the chemoRT arm had an 18% higher
analyses have shown that treatment plan modifications rate of locoregional control at 5 years and a 32% longer

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colostomy-free interval.100 The United Kingdom Coordi- as an alternative to 5-FU in chemoRT regimens for non-
nating Committee on Cancer Research randomized ACT I metastatic anal cancer.136–139 Doses throughout the radia-
trial confirmed that chemoRT with 5-FU and mitomy- tion course on treatment days may offer improved
cin was more effective in controlling local disease than radiation sensitization compared with 2 courses of 5-FU
RT alone (relative risk [RR], 0.54; 95% CI, 0.42–0.69; infusion during the chemoRT course. A retrospective study
P,.0001), although no significant differences in OS compared results for 58 patients treated with capecitabine
were observed at 3 years.125 A published follow-up study to 47 patients treated with infusional 5-FU; both groups
involving these patients showed that a clear benefit of also received mitomycin and concurrent RT.138 No signifi-
chemoRT remains after 13 years, including a benefit in cant differences were seen in clinical complete response,
OS.126 The median survival was 5.4 years in the RT arm 3-year locoregional control, 3-year OS, or colostomy-free
and 7.6 years in the chemoRT arm. There was also a re- survival between the 2 groups. Another retrospective
duction in the risk of dying from anal cancer (HR, 0.67; study involved 27 patients treated with capecitabine and
95% CI, 0.51–0.88; P5.004). A systematic review and 62 patients treated with infusional 5-FU; as in the other
meta-analysis comparing outcomes in patients with study, both groups also received mitomycin and RT.137
stage I anal carcinoma found an increased 5-year OS in Grade 3/4 hematologic toxicities were significantly lower
patients treated with chemoRT compared with RT alone in the capecitabine group, with no oncologic outcomes
(RR, 1.18; 95% CI, 1.10–1.26; P,.00001) but no significant reported. A phase II study found that chemoRT with
difference in 5-year DSF (RR, 1.01; 95% CI, 0.92–1.11; capecitabine and mitomycin was safe and resulted in a
P5.87.127 Conversely, a population-based cohort analysis 6-month locoregional control rate of 86% (95% CI, 0.72–0.94)
of Medicare-eligible (.65 years of age or with an eligible in patients with localized anal cancer.140 Although data for
disability) patients with stage I anal cancer showed no this regimen are limited, the panel recommends mitomycin/
difference in OS, cause-specific survival, colostomy-free capecitabine 1 RT as an alternative to mitomycin/5-FU 1
survival, or DFS with chemoRT versus RT alone after ad- RT in the setting of stage I through III anal cancer.
justment using propensity score methods.128 Therefore, Cisplatin as a substitute for 5-FU was evaluated in a
this study concludes that RT alone may allow for ade- phase II trial, and results suggest that cisplatin-containing
quate oncologic outcomes for highly select patients with and 5-FU–containing chemoRT may be comparable for
stage I anal cancer, although it is important to note that this treatment of locally advanced anal cancer.129
study did not differentiate between anal canal and perianal The efficacy of replacing mitomycin with cisplatin
cancers. Current NCCN Guidelines recommendations are has also been assessed. The phase III UK ACT II trial
noted in subsequent sections (“Recommendations for the compared cisplatin with mitomycin and also looked at
Primary Treatment of Anal Canal Cancer,” page 666 and the effect of additional maintenance chemotherapy fol-
“Recommendations for the Primary Treatment of Perianal lowing chemoRT.141 In this study, more than 900 patients
Cancer,” page 667). with newly diagnosed anal cancer were randomly as-
A few studies have addressed the efficacy and safety of signed to primary treatment with either 5-FU/mitomycin
specific chemotherapeutic agents in the chemoRT regimens or 5-FU/cisplatin with RT. A continuous course (ie, no
used in the treatment of anal carcinoma.98,129,130 In a treatment gap) of radiation of 50.4 Gy was administered
phase III Intergroup study, patients receiving chemoRT in both arms, and patients in each arm were further ran-
with the combination of 5-FU and mitomycin had a domized to receive 2 cycles of maintenance therapy
lower colostomy rate (9% vs 22%; P5.002) and a higher with 5-FU and cisplatin or no maintenance therapy. At a
4-year DFS (73% vs 51%; P5.0003) compared with pa- median follow-up of 5.1 years, no differences were seen
tients receiving chemoRT with 5-FU alone, indicating that in the primary endpoint of complete response rate in ei-
mitomycin is an important component of chemoRT in ther arm for the chemoRT comparison or in the primary
the treatment of anal carcinoma.130 The OS rate at 4 years endpoint of progression-free survival (PFS) for the com-
was the same for the 2 groups, however, reflecting the parison of maintenance therapy versus no maintenance
ability to treat patients with recurrent cancer with addi- therapy. In addition, a secondary endpoint, colostomy,
tional chemoRT or an APR. The phase II JROSG 10-2 trial did not show differences based on the chemotherapeu-
of 31 patients with squamous cell anal cancer treated tic components of chemoRT. These results demonstrate
with concurrent chemoRT with 5-FU and mitomycin in that replacement of mitomycin with cisplatin in chemoRT
Japan has reported 2-year DFS, OS, local control, and does not affect the rate of complete response, nor
colostomy-free survival of 77.4%, 93.5%, 83.9%, and 80.6%, does administration of maintenance therapy decrease the
respectively.131 rate of disease recurrence after primary treatment with che-
Capecitabine, an oral fluoropyrimidine prodrug, is an moRT in patients with anal cancer.
accepted alternative to 5-FU in the treatment of colon Cisplatin as a substitute for mitomycin in the treat-
and rectal cancer.132–135 Capecitabine has been assessed ment of patients with nonmetastatic anal carcinoma was

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also evaluated in the randomized phase III Intergroup There has also been interest in the use of biologic
RTOG 98-11 trial. The role of induction chemotherapy therapies for the treatment of anal cancer. A phase III trial
was also assessed. In this study, 682 patients were ran- is investigating the use of the PD-1 inhibitor, nivolumab,
domly assigned to receive either (1) induction 5-FU 1 following combined modality therapy for high-risk anal
cisplatin for 2 cycles followed by concurrent chemoRT carcinoma ([Link] identifier: NCT03233711).150
with 5-FU and cisplatin; or (2) concurrent chemoRT with This trial has completed enrollment of 344 participants,
5-FU and mitomycin.98,142 A significant difference was and results are pending. Cetuximab is an epidermal
observed in the primary endpoint, 5-year DFS, in favor of growth factor receptor inhibitor, whose antitumor activity
the mitomycin group (57.8% vs 67.8%; P5.006).142 Five- is dependent on the presence of wild-type KRAS.151 Be-
year OS was also significantly better in the mitomycin cause KRAS mutations appear to be very rare in anal can-
arm (70.7% vs 78.3%; P5.026).142 In addition, 5-year cer,152,153 the use of an epidermal growth factor receptor
colostomy-free survival showed a trend toward statisti- inhibitor such as cetuximab has been considered to be a
cal significance (65.0% vs 71.9%; P5.05), again in favor promising avenue of investigation. The phase II ECOG
of the mitomycin group. Because the 2 treatment arms 3205 and AIDS Malignancy Consortium 045 trials evalu-
in the RTOG 98-11 trial differed with respect to use of ated the safety and efficacy of cetuximab with cisplatin/
either cisplatin or mitomycin in concurrent chemoRT 5-FU and radiation in immunocompetent (E3205) pa-
as well as inclusion of induction chemotherapy in the tients and PLWH (AMC045) with anal squamous cell
cisplatin-containing arm, it is difficult to attribute the carcinoma.154,155 Results from E3205 and AMC045 were
differences to the substitution of cisplatin for mitomy- published in 2017. In a post hoc analysis of E3205, the
cin or to the use of induction chemotherapy.123,143 How- 3-year locoregional failure rate was 21% (95% CI, 7%–26%)
ever, because ACT II demonstrated that the 2 chemoRT by Kaplan-Meier estimate.154 The toxicities associated with
regimens are equivalent, some have suggested that re- the regimen were substantial, with grade 4 toxicity occur-
sults from RTOG 98-11 suggest that induction chemo- ring in 32% of the study population and 3 treatment-
therapy is probably detrimental.144 associated deaths (5%). In AMC045, the 3-year locoregional
Results from ACCORD 03 also suggest that there is failure rate was 20% (95% CI, 10%–37%) by Kaplan-Meier
no benefit of a course of chemotherapy given before estimate.155 Grade 4 toxicity and treatment-associated rates
chemoRT.145 In this study, patients with locally ad- were similar to those seen in E3205, at 26% and 4%, re-
vanced anal cancer were randomized to receive induc- spectively. Two other trials that have assessed the use of
tion therapy with 5-FU/cisplatin or no induction therapy cetuximab in this setting have also found it to increase
followed by chemoRT (they were further randomized to toxicity, including a phase I study of cetuximab with
receive an additional radiation boost or not). No differ- 5-fluorouracil, cisplatin, and radiation.156 The ACCORD
ences were seen between tumor complete response, tu- 16 phase II trial, which was designed to assess response
mor partial response, 3-year colostomy-free survival, rate after chemoRT with cisplatin/5-FU and cetuximab,
local control, event-free survival, or 3-year OS. After a was terminated prematurely because of extremely high
median follow-up of 50 months, no advantage to induction rates of serious adverse events.157 The 15 evaluable pa-
chemotherapy (or to the additional radiation boost) was tients from ACCORD 16 had a 4-year DFS rate of 53%
observed, consistent with earlier results. A systematic re- (95% CI, 28%–79%), and 2 of the 5 patients who com-
view of randomized trials also showed no benefit to a pleted the planned treatments had locoregional
course of induction chemotherapy.146 recurrences.158
A retrospective analysis, however, suggests that in- For older patients or those who are unlikely to toler-
duction chemotherapy preceding chemoRT may be ben- ate mitomycin, the optimal chemotherapy regimen re-
eficial for the subset of patients with T4 anal cancer.147 mains uncertain. Some NCCN Panel members have used
The 5-year colostomy-free survival rate was significantly a combination of weekly cisplatin and daily 5-FU on days
better in patients with T4 anal cancer who received in- of RT159 for chemoRT in localized anal cancer. Other po-
duction 5-FU/cisplatin compared with those who did not tential strategies for this patient population may include
(100% vs 38 6 16.4%, P5.0006). capecitabine 1 RT or RT alone (without chemotherapy).
The combination of 5-FU, mitomycin C, and cis- However, due to a lack of data supporting this ap-
platin has also been studied in a phase II trial but was proach and differing strategies among panel members,
found to be too toxic.148 The safety and efficacy of capeci- there are not yet defined recommendations for patients
tabine/oxaliplatin with radiation for the treatment of lo- with anal cancer who are not candidates for intensive
calized anal cancer has been investigated in a phase II therapy. Use of a geriatric assessment to guide manage-
study, which reported that the regimen was safe, with ment and elicitation of the patient’s goals and objec-
promising efficacy, although larger trials would be needed tives with regard to their cancer diagnosis is critical to
to confirm these results.149 inform shared decision-making discussions in these

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situations (See the NCCN Guidelines for Older Adult of a planned treatment break in the ACT II trial was con-
Oncology at [Link]). sidered to be at least partially responsible for the high
colostomy-free survival rates observed in that study (74%
Radiation Therapy at 3 years).141 A post hoc analysis from the ACT II trial
Before the start of RT, patients should be counseled on in- revealed worse outcomes if the planned RT dose was ex-
fertility risks and given information regarding sperm bank- tended to more than 42 days, with a significant increase in
ing or oocyte, egg, or ovarian tissue banking, as appropriate. the risk of PFS event (P5.01) and worse OS (P5.006).167
In addition, patients should be counseled on risks for Although results of these and other studies have supported
early treatment-induced menopause and changes to sex- the benefit of delivery of chemoRT over shorter time peri-
ual function. See the NCCN Guidelines for Survivorship ods,168–170 treatment breaks in the delivery of chemoRT are
and the NCCN Guidelines for Adolescent and Young Adult required in up to 80% of patients because chemoRT-related
Oncology (available at [Link]) for more information. toxicities are common.170 For example, it has been reported
Patients should be considered for vaginal dilators daily that one-third of patients receiving primary chemoRT for
during treatment, which can reduce RT doses to sexual anal carcinoma at RT doses of 30 Gy in 3 weeks develop
organs at risk,160 and instructed on the symptoms of vagi- acute anoproctitis and perineal dermatitis, increasing to
nal stenosis. one-half to two-thirds of patients when RT doses of 54 to
The optimal dose and schedule of RT for anal carci- 60 Gy are administered in 6 to 7 weeks.82
noma continues to be explored and has been evaluated Some of the reported late side effects of chemoRT in-
in a number of nonrandomized studies. In one study of clude increased frequency and urgency of defecation, chronic
patients with early-stage (T1 or Tis) anal canal cancer, perineal dermatitis, dyspareunia, and impotence.171,172 In
most patients were effectively treated with RT doses of 40 some cases, severe late RT complications, such as anal ulcers,
to 50 Gy for Tis lesions and 50 to 60 Gy for T1 lesions.161 stenosis, and necrosis, may necessitate surgery involving
In another study, in which the majority of patients had colostomy.172 In addition, results from a retrospective
stage II/III anal canal cancer, local control of disease was cohort study of data from the SEER registry showed the
higher in patients who received RT doses greater than 50 risk of subsequent pelvic fracture to be 3-fold higher in
Gy than in those who received lower doses (86.5% vs female patients $65 years undergoing RT for anal cancer
34%, P5.012).162 In a third study of patients with T3, T4, compared with female patients of the same age with
or lymph node-positive tumors, RT doses of $54 Gy ad- anal cancer who did not receive RT.173
ministered with limited treatment breaks (,60 days) were An increasing body of literature suggests that toxicity
associated with increased local control.163 The effect of can be reduced with advanced radiation delivery techni-
further escalation of radiation dose was assessed in the ques.114,174–184 IMRT uses detailed beam shaping to target
ACCORD 03 trial, with the primary endpoint of colostomy- specific volumes and limit the exposure of normal tis-
free survival at 3 years.145 No benefit was seen with the sue.183 Multiple pilot studies have demonstrated reduced
higher dose of radiation. These results are supported by toxicity while maintaining local control using IMRT. For
much earlier results from the RTOG 92-08 trial164 and sug- example, in a cross-study comparison of a multicenter
gest that doses .59 Gy provide no additional benefit to pa- study of 53 patients with anal cancer treated with concurrent
tients with anal cancer. The randomized, phase II 5-FU/mitomycin chemotherapy and IMRT compared with
DECREASE study (NCT04166318) is currently evaluating patients in the 5-FU/mitomycin arm of the randomized
how well lower-dose chemoRT works in comparison with RTOG 98-11 study, which used conventional 3D RT, the rates
standard-dose chemoRT for patients with stage I or IIA of grade 3–4 dermatologic toxicity were 38%/0% for IMRT-
anal cancer.165 Patients on this study are randomized to treated patients compared with 43%/5% for those undergo-
either 28 fractions (standard-dose) or 20 or 23 fractions ing conventional RT.98,183 No decrease in treatment effective-
(deintensified dose) of intensity-modulated RT (IMRT). ness or local control rates was observed with use of IMRT,
Study completion is expected in 2025. although the small sample size and short duration of follow-
There is evidence that treatment interruptions, either up limit the conclusions drawn from such a comparison. In
planned or required due to treatment-related toxicity, one retrospective comparison between IMRT and conven-
can compromise the effectiveness of treatment.114 In the tional radiotherapy, IMRT was less toxic and showed better
phase II RTOG 92-08 trial, a planned 2-week treatment efficacy in 3-year OS, locoregional control, and PFS.185 In a
break in the delivery of chemoRT to patients with anal larger retrospective comparison, no significant differences
cancer was associated with increased locoregional failure in local recurrence-free survival, distant metastasis-free sur-
rates and lower colostomy-free survival rates when com- vival, colostomy-free survival, and OS at 2 years were seen
pared with patients who only had treatment breaks for between patients receiving IMRT and those receiving 3D
severe skin toxicity,166 although the trial was not designed conformal radiotherapy, despite the fact that the IMRT
for that particular comparison. In addition, the absence group had a higher average N stage.186

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RTOG 0529 was a prospective clinical trial investigat- 14 Gy. The consensus of the panel is that IMRT is preferred
ing if dose-painted IMRT/5-FU/mitomycin could de- over 3D conformal RT in the treatment of anal carci-
crease the rate of gastrointestinal and genitourinary noma.191 IMRT requires expertise and careful target design
adverse effects compared with patients treated with con- to avoid reduction in local control by marginal miss.114 The
ventional radiation/5-FU/mitomycin from RTOG 98-11. clinical target volumes for anal cancer used in the RTOG
This trial did not meet its primary endpoint of reducing 0529 trial have been described in detail.191 Also see the
grade 21 combined acute genitourinary and gastrointes- RTOG Consensus Panel document (available at https://
tinal adverse events by 15% compared with conventional [Link]/Portals/0/Scientific%20Program/
radiation on RTOG 98-11.187 Of 52 evaluable patients, the CIRO/Atlases/[Link] ) for
grade 21 combined acute adverse event rate was 77%; the more details of the contouring atlas defined by RTOG.
rate in RTOG 98-11 was also 77%. However, significant re- For untreated patients presenting with synchronous
ductions were seen in grade 21 hematologic events (73% local and metastatic disease, chemoRT to the primary
vs 85%; P5.032), grade 31 gastrointestinal events (21% vs site can be considered for local control after first-line
36%; P5.008), and grade 31 dermatologic events (23% vs chemotherapy, as described in these guidelines. For re-
49%; P,.0001). Subsequently, long-term outcomes and currence in the primary site or nodes after previous
chemoRT, surgery should be performed if possible, and,
toxicities of patients with anal cancer treated with dose-
if not, palliative chemoRT can be considered based on
painted IMRT as per RTOG 0529 have been reported.188,189
symptoms, extent of recurrence, and prior treatment.
Of 99 eligible patients identified in the 2017 publication,
92% had a clinically complete response after a median
Surgical Management
follow-up of 49 months.189 The 4-year OS was 85.5% and
Local excision is used for anal cancer in 2 situations. The
the 4-year event-free survival was 75.5%. The rate of grade
first is for superficially invasive squamous cell carcinoma
$2 nonhematologic late toxicities was 15%. In a longer-
(SISCCA), which is defined as anal cancer that has been
term follow-up with 52 eligible patients, the 8-year OS was completely excised, with #3-mm basement membrane
68% and the 8-year DFS was 62%.188 The rate of grade 2 late invasion and a maximal horizontal spread of #7 mm
adverse events was 55%, 16% for grade 3, 0 for grade 4, and (T1, NX).192 SISCCA are generally found incidentally in
4% for grade 5 events. the setting of a biopsy or excision of what is thought to
A retrospective cohort study using the 2014 linkage be a benign lesion such as a condyloma, hemorrhoid, or
of the SEER-Medicare database showed that IMRT is as- anal skin tag. Such lesions are being seen with increasing
sociated with higher total costs than 3D conformal radia- frequency because anal cancer screening in populations
tion (median total cost, $35,890 vs $27,262; P,.001), but at high risk is becoming more common. For SISCCA that
unplanned healthcare utilization costs (ie, hospitaliza- are noted to have histologically negative margins in care-
tions and emergency department visits) are higher for fully selected patients followed up by an experienced pro-
those receiving conformal radiation (median, $711 vs vider and/or team, local excision alone with a structured
$4,957 at 1 year; P5.02).190 surveillance plan may represent adequate treatment. A
Recommendations regarding RT doses follow the careful surveillance plan is necessary because observa-
multifield technique used in the RTOG 98-11 trial.98 tional studies have reported detection of high-grade squa-
After clinical and radiologic staging, CT-based simulation is mous intraepithelial lesions in 74% of patients after local
performed for radiation treatment planning. If available, excision.193 A retrospective study described characteris-
MRI pelvis, PET/CT, or PET/MRI (if available) at the time tics, treatment, and outcomes of 17 patients with
of simulation may be helpful to define local and regional completely excised invasive anal cancer, 7 of whom met
target structures. All patients should receive a minimum the criteria for classification as superficially invasive.194
RT dose of 45 Gy to the primary cancer. The recommended Those with positive margins (#2 mm for anal canal cancer
initial RT dose is 30.6 Gy to the pelvis, anus, perineum, and and ,1 cm for perianal cancer) received local radiation,
inguinal nodes; there should be attempts to reduce the and all patients underwent surveillance. After a median
dose to the femoral heads. Field reduction off the superior follow-up of 45 months, no differences were seen in
field border and node-negative inguinal nodes is recom- 5-year OS (100% for the entire cohort) or 5-year cancer
mended after delivery of 30.6 Gy and 36 Gy, respectively. recurrence-free survival rates (87% for the entire cohort)
For patients treated with an anteroposterior–posteroanterior between the groups with superficially invasive and inva-
rather than multifield technique, the dose to the lateral sive cancer.
inguinal region should be brought to the minimum dose of Local excision is also used for T1,N0, well-differentiated
36 Gy using an anterior electron boost matched to the PA or select T2,N0 perianal (anal margin) cancer that does not
exit field. Patients with disease clinically staged as node- involve the sphincter (also see “Recommendations for the
positive or T2–T4 should receive an additional boost of 9 to Primary Treatment of Perianal Cancer,” page 667). In these

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cases, a 1-cm margin is recommended. A retrospective co- immunodeficient (14 PLWH) patients showed no differ-
hort study that included 2,243 adults from the National ence in the efficacy or toxicity of chemoRT.206 A population-
Cancer Database diagnosed with T1,N0 anal canal cancer based study of almost 2 million patients with cancer,
between 2004 and 2012 found that the use of local excision including 6,459 PLWH, found no increase in cancer-specific
in this population increased over time (17.3% in 2004 to mortality for anal cancer in PLWH.208 Although the num-
30.8% in 2012; P,.001).195 No significant difference in bers of PLWH in these studies have been small, the efficacy
5-year OS was seen based on management strategy (85.3% and safety results appear similar regardless of HIV status.
for local excision; 86.8% for chemoRT; P5.93). Many Overall, the panel believes that PLWH who have anal
patients with T1 or selected T2 perianal cancers will have cancer should be treated as per these guidelines and that
concomitant high-grade squamous intraepithelial lesions modifications to treatment of anal cancer should not be
of the anal canal, therefore it is important to look for such made solely on the basis of HIV status. Additional consid-
anal canal involvement when conservative management erations for PLWH who have anal cancer are outlined in
(local excision) is being considered. the NCCN Guidelines for Cancer in People Living with
Radical surgery in anal cancer (APR) is reserved for HIV (available at [Link]), including the use of normal
local recurrence or disease persistence (see “Treatment
tissue-sparing radiation techniques, the consideration of
of Locally Progressive or Recurrent Anal Carcinoma,”
nonmalignant causes for lymphadenopathy, and the need
page 667).
for more frequent posttreatment surveillance anoscopy for
PLWH. Poor performance status in PLWH and anal cancer
Treatment of Anal Cancer in Patients Living With HIV/AIDS
may be from HIV, cancer, or other causes. The reason for
As discussed previously (see “Risk Factors,” page 654),
PLWH have been reported to be at increased risk for anal poor performance status should be considered when mak-
carcinoma.17,27–30 Some evidence suggests that ART may ing treatment decisions. Treatment with ART may improve
be associated with a decrease in the incidence of high- poor performance status related to HIV.
grade AIN and its progression to anal cancer.34,196 How-
ever, the incidence of anal cancer in PLWH has not de-
creased much, if at all, over time.26,28,30,33 Recommendations for the Primary Treatment
Most evidence regarding outcomes in PLWH with of Anal Canal Cancer
anal cancer comes from retrospective comparisons, a Currently, concurrent chemoRT is the recommended pri-
few of which found worse outcomes in PLWH.197–199 For mary treatment of patients with nonmetastatic anal canal
example, a cohort comparison of 40 PLWH with anal ca- cancer as well as for patients with positive para-aortic
nal cancer and 81 HIV-negative patients with anal canal lymph nodes that can be included in the radiation field, al-
cancer found local relapse rates to be 4 times higher in though only limited retrospective data support use in this
PLWH at 3 years (62% vs 13%) and found significantly setting.209 Mitomycin/5-FU or mitomycin/capecitabine is
higher rates of severe acute skin toxicity for PLWH.198 administered concurrently with radiation.98,137–139 Alterna-
However, no differences in rates of complete response tively, 5-FU/cisplatin can be given with concurrent radia-
or 5-year OS were observed between the groups in that tion (category 2B).210 Most studies have delivered 5-FU as
study. Another systematic review and meta-analysis of a protracted 96- to 120-hour infusion during the first and
40 studies including 3,720 patients with localized squa- fifth weeks of RT, and bolus injection of mitomycin is typi-
mous cell carcinoma of the anus who were treated with cally given on the first or second day of the 5-FU infusion.82
chemoRT, 34% of whom were HIV-positive, found a Capecitabine is given orally, Monday through Friday, on
greater risk of grade 3 and higher cutaneous toxicities each day that RT is given, for 4 or 6 weeks, with bolus injec-
(RR 5 1.34), and worse 3-year DFS (RR 5 1.32) and OS tion of mitomycin and concurrent radiation.137,139 See
(RR 5 1.77) rates, in PLWH compared with those who ANAL-B 1 of 3 (page 658) for more information on these
were HIV-negative.199 regimens.
Most studies, however, have found outcomes to be An analysis of the National Cancer Database found
similar in PLWH and HIV-negative patients.200–207 In a that only 61.5% of patients with stage I anal canal cancer
retrospective cohort study of 1,184 veterans diagnosed received chemoRT as recommended in these guide-
with squamous cell carcinoma of the anus between 1998 lines.211 Patients who were male, with age $70 years, had
and 2004 (15% of whom tested positive for HIV), no dif- smaller or lower-grade tumors, or who had been evalu-
ferences with respect to receipt of treatment or 2-year ated at academic facilities were more likely than others
survival rates were observed when the group of PLWH to be treated with excision alone. In a separate analysis of
was compared with the group of patients testing negative the National Cancer Database, 88% of patients with stage
for HIV.202 Another study of 36 consecutive patients with II–III anal canal cancer received chemoRT.212 Males,
anal cancer, including 19 immunocompetent and 17 Black patients, those with multiple comorbidities, and

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those treated in academic facilities were less likely to re- at 3-month intervals. The panel recommends against the
ceive combined modality treatment. use of PET/CT imaging as part of this re-evaluation strat-
RT is associated with significant side effects. Patients egy due to concerns for false-positivity from local inflam-
should be counseled on infertility risks and given infor- mation from RT leading to unnecessary surgeries. If
mation regarding sperm, oocyte, egg, or ovarian tissue biopsy-proven disease progression occurs, further inten-
banking before treatment. In addition, patients should sive treatment is indicated (see “Treatment of Locally Pro-
be considered for vaginal dilators and should be in- gressive or Recurrent Anal Carcinoma,” next section).
structed on the symptoms of vaginal stenosis. Although a clinical assessment of progressive disease
requires histologic confirmation, patients can be classified
Recommendations for the Primary Treatment as having a complete remission without biopsy verifica-
of Perianal Cancer tion if clinical evidence of disease is absent. The panel rec-
Perianal lesions can be treated with either local excision ommends that these patients undergo evaluation every 3
or chemoRT depending on the clinical stage. Primary to 6 months for 5 years, including DRE and inguinal node
treatment of patients with T1,N0 well-differentiated or palpation. Anoscopic evaluation is recommended every 6
select smaller T2,N0 perianal (anal margin) cancer that to 12 months for 3 years. Annual chest, abdominal, and
does not involve the sphincter is by local excision with pelvic CT with contrast or chest CT without contrast and
adequate margins. The ASCRS defines an adequate mar- abdominal/pelvic MRI with contrast is recommended for
gin as 1 cm.56 If the margins are not adequate, re-excision 3 years for patients who initially had stage II–III disease.
is the preferred treatment option. Local RT with or with-
out continuous infusion 5-FU/mitomycin, mitomycin/ Treatment of Locally Progressive or Recurrent
capecitabine, or 5-FU/cisplatin (category 2B) can be con- Anal Carcinoma
sidered as alternative treatment options when surgical Despite the effectiveness of chemoRT in the primary treat-
margins are inadequate. For all other perianal cancers, ment of anal carcinoma, rates of locoregional failure of
the treatment options are the same as for anal canal can- 10%–30% have been reported.214,215 Some of the disease
cer (see previous sections).98,137–139,210 characteristics that have been associated with higher re-
currence rates after chemoRT include higher T stage and
Surveillance Following Primary Treatment higher N stage (also see “Prognostic Factors,” page 660).216
Following primary treatment of nonmetastatic anal cancer, Evidence of progression found on DRE should be fol-
the surveillance and follow-up treatment recommenda- lowed by biopsy as well as restaging with CT and/or PET/
tions for perianal and anal canal cancer are the same (see CT imaging (see ANAL-4, page 657). Patients with biopsy-
ANAL-3, page 656). Patients are re-evaluated using DRE proven locally progressive disease are candidates for radi-
between 8 and 12 weeks after completion of chemoRT. cal surgery with an APR and colostomy.215 In an attempt to
Following re-evaluation, patients are classified according avoid surgery, the use of immunotherapy with nivolumab
to whether they have a complete remission of disease, per- or pembrolizumab may be considered prior to APR (cate-
sistent disease, or progressive disease. Patients with persis- gory 2B) as some patients may have a good response. How-
tent disease but without evidence of progression may be ever, it should be noted that this approach is based on
managed with close follow-up (in 4 weeks) to see if further institutional experience only and there are currently no
regression occurs. published data supporting its use in this setting of other-
The National Cancer Research Institute’s ACT II study wise curative intent surgery.
compared different chemoRT regimens and found no dif- A multicenter retrospective cohort study looked at
ference in OS or PFS.141 Interestingly, 72% of patients in this the cause-specific colostomy rates in 235 patients with
trial who did not show a complete response at 11 weeks anal cancer who were treated with radiotherapy or
from the start of treatment had achieved a complete re- chemoRT from 1995 to 2003.217 The 5-year cumulative
sponse by 26 weeks. The 5-year survival was superior in pa- incidence rates for tumor-specific and therapy-specific
tients who experienced complete response at 26 weeks.213 colostomy were 26% (95% CI, 21%–32%) and 8% (95% CI,
Based on these results, the panel believes it may be appro- 5%–12%), respectively. Larger tumor size (.6 cm) was a risk
priate to follow patients who have not experienced a com- factor for tumor-specific colostomy, while local excision
plete clinical response with persistent anal cancer for up to prior to radiotherapy was a risk factor for therapy-specific
6 months after completion of radiation and chemotherapy, colostomy. However, it should be noted that these patients
as long as there is no evidence of progressive disease during were treated with older chemotherapy and RT regimens,
this period of follow-up. Persistent disease may continue to which could account for these high colostomy rates.218
regress for up to 6 months from the start of treatment, and In studies involving a minimum of 25 patients under-
APR can thereby be avoided in some patients. In these pa- going an APR for anal carcinoma, 5-year survival rates of
tients, observation and re-evaluation should be performed 39%–66% have been observed.214,215,219–223 Complication

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rates were reported to be high in some of these studies. Following treatment of inguinal node recurrence,
Factors associated with worse prognosis after APR include patients should have a DRE and inguinal node palpation
an initial presentation of node-positive disease and RT every 3 to 6 months for 5 years. In addition, anoscopy
doses ,55 Gy used in the treatment of primary disease.215 every 6 to 12 months and annual chest, abdominal, and
The general principles for APR technique are similar pelvic CT with contrast or chest CT without contrast and
to those for distal rectal cancer and include the incorpo- abdominal/pelvic MRI with contrast are recommended
ration of meticulous total mesorectal excision. However, for 3 years.
APR for anal cancer may require wider lateral perianal
margins than are required for rectal cancer. A retrospec- Treatment of Metastatic Anal Cancer
tive analysis of the medical records of 14 patients who It has been reported that the most common sites of anal can-
received intraoperative RT during APR revealed that in- cer metastasis outside of the pelvis are the liver, lung, and ex-
traoperative RT is unlikely to improve local control or to trapelvic lymph nodes.229 Since anal carcinoma is a rare
give a survival benefit.224 cancer and only 10%–20% of patients with anal carcinoma
Because of the necessary exposure of the perineum present with extrapelvic metastatic disease,229 only limited
to radiation, patients with anal cancer are prone to poor data are available on this population of patients. Despite this
perineal wound healing. It has been shown that for pa- fact, evidence indicates that systemic therapy has some ben-
tients undergoing an APR that was preceded by RT, clo- efit in patients with metastatic anal carcinoma. See ANAL-B
sure of the perineal wound using rectus abdominis 2 of 3 (page 659) for more information on the systemic
myocutaneous flap reconstruction results in decreased therapy regimens recommended for metastatic anal cancer.
perineal wound complications.225,226 Reconstructive tis- Palliative chemoRT to the primary site can be ad-
sue flaps for the perineum, such as the vertical rectus or ministered after upfront chemotherapy for local control
local myocutaneous flaps, should therefore be consid- of a symptomatic bulky primary. In fact, an analysis of
ered for patients with anal cancer undergoing an APR. the National Cancer Database reported that patients
Inguinal node dissection is recommended for recur- with newly diagnosed metastatic anal cancer who re-
rence in that area and for patients who require an APR ceived definitive pelvic RT in addition to chemotherapy
but have already received groin radiation. Inguinal node had longer median OS than those who received chemo-
dissection can be performed with or without an APR de- therapy alone (21.3 vs 15.9 months; HR, 0.70; 95% CI,
pending on whether disease is isolated to the groin or 0.61-0.81; P,.001).230 A retrospective analysis of 106 pa-
has occurred in conjunction with recurrence or persis- tients with squamous cell carcinoma reported that
tence at the primary site. resection or ablation of liver metastases can result in
Patients who develop inguinal node metastasis who do long-term survival and that patients with anal cancer had
not undergo an APR can be considered for palliative RT to better outcomes than those with nonanal squamous cell
the groin with or without 5-FU/mitomycin or mitomycin/ carcinoma, although this approach is not currently
capecitabine if no prior RT to the groin was given. Radiation included in the NCCN Guidelines for Anal Carcinoma.231
therapy technique and doses are dependent on dosing and
First-Line Treatment of Metastatic Anal Cancer
technique of prior treatment (see the guidelines pages). If
Based on results from the phase II International Multi-
RT was given previously, 5-FU/cisplatin chemotherapy may
centre InterAACT study, carboplatin in combination with
be given (category 2B).
paclitaxel has been noted as the preferred regimen for
first-line treatment of metastatic anal cancer by the NCCN
Surveillance Following Treatment of Recurrence Panel.232 In this trial, 91 patients with previously un-
Following APR, patients should undergo re-evaluation ev- treated, unresectable, locally recurrent or metastatic
ery 3 to 6 months for 5 years, including clinical evalua- anal squamous cell carcinoma were randomized to either
tion for nodal metastasis (ie, inguinal node palpation). In carboplatin 1 paclitaxel or cisplatin 1 5-FU. Although re-
addition, it is recommended that these patients undergo sponse rates were similar between carboplatin 1 pacli-
annual chest, abdominal, and pelvic CT with contrast or taxel and cisplatin 1 5-FU (59% and 57%, respectively),
chest CT without contrast and abdominal/pelvic MRI carboplatin 1 paclitaxel showed lower toxicity compared
with contrast for 3 years. In one retrospective study of 105 with cisplatin 1 5-FU (71% vs 76% grade $3 toxicity and
patients with anal canal carcinoma who had an APR be- 36% vs 62% [P5.016] serious adverse events). Median
tween 1996 and 2009, the overall recurrence rate following PFS and OS were 8.1 and 20 months for carboplatin 1
APR was 43%.227 Those with T3/4 tumors or involved paclitaxel and 5.7 and 12.3 months for cisplatin 1 5-FU
margins were more likely to experience recurrence. The (HR for OS, 2.0; 95% CI, 1.15–3.47; P5.014).232 The re-
5-year survival rate after APR has been reported to be sults from the InterAACT trial are in agreement with
60%–64%.227,228 older studies that showed that chemotherapy with a

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Anal Carcinoma, Version 2.2023 NCCN GUIDELINES®

fluoropyrimidine-based regimen 1 cisplatin210,233–235 or a the addition of the checkpoint inhibitor, retifanlimab, to

platinum-based therapy 1 paclitaxel234,236,237 benefited carboplatin/paclitaxel chemotherapy and comparing it to
some patients with metastatic anal carcinoma. chemotherapy alone.244 This trial expects to enroll 300
Other recommended treatment options include 5-FU, participants with previously untreated metastatic anal
leucovorin, and cisplatin (FOLFCIS); 5-FU, leucovorin, and carcinoma and expected completion is in 2024.
oxaliplatin (FOLFOX); 5-FU 1 cisplatin (category 2B re-
flecting its similar efficacy, but higher toxicity, when com- Second-Line Treatment of Metastatic Anal Cancer
pared with carboplatin 1 paclitaxel in a randomized trial); A single-arm, multicenter phase 2 trial assessed the
or modified docetaxel, cisplatin, and 5-FU (DCF, category safety and efficacy of the anti-PD-1 antibody nivolumab
2B). A retrospective study of 53 patients with advanced for refractory metastatic anal cancer.245 Two complete
anal squamous cell carcinoma who received FOLFCIS as responses and 7 partial responses were seen among the
first-line therapy showed that this regimen was safe and ef- 37 enrolled participants who received at least one dose, for
fective in this patient population. The response rate was a response rate of 24% (95% CI, 15–33). The KEYNOTE-028
48%, PFS was 7.1 months, and OS was 22.1 months.238 The trial is a multicohort, phase Ib trial of the anti-PD-1 anti-
safety of FOLFOX in patients with anal cancer has been body pembrolizumab in 24 patients with PD-L1–positive
demonstrated in a case report.239 Despite the limited data advanced squamous cell carcinoma of the anal canal.246
for FOLFOX in this setting, the panel added it based on Four partial responses were seen, for a response rate of
consensus and its current use as a standard option at 17% (95% CI, 5%–37%), and 10 patients (42%) had stable
many NCCN Member Institutions. With use of FOLFOX, disease, for a disease control rate of 58%. In both trials,
the panel recommends strong consideration of discontinu- toxicities were manageable, with 13% and 17% experienc-
ation of oxaliplatin after 3-4 months (or sooner for unac- ing grade 3 adverse events with nivolumab and pembroli-
ceptable neurotoxicity) while maintaining other agents zumab, respectively.245,246 The phase II KEYNOTE-158
until time of disease progression.240 Oxaliplatin may be re- study investigated the use of pembrolizumab in patients
introduced if it was discontinued for neurotoxicity rather with noncolorectal microsatellite instability-high/deficient
than for disease progression. mismatch repair cancers, including patients with anal cancer
DCF is another regimen that has been evaluated for (cohort A).247,248 A total of 112 patients with anal cancer were
metastatic anal cancer.241,242 A single-arm phase II trial enrolled and treated, 67% of whom had PD-L1-positive
evaluated this regimen in patients with previously un- disease.248 A total of 11% of patients (95% CI, 6–18) had an
treated, advanced anal squamous cell carcinoma. This objective response, with responses in 15% (95% CI,
trial demonstrated the efficacy of DCF (both standard 8%–25%) of patients with PD-L1-positive disease and in
and modified regimens) in this setting and reported better 3% (95% CI, 0%–17%) with PD-L1-negative disease. Seri-
tolerability of modified DCF compared with the standard ous treatment-related adverse events were noted in 11%
regimen.241 The median PFS was 10.7 months for the stan- of patients, with 25% of patients having immune-mediated
dard DCF regimen and 11.0 months for the modified regi- events. This study demonstrated the clinical benefit of
men. For the standard regimen, 83% of patients had at least pembrolizumab for patients with previously treated
one grade 3–4 AE, while 53% had at least one grade 3–4 advanced anal squamous cell carcinoma.
adverse event when treated with modified DCF. The most A phase II clinical trial ([Link] identifier:
common grade 3–4 adverse events were neutropenia, diarrhea, NCT02314169) is also underway investigating the efficacy
asthenia, anemia, lymphopenia, mucositis, and vomiting. and safety of nivolumab, with or without ipilimumab, for
Based on these results, the panel added modified DCF as an patients with refractory metastatic anal canal cancer.249
option for metastatic anal cancer, with the category 2B This trial has an estimated enrollment of 137 participants
designation reflecting concerns voiced by some panel and is expected to complete in February 2024. Other tri-
members about potentially higher toxicity with modified als have investigated novel second-line agents for meta-
DCF compared with the other regimens recommended for static anal cancer, including the phase 2 PODIUM-202
metastatic anal cancer. trial of retifanlimab for advanced or metastatic squamous
Several ongoing clinical trials are investigating whether cell carcinoma of the anal canal that progressed after
checkpoint inhibitors could have a role in the first-line platinum-based chemotherapy.250
treatment of metastatic anal cancer. NCT04444921 is a ran- Although further studies of PD-1/PD-L1 inhibitors
domized, phase 3 trial comparing chemotherapy alone are warranted, the panel added nivolumab and pembro-
(carboplatin and paclitaxel) to chemotherapy 1 nivolumab lizumab as preferred options for patients with meta-
for treatment-naïve metastatic anal cancer.243 This study is static anal cancer who have experienced progression on
expected to enroll 205 participants and complete in 2023. first-line chemotherapy in the 2018 version of these
POD1UM-303/InterAACT2 is a similar, phase 3 global study guidelines. Microsatellite instability/mismatch repair test-
([Link] identifier: NCT04472429) investigating ing is not required. Microsatellite instability is uncommon

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 NCCN GUIDELINES® Anal Carcinoma, Version 2.2023

in anal cancer,251 and as discussed previously, responses to pain, and insomnia.254,258–260 Therefore, survivors of anal
PD-1/PD-L1 inhibitors occur in 20%–24% of patients.245,246 cancer should be screened regularly for distress.
Anal cancers may be responsive to PD-1/PD-L1 inhibitors The NCCN Guidelines for Survivorship (available at
because they often have high PD-L1 expression and/or a high [Link]) provide screening, evaluation, and treat-
tumor mutational load despite being microsatellite stable.251 ment recommendations for common consequences of
The panel also notes that platinum-based chemo- cancer and cancer treatment to aid healthcare profes-
therapy should not be given in second line if disease pro- sionals who work with survivors of adult-onset cancer
gressed on platinum-based therapy in first line. in the posttreatment period, including those in specialty
cancer survivor clinics and primary care practices. These
Survivorship guidelines include many topics with potential relevance to
The panel recommends that a prescription for survivor- survivors of anal cancer, including anxiety, depression, and
ship and transfer of care to the primary care physician distress; cognitive dysfunction; fatigue; pain; sexual
be written.252 The oncologist and primary care provider dysfunction; sleep disorders; healthy lifestyles; and
should have defined roles in the surveillance period, immunizations. Concerns related to employment,
with roles communicated to the patient. The care plan insurance, and disability are also discussed.
should include an overall summary of treatments re-
ceived, including surgeries, radiation treatments, and
chemotherapy. The possible expected time to resolution Summary
of acute toxicities, long-term effects of treatment, and The NCCN Anal Carcinoma Guidelines Panel believes
possible late sequelae of treatment should be described. that a multidisciplinary approach including physicians
Finally, surveillance and health behavior recommenda- from gastroenterology, medical oncology, surgical oncol-
tions should be part of the care plan. ogy, radiation oncology, and radiology is necessary for
Disease-preventive measures, such as immuniza- treating patients with anal carcinoma.
tions; early disease detection through periodic screen- Recommendations for the primary treatment of
ing for second primary cancers (eg, breast, cervical, or perianal cancer and anal canal cancer are very similar and
prostate cancers); and routine good medical care and include chemoRT in most cases. The exception is small, well
monitoring are recommended (see the NCCN Guidelines or moderately differentiated perianal lesions and superfi-
for Survivorship, available at [Link]). Additional health cially invasive lesions, which can be treated with margin-
monitoring should be performed as indicated under the negative local excision alone. Follow-up clinical evaluations
care of a primary care physician. Survivors are encouraged are recommended for all patients with anal carcinoma
to maintain a therapeutic relationship with a primary care because additional curative-intent treatment is possible.
physician throughout their lifetime.253 Patients with biopsy-proven evidence of locally recurrent or
Other recommendations include monitoring for late persistent disease after primary treatment should undergo an
sequelae of anal cancer or the treatment of anal cancer. APR with groin dissection if there is clinical evidence of
Late toxicity from pelvic radiation can include bowel dys- inguinal nodal metastasis. Patients with a regional recur-
function (ie, increased stool frequency, fecal inconti- rence in the inguinal nodes can be treated with an inguinal
nence, flatulence, rectal urgency), urinary dysfunction, node dissection, with consideration of RT with or without
and sexual dysfunction (ie, impotence, dyspareunia, vagi- chemotherapy if no prior RT to the groin was given.
nal stenosis, vaginal dryness, reduced libido).254–258 Anal Patients with evidence of extrapelvic metastatic disease
cancer survivors also report significantly reduced global should be treated with systemic therapy. The panel en-
quality of life, with increased frequency of somatic symp- dorses the concept that treating patients in a clinical trial
toms including fatigue, dyspnea, nausea, appetite loss, has priority over standard or accepted therapy.

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676 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 21 Issue 6 | June 2023
Anal Carcinoma, Version 2.2023 NCCN GUIDELINES®

Individual Disclosures for the Anal Carcinoma Panel

Promotional Advisory Boards, Consultant,
Panel Member Clinical Research Support/Data Safety Monitoring Board Scientific Advisory Boards, Consultant, or Expert Witness or Speakers Bureau Specialties

Mahmoud M. Al-Hawary, MD None None None Diagnostic/Interventional radiology

Nilofer Azad, MD Agios, Inc.; Array; Atlas; Bayer HealthCare; Bristol-Myers Squibb Company; Celgene AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Incyte Corporation; AstraZeneca Pharmaceuticals LP Medical oncology
Corporation; Daiichi- Sankyo Co.; Debio; Eli Lilly and Company; EMD Serono; Incyte Mirati; QED
Corporation; Merck & Co., Inc.; Taiho Pharmaceuticals Co., Ltd.

Al B. Benson III, MD Astellas Pharma US, Inc.; Boehringer Ingelheim GmbH; Boston Scientific Corporation; Bristol- Therabionic; Apexigen; Artemida; BioScend; Bristol-Myers Squibb Company; None Medical oncology
Myers Squibb Company; GSK; Mirati; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Grail; HalioDx; Janssen Oncology; Merck Sharpe & Dohme; Natera; Pfizer
Corporation; Pfizer Inc.; Tempus; Terumo; Therabionic Inc./Hospira Inc.; TUKYSA; Xencor

Yi-Jen Chen, MD, PhD None None None Radiotherapy/Radiation oncology

Kristen K. Ciombor, MD Array; Bristol-Myers Squibb Company; Calithera; Daiichi- Sankyo Co.; Genentech, Inc.; Incyte Incyte Corporation; Personalis; Pfizer Inc.; Replimune; SeaGen None Medical oncology
Corporation; Merck & Co., Inc.; Nucana; Pfizer Inc.

Stacey Cohen, MD GlaxoSmithKline Bayer HealthCare; Cancer Study Group; Delcath; Eisai Inc.; Guidepoint; None Medical oncology
Helsell Fettermann; Istari Oncology

Harry S. Cooper, MD None None None Pathology

Dustin Deming, MD Aadi Biosciences; Arcus; Bristol-Myers Squibb Company; Curegenix; Eli Lilly and Company; Bayer HealthCare; Eli Lilly and Company; Illumina; Pfizer Inc.; Promega; None Medical oncology
EMD Serono; Genentech, Inc.; Ipsen; Merck & Co., Inc.; Natera; Pfizer Inc.; Promega; Seattle Genetics, Inc.
Revolution Medicine; Seattle Genetics, Inc.; STRATA Oncology

Ignacio Garrido-Laguna, MD, Amgen Inc.; Genentech, Inc.; GlaxoSmithKline; Halozyme, Inc.; MedImmune Inc.; Navire; Cancer Study Group; Jazz Pharmaceuticals Inc.; Kanaph Therapeutics; None Medical oncology
PhD Novartis Pharmaceuticals Corporation; Pfizer Inc.; Seattle Genetics, Inc.; SOTIO, LLC; Tolero; OncXerna
Trishula; Yingli

Jean L. Grem, MD Processa Pharmaceuticals None None Medical oncology

J. Randolph Hecht, MD A2; Amgen Inc.; Astellas Pharma US, Inc.; Bold; Camrus; Crinetics; Exelixis Inc.; Gilead Actym; Astellas Pharma US, Inc.; Deciphera Pharmaceuticals, Inc.; Exelixis None Medical oncology
Sciences, Inc.; NGM; TESARO, Inc.; Tizona Inc.; Gilead Sciences, Inc.; IGM; Mirati; Notch; Rafael; ZelamBio

Sarah Hoffe, MD Galera, second trial, GRECO-2; Varian Medical Systems, Inc.; ViewRay Beyond the White Coat; Galera; University of South Florida MyCareGorithm; Rittenhouse , I have signed Radiotherapy/Radiation oncology
a paper for future stock options but
have not been received anything to this date

Joleen Hubbard, MD None Bayer HealthCare; BeiGene; Incyte Corporation; Merck & Co., Inc.; Taiho None Medical oncology; Hematology/
Pharmaceuticals Co., Ltd. Hematology oncology

Steven Hunt, MD No commercial interest. This is a lab developed system for photoacoustic imaging of tumors. None None Surgery/Surgical oncology

Hisham Hussan, MD None None None Gastroenterology

William Jeck, MDa Pathology

Kimberly L. Johung, MD, PhD None None None Radiotherapy/Radiation oncology

Nora Joseph, MD None None None Pathology

Natalie Kirilcuk, MD None None None Surgery/Surgical oncology

Smitha Krishnamurthi, MD Agenus; Aravive Biologics, Inc; BioMed Valley; Bristol-Myers Squibb Company; Natera; Pfizer None None Medical oncology; Internal
Inc. medicine

Jennifer Maratt, MD None None None Gastroenterology

Wells A. Messersmith, MD ALX Oncology; Amgen Inc.; BeiGene; CanBAS; Criterium; Exelixis Inc.; Experimental Drug takeda None Medical oncology
Development Centre (Singapore); Fate Therapeutics; Mirati; NGM; Pfizer Inc.; PureTech; QED
Therapeutics; Rascal Therapeutics; Zymeworks

Jeffrey Meyerhardt, MD, MPH None None None Medical oncology

Eric D. Miller, MD, PhD EMD Serono None None Radiotherapy/Radiation oncology

Mary F. Mulcahy, MD None None None Hematology/Hematology oncology;

Medical oncology

Steven Nurkin, MD, MS None Merck & Co., Inc. None Surgery/Surgical oncology

Michael J. Overman, MDa None None 3dmed; AbbVie, Inc.; agilvax; Eisai Inc.; Gilead Medical oncology; Hematology/
Sciences, Inc.; gritstone; Janssen Hematology oncology
Pharmaceutica Products, LP; Merck & Co., Inc.;
Novartis Pharmaceuticals Corporation;
Pfizer Inc.; Phanes; Takeda
Pharmaceuticals North America, Inc.

Aparna Parikh, MD AbbVie, Inc.; Bayer HealthCare; Bristol-Myers Squibb Company; C2i; Checkmate; CVS; Daiichi- C2i equity but no valuation yet; Parithera; Xcures; XGenomes equity but None Medical oncology
Sankyo Co.; Delcath; Eli Lilly and Company; erasca; Foundation Medicine; Genentech, Inc.; no valuation yet
Inivata; Karkinos; Mirati; Novartis Pharmaceuticals Corporation; Parithera; Pfizer Inc.; PMV
Pharma; Puretech; Saga; Scare; Seagen; Taiho Pharmaceuticals Co., Ltd.; Up to Date; Value
Analytics Lab

Hitendra Patel, MD None Epinoma None Medical oncology

Katrina Pedersen, MD, MSa Arcus; BioLineRx; Boston Biomedical; Bristol-Myers Squibb Company; Daiichi- Sankyo Co.; AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Novartis Pharmaceuticals WebMD/MedScape Medical oncology
HCW Biologics; Incyte Corporation; Ipsen; MedImmune Inc.; Merck & Co., Inc.; Natera; Corporation; SAGA Diagnostics; Taiho Pharmaceuticals Co., Ltd.
Nouscom; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Pierre-Fabre; Rafael; Roche
Laboratories, Inc.

Leonard Saltz, MD None Genor Biopharma None Medical oncology; Hematology/

Hematology oncology; Internal
medicine

Charles Schneider, MD None None None Medical oncology

David Shibata, MD None None None Medical oncology

John M. Skibber, MD None None None Surgery/Surgical oncology

Constantinos T. Sofocleous, MD, Boston Scientific Corporation; Ethicon, Inc.; Memorial Sloan Kettering IMRAS; NIH/NCI; Ethicon, Inc.; Medtronic, Inc.; TERUMO; Varian Medical Systems, Inc. None Diagnostic/Interventional radiology
PhD SIRTEX; Society of Interventional Oncology

Eden Stotsky-Himelfarb, BSN, RN None None None Medical oncology; Surgery/Surgical

oncology; Patient advocate

Anna Tavakkoli, MD, MSc None None None Gastroenterology

Alan P. Venook, MD Amgen Inc. Amgen Inc.; Bayer HealthCare; Bristol-Myers Squibb Company; Exact None Medical oncology; Hematology/
Sciences; Exelixis Inc.; GlaxoSmithKline; Merck & Co., Inc.; Pfizer Inc. Hematology oncology

Christopher G. Willett, MD None None None Radiotherapy/Radiation oncology

Grant Williams, MD, MSPH None None None Medical oncology

The NCCN Guidelines Staff have no conflicts to disclose.

a
The following individuals have disclosures relating to employment/governing board, patent, equity, or royalty:
William Jeck, MD: Seattle Genetics, Inc.
Michael J. Overman, MD: UpToDate
Katrina Pedersen, MD, MS: UpToDate

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