Anal

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Anal Carcinoma
Version 2.2023 — April 28, 2023
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Version 2.2023, 04/28/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 2.2023 NCCN Guidelines Index

Table of Contents
Anal Carcinoma Discussion
*Al B. Benson, III, MD/Chair † William Jeck, MD ≠ Hitendra Patel, MD †

Robert H. Lurie Comprehensive Cancer Duke Cancer Institute UC San Diego Moores Cancer Center
Center of Northwestern University Kimberly L. Johung, MD, PhD § *Katrina Pedersen, MD, MS †
*Alan P. Venook, MD/Vice-Chair † ‡ Yale Cancer Center/Smilow Cancer Hospital Siteman Cancer Center at Barnes-
UCSF Helen Diller Family Nora Joseph, MD ≠
Comprehensive Cancer Center Jewish Hospital and Washington
University of Michigan Rogel Cancer Center University School of Medicine
Mahmoud M. Al-Hawary, MD ф Natalie Kirilcuk, MD ¶
University of Michigan Rogel Cancer Center Leonard Saltz, MD † ‡ Þ
Stanford Cancer Institute Memorial Sloan Kettering Cancer Center
Nilofer Azad, MD † Smitha Krishnamurthi, MD † Þ
The Sidney Kimmel Comprehensive Charles Schneider, MD †
Cancer Center at Johns Hopkins Case Comprehensive Cancer Center/ Abramson Cancer Center
University Hospitals Seidman Cancer Center at the University of Pennsylvania
Yi-Jen Chen, MD, PhD § and Cleveland Clinic Taussig Cancer Institute
City of Hope National Medical Center Jennifer Maratt, MD ¤ *David Shibata, MD ¶
Kristen K. Ciombor, MD † Indiana University Melvin and Bren Simon The University of Tennessee
Vanderbilt-Ingram Cancer Center Comprehensive Cancer Center Health Science Center
*Stacey Cohen, MD † Wells A. Messersmith, MD † John M. Skibber, MD ¶
Fred Hutchinson Cancer Center University of Colorado Cancer Center The University of Texas
MD Anderson Cancer Center
Harry S. Cooper, MD ≠ Jeffrey Meyerhardt, MD, MPH †
Fox Chase Cancer Center Dana-Farber Brigham and Women’s Constantinos T. Sofocleous, MD, PhD ф
Cancer Center Memorial Sloan Kettering Cancer Center
*Dustin Deming, MD † Eden Stotsky-Himelfarb, BSN, RN † ¶ ¥
*Eric D. Miller, MD, PhD §
University of Wisconsin Carbone Cancer Center The Sidney Kimmel Comprehensive
The Ohio State University Comprehensive Cancer Center at Johns Hopkins
Ignacio Garrido-Laguna, MD, PhD † Cancer Center - James Cancer Hospital
Huntsman Cancer Institute and Solove Research Institute Anna Tavakkoli, MD, MSc ¤
at the University of Utah UT Southwestern Simmons
Jean L. Grem, MD † Mary F. Mulcahy, MD ‡ † Comprehensive Cancer Center
Fred & Pamela Buffett Cancer Center Robert H. Lurie Comprehensive Cancer
Center of Northwestern University Christopher G. Willett, MD §
J. Randolph Hecht, MD † Duke Cancer Institute
UCLA Jonsson Comprehensive Cancer Center Steven Nurkin, MD, MS ¶
Roswell Park Comprehensive Cancer Center *Grant Williams, MD, MSPH †
Sarah Hoffe, MD § O’Neal Comprehensive Cancer Center at UAB
Moffitt Cancer Center *Michael J. Overman, MD † ‡
The University of Texas NCCN
Joleen Hubbard, MD † ‡ Frankie Algieri
Mayo Clinic Cancer Center MD Anderson Cancer Center Lisa Gurski, PhD
Steven Hunt, MD ¶ Aparna Parikh, MD † Jenna Snedeker, MS, ASCP
Siteman Cancer Center at Barnes- Massachusetts General Hospital Cancer Center Katie Stehman, MMS, PA-C
Jewish Hospital and Washington ф Diagnostic/Interventional ≠ Pathology
University School of Medicine
Hisham Hussan, MD ¤
Continue radiology
¤ Gastroenterology
¥ Patient advocate
§ Radiotherapy/Radiation
UC Davis Comprehensive Cancer Center ‡ Hematology/Hematology oncology
oncology ¶ Surgery/Surgical oncology
NCCN Guidelines Panel Disclosures Þ Internal medicine * Discussion Section Writing
† Medical oncology Committee

Table of Contents
NCCN Anal Carcinoma Panel Members Clinical Trials: NCCN believes that
Summary of the Guidelines Updates the best management for any patient
with cancer is in a clinical trial.
Participation in clinical trials is
Workup and Treatment - Anal Canal Cancer (ANAL-1) especially encouraged.
Workup and Treatment - Perianal Cancer (ANAL-2) Find an NCCN Member Institution:
Follow-up Therapy and Surveillance (ANAL-3) https://www.nccn.org/home/member-
institutions.
Principles of Surgery (ANAL-A) NCCN Categories of Evidence and
Consensus: All recommendations
Principles of Systemic Therapy (ANAL-B) are category 2A unless otherwise
Principles of Radiation Therapy (ANAL-C) indicated.
Principles of Survivorship (ANAL-D) See NCCN Categories of Evidence
and Consensus.
Staging (ST-1) NCCN Categories of Preference:
All recommendations are considered
Abbreviations (ABBR-1) appropriate.
See NCCN Categories of Preference.
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN 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 any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
not be reproduced in any form without the express written permission of NCCN. ©2023.

Table of Contents
Updates in Version 2.2023 of the NCCN Guidelines for Anal Carcinoma from Version 1.2023 include:
MS-1
• The Discussion section has been updated to reflect the changes in the algorithm.
Updates in Version 1.2023 of the NCCN Guidelines for Anal Carcinoma from Version 2.2022 include:
ANAL-1 – Capecitabine + RT wording revised: Capecitabine 825 mg/m² PO
• Workup twice daily 5 days/week + XRT x 5 weeks. Capecitabine 825 mg/m2
Bullet 8 modified: Gynecologic exam for females, including screening for PO twice daily on days 1–5 for 5 weeks with RT
cervical cancer (Also for ANAL-2) ANAL-B 3 of 3
• Primary Treatment; Metastatic Disease • References have been updated.
Preferred added to carboplatin/paclitaxel regimen (for ANAL-1 through ANAL-C 1 of 5
ANAL-4) • Principles of Radiation Therapy
◊ Footnote removed: Carboplatin/paclitaxel is the only regimen Treatment Information; Simulation
supported by randomized data and may be preferred over 5-FU/ ◊ Sub-bullet 1 revised: If available, PET/CT, MRI pelvis, or PET/MRI (if
cisplatin due to toxicity profiles. (for ANAL-1 through ANAL-4) available) at the time of simulation may be helpful to define local and
Pathway revised for metastatic disease: Re-evaluate and consider regional target structures.
chemo/RT to the primary site with 5-FU or Capecitabine for local control ANAL-C 2 of 5
(Also for ANAL-2) • Treatment Information, (continued)
ANAL-3 Target Volume Definition
• Surveillance ◊ Sub-bullet 4 revised: In defining the gross disease CTV around the
Local recurrence and Metastatic disease primary tumor, an approximately 2.5 1- to 2-cm margin around GTV
◊ Bullet added: PET/CT scan is not indicated (Also for ANAL-4) should be used with manual editing to avoid muscle or bone at low
• Footnote added to APR: Consider the use of immunotherapy (nivolumab risk for tumor infiltration.
or pembrolizumab) (category 2B) before proceeding to APR. Institutional ANAL-C 5 of 5
experience has demonstrated that some patients receive a good • Quality Assurance and Image-Guided Treatment Delivery
response and can avoid surgery. Sub-bullet added: If it is not possible to achieve the dosimetric goals in
ANAL-B 1 of 3 and ANAL-B 2 of 3 Table 2, small bowel max point dose should be limited to 50 Gy, V45 Gy
• Principles of Systemic Therapy should be <195 cc for a bowel bag avoidance structure, and V15 should
These pages have been extensively revised and separated into two be <120cc for individual small bowel loops.
pages: Localized Cancer and Metastatic Cancer ◊ Reference added: Kavanagh B, Pan C, Dawson L, et al. Radiation
Footnote added to both pages: Monday–Friday, on each day that RT dose-volume effects in the stomach and small bowel. Int J Radiat
is given throughout the duration of RT (typically 28–30 treatment days Oncol Biol Phys 2010;76:S101-107.
depending on stage) ANAL-D 1 of 2
◊ Localized Cancer • Principles of Survivorship
– Language revised for all regimens: Concurrent radiotherapy Survivorship Care Planning
(ANAL-C) with RT ◊ Sub-bullet added: Fertility counseling
– Mitomycin dose capped at 20 mg in all instances. Counseling Regarding Healthy Lifestyle and Wellness
◊ Metastatic Cancer ◊ Bullet 6 revised: Eliminate or limit alcohol consumption; no more than
– Footnote added to mFOLFOX6: Discontinuation of oxaliplatin 1 drink/day for females, and 2 drinks/day for males. Drink alcohol
should be strongly considered after 3 to 4 months of therapy (or sparingly, if at all.
sooner for unacceptable neurotoxicity) while maintaining other ST-1
agents until time of progression. Oxaliplatin may be reintroduced • The TNM Staging Classification for Anal Carcinoma has been updated
if it was discontinued for neurotoxicity rather than for disease based on the 9th edition of the American Joint Committee on Cancer
progression. (AJCC)
– 5-FU + RT wording revised: 5-FU 225 mg/m² IV over 24 hours
(continuous infusion) 5 or 7 days/week during XRT 5-FU 225 mg/m2
IV over 24 hours (continuous infusion) daily on days 1–5 or 1–7 for
5 weeks with RT UPDATES
Version 2.2023, 04/28/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®

Table of Contents
CLINICAL WORKUP CLINICAL PRIMARY TREATMENTg

PRESENTATION • Digital rectal examination STAGE
(DRE)
• Inguinal lymph node Locoregional Mitomycin/5-FUh + radiation therapy (RT)i
Follow-up
evaluation diseasee or
Therapy and
• Consider biopsy or fine (± positive Mitomycin/capecitabineh + RTi
needle aspiration (FNA) if Surveillance
para-aortic or
(ANAL-3)
suspicious nodes lymph 5-FU/cisplatinh + RTi (category 2B)
• Chest/abdominal CTc + nodes)f
Biopsy: pelvic CT or MRI Carboplatin/
Anal • Consider positron emission
squamous paclitaxel Re-evaluate and
canal tomography (PET)/CTd or
cell (preferred)h consider chemo/
cancera PET/MRI (if available)
carcinomab or RT to the primary Nivolumabh,j
• Anoscopy FOLFOXh siteh,i with 5-FU or
• HIV testing (if HIV status or or Capecitabine Pembrolizumabh,j
unknown) Metastatic FOLFCISh for local control
• Gynecologic exam, disease or
including screening for 5-FU/cisplatinh
cervical cancer (category 2B)
• Fertility risk discussion/ or
counseling in appropriate Modified docetaxel/ Nivolumabh,j
patients cisplatin/fluorouracil or
(DCF)h (category 2B) Pembrolizumabh,j
a The superior border of the functional anal canal, separating it from the rectum, has been defined as the palpable upper border of the anal sphincter and puborectalis
muscles of the anorectal ring. It is approximately 3 to 5 cm in length, and its inferior border starts at the anal verge, the lowermost edge of the sphincter muscles,
corresponding to the introitus of the anal orifice.
b For melanoma histology, see the NCCN Guidelines for Melanoma: Cutaneous; for adenocarcinoma, see the NCCN Guidelines for Rectal Cancer.
c CT should be with IV and oral contrast. Pelvic MRI with contrast. If intravenous iodinated contrast material is contraindicated due to significant contrast allergy or renal
failure, then MRI examination of the abdomen and pelvis with IV gadolinium-based contrast agent (GBCA) can be obtained in select patients (see American College of
Radiology contrast manual: https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf). Intravenous contrast is not required for the chest CT.
d PET/CT scan does not replace a diagnostic CT. PET/CT performed skull base to mid-thigh.
e Principles of Surgery (ANAL-A).
f Para-aortic nodes that can be included in a radiation field.
g Modifications to cancer treatment should not be made solely based on HIV status. See NCCN Guidelines for Cancer in People with HIV.
h Principles of Systemic Therapy (ANAL-B).
i Principles of Radiation Therapy (ANAL-C).
j NCCN Guidelines for the Management of Immunotherapy‑Related Toxicities.
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
ANAL-1

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CLINICAL WORKUP CLINICAL STAGE PRIMARY TREATMENTg

PRESENTATION T1, N0
Well or Adequate
Observe
moderately margins
• DRE differentiated Local
• Inguinal lymph node Re-excisione (preferred)
or select T2, excisione or
evaluation N0 (that does Inadequate Consider local RTi
Consider biopsy or not involve margins ± 5-FU/mitomycinh or Follow-up
FNA if suspicious sphincter) Capecitabine/mitomycinh or Therapy and
nodes 5-FU/cisplatinh (category 2B) Surveillance
• Chest/abdominal CTc T1, N0 Poorly (ANAL-3)
+ pelvic CT or MRI differentiated or 5-FU/mitomycinh + RTi
Consider PET/CTd or T2–T4, N0 or or
Biopsy:
PET/MRI (if available) e Capecitabine/mitomycinh + RTi
Perianal squamous Any T, N+ (± positive or
• Anoscopy para-aortic lymph
cancerk cell f 5-FU/cisplatinh + RTi (category 2B)
• HIV testing (if HIV nodes)
carcinomab
status unknown)
• Gynecologic exam, Carboplatin/paclitaxel
including screening (preferred)h
or Re-evaluate and
for cervical cancer FOLFOXh consider chemo/
• Consider fertility risk or RT to the primary Nivolumabh,j
discussion/counseling Metastatic FOLFCISh or
disease siteh,i with 5-FU
in appropriate or or Capecitabine Pembrolizumabh,j
patients 5-FU/cisplatinh for local control
(category 2B)
or Nivolumabh,j
Modified DCFh or
(category 2B) Pembrolizumabh,j
b For melanoma histology, see the NCCN Guidelines for Melanoma: Cutaneous; for
adenocarcinoma, see the NCCN Guidelines for Rectal Cancer. e Principles of Surgery (ANAL-A).
c CT should be with IV and oral contrast. Pelvic MRI with contrast. If intravenous f Para-aortic nodes that can be included in a radiation field.
iodinated contrast material is contraindicated due to significant contrast allergy g Modifications to cancer treatment should not be made solely based on HIV status.
or renal failure, then MRI examination of the abdomen and pelvis with IV GBCA NCCN Guidelines for Cancer in People with HIV.
can be obtained in select patients (see American College of Radiology contrast h Principles of Systemic Therapy (ANAL-B).
manual: https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_ i Principles of Radiation Therapy (ANAL-C).
Media.pdf). Intravenous contrast is not required for the chest CT. j NCCN Guidelines for the Management of Immunotherapy‑Related Toxicities.
d PET/CT scan does not replace a diagnostic CT. PET/CT performed skull base to k The perianal region starts at the anal verge and includes the perianal skin over a
mid-thigh. 5-cm radius from the squamous mucocutaneous junction.

ANAL-2

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FOLLOW-UP SURVEILLANCE TREATMENT SURVEILLANCEo

• Inguinal node palpation
every 3–6 mo for 5 y
• Chest/abdominal/pelvic
Local Abdominoperineal CT with contrast or chest
recurrence resection (APR)e,n,p CT without contrast and
abdominal/pelvic MRI with
• DRE every 3–6 mo contrast annually for 3 y
for 5 y • PET/CT scan is not
• Inguinal node and/or indicated Metastatic
palpation every 3–6 disease,
mo for 5 y • Groin dissectione • DRE every 3–6 mo for 5 y see below
• Anoscopy every • Consider RT,i if no prior RT to • Inguinal node palpation
6–12 mo x 3 y Inguinal groin ± 5-FU/mitomycinh every 3–6 mo for 5 y
Complete • Chest/abdominal/ node or Mitomycin/capecitabineh • Anoscopy every 6–12 mo
recurrence • Carboplatin/paclitaxel or x3y
remission pelvic CT with 5-FU/cisplatinh (category 2B), • Chest/abdominal/pelvic
contrast or chest if prior RT CT with contrast or chest
CT without contrast CT without contrast and
and abdominal/ Carboplatin/paclitaxel abdominal/pelvic MRI with
Evaluate pelvic MRI with (preferred)h contrast annually for 3 y
in 8–12 contrast annually or • PET/CT scan is not
wk with for 3 y (stage II–III) Metastatic FOLFOXh indicated
exam + or
Persistent diseasel diseasem FOLFCISh Nivolumabh,j
DRE (ANAL-4) or or
Progressive diseasel 5-FU/cisplatinh (category 2B) Pembrolizumabh,j
(ANAL-4) or
Modified DCFh (category 2B)
e Principles of Surgery (ANAL-A). m Palliative RT may be considered in symptomatic patients. Records of

h Principles of Systemic Therapy (ANAL-B). previous RT should be carefully reviewed and considered prior to potential
i Principles of Radiation Therapy (ANAL-C). re-irradiation of previously irradiated fields. Principles of Radiation Therapy
j NCCN Guidelines for the Management of Immunotherapy‑Related Toxicities. (ANAL-C).
l Based on the results of the ACT-II study, it may be appropriate to follow patients
who n Consider muscle flap reconstruction.
have not achieved a complete clinical response with persistent anal cancer up to 6 o Principles of Survivorship (ANAL-D)
months following completion of RT and chemotherapy as long as there is no evidence p Consider the use of immunotherapy (nivolumab or pembrolizumab)
of progressive disease during this period of follow-up. Persistent disease may continue (category 2B) before proceeding to APR. Institutional experience has
to regress even at 26 weeks from the start of treatment. James RD, et al. Lancet Oncol demonstrated that some patients receive a good response and can avoid
2013;14:516-524. surgery.

ANAL-3

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TREATMENT SURVEILLANCEo
• Inguinal node palpation
every 3–6 mo for 5 y
APRn,p + groin • Chest/abdominal/pelvic Metastatic
Locally
dissection, if positive CT with contrast or chest disease,
recurrent
inguinal nodes CT without contrast and see below
abdominal/pelvic MRI with
Progressive Biopsy Carboplatin/paclitaxel
Restageq contrast annually for 3 y
diseasel proven (preferred)h
• PET/CT scan is not
or
indicated
FOLFOXh
Metastatic
or
diseasem Nivolumabh,j
FOLFCISh
or or
5-FU/cisplatinh (category 2B) Pembrolizumabh,j
or
Modified DCFh (category 2B)
Progression on
serial exams
Persistent Re-evaluateq Continue If progression or
diseasel in 4 wk Regression or persistent disease
observation and
no progression
re-evaluateq at Complete
on serial exams Surveillance (ANAL-3)
3-mo intervals remission
m Palliative RT may be considered in symptomatic patients. Records of previous

h Principles of Systemic Therapy (ANAL-B). RT should be carefully reviewed and considered prior to potential re-irradiation of
j NCCN Guidelines for the Management of Immunotherapy‑Related Toxicities. previously irradiated fields. Principles of Radiation Therapy (ANAL-C).
l Based on the results of the ACT-II study, it may be appropriate to follow patients n Consider muscle flap reconstruction.
who have not achieved a complete clinical response with persistent anal cancer o Principles of Survivorship (ANAL-D).
up to 6 months following completion of RT and chemotherapy as long as there p Consider the use of immunotherapy (nivolumab or pembrolizumab) (category 2B)
is no evidence of progressive disease during this period of follow-up. Persistent before proceeding to APR. Institutional experience has demonstrated that some
disease may continue to regress even at 26 weeks from the start of treatment. patients receive a good response and can avoid surgery.
James RD, Lancet Oncol 2013;14:516-524. q Use imaging studies as per initial workup.

ANAL-4

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PRINCIPLES OF SURGERY
Local Excision
• Superficially Invasive Squamous Cell Carcinoma (SISCCA)
SISCCA are anal cancers that are generally found incidentally in the setting of a biopsy or excision of what is thought to be a benign lesion
such as a condyloma, hemorrhoid, or anal skin tag.
For such lesions that are noted to have histologically negative margins in carefully selected patients followed by an experienced provider
and/or team, local excision alone with a structured surveillance plan may represent adequate treatment.
• Perianal (Anal Margin) Cancer
T1N0, moderately to well-differentiated or select T2N0 squamous cell carcinoma (SCC) of the perianal (anal margin) region may be
adequately treated by local excision with 1-cm margins.
◊ Local surgical excision of select, early lesions may be considered:
– Where the tumor forms a discrete lesion arising from the perianal skin that is clearly separate from the anal canal
– Where negative margin excision can be accomplished without compromise of the adjacent sphincter muscles
– Where there is no evidence of regional nodal involvement
Radical Surgery
• Local Recurrence/Persistence
APR is the primary treatment.
General principles for APR are similar to those for distal rectal cancer and include the incorporation of total mesorectal excision (TME).
APR for anal cancer may require wider lateral perianal margins.
Due to the necessary exposure of the perineum to radiation, patients are prone to poor perineal wound healing and may benefit from the
use of reconstructive tissue flaps for the perineum such as the vertical rectus or local myocutaneous flaps.
• Inguinal Recurrence
Patients who have already received groin radiation should undergo an inguinal node dissection.
Groin dissection can be done with or without APR depending on whether disease is isolated to the groin or is in conjunction with
recurrence/persistence at the primary site.

ANAL-A

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PRINCIPLES OF SYSTEMIC THERAPY – LOCALIZED CANCER
Chemo/RT for Localized Cancer

Preferred Regimens Other Recommended Regimens
• 5-FU + mitomycin + RT • 5-FU + cisplatin + RT
• Capecitabine + mitomycin + RT
Systemic Therapy Regimens and Dosing – Localized Cancer
• 5-FU + mitomycin + RT1,2

Continuous infusion 5-FU 1000 mg/m2/day IV days 1–4 and 29–32
Mitomycin 10 mg/m2 IV bolus days 1 and 29 (capped at 20 mg) with RT
or
Continuous infusion 5-FU 1000 mg/m2/day IV days 1–4 and 29–32
Mitomycin 12 mg/m2 on day 1 (capped at 20 mg) with RT
• Capecitabine + mitomycin + RT3,4

Capecitabine 825 mg/m2 PO BIDa
Mitomycin 10 mg/m2 days 1 and 29 (capped at 20 mg) with RT
or
Capecitabine 825 mg/m2 PO BID days 1–5a
Mitomycin 12 mg/m2 IV bolus day 1 (capped at 20 mg) with RT
• 5-FU + cisplatin + RT5

Cisplatin 75 mg/m2 day 1
Continuous infusion 5-FU 1000 mg/m2/day IV days 1–4
Repeat every 4 weeks with RT
a Monday–Friday, on each day that RT is given throughout the duration of RT (typically 28–30 treatment days depending on stage).
Note: All recommendations are category 2A unless otherwise indicated. References

ANAL-B
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PRINCIPLES OF SYSTEMIC THERAPY – METASTATIC CANCER
First-Line Therapy for Metastatic Cancer Subsequent Therapy Chemo/RT to the

Primary Site for Local
Preferred Regimens Other Recommended Regimens Preferred Regimens Control
• Carboplatin + paclitaxel • 5-FU + cisplatin • Nivolumab
• FOLFCIS • Pembrolizumab
• mFOLFOX6b if neither previously received • 5-FU + RT
• Modified DCF • Capecitabine + RT
Systemic Therapy Regimens and Dosing – Metastatic Cancer

• Carboplatin + paclitaxel • FOLFCIS10 • Nivolumab13
Carboplatin AUC 5 IV day 1 Cisplatin 40 mg/m2 IV over 30 minutes on day 1* Nivolumab 240 mg IV every 2 weeks
Paclitaxel 175 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1* or Nivolumab 3 mg/kg IV every 2 weeks
Repeat every 21 days6 5-FU 400 mg/m2 IV bolus on day 1, or Nivolumab 480 mg IV every 4 weeks
or then 1000 mg/m2/day x 2 days
Carboplatin AUC 5 IV day 1 (total 2000 mg/m2 over 46–48 hours) • Pembrolizumab14
Paclitaxel 80 mg/m2 IV days 1, 8, 15 IV continuous infusion Pembrolizumab 200 mg IV every 3 weeks
Repeat every 28 days7 Repeat every 2 weeks or Pembrolizumab 2 mg/kg IV every 3 weeks
*Cisplatin and leucovorin are given concurrently or Pembrolizumab 400 mg IV every 6 weeks
• 5-FU + cisplatin
Cisplatin 60 mg/m2 day 1 • mFOLFOX611 Chemo/RT
Continuous infusion 5-FU 1000 mg/m2/day Oxaliplatin 85 mg/m2 IV day 1 • 5-FU + RT
IV days 1–4 Leucovorin 400 mg/m2 IV day 1 5-FU 225 mg/m2 IV over 24 hours (continuous
Repeat every 3 weeks8 5-FU 400 mg/m2 IV bolus on day 1,
then 1200 mg/m2/day x 2 days infusion) daily on days 1–5 or 1–7 for 5 weeks
or
(total 2400 mg/m2 over 46–48 hours) with RT15-17
Cisplatin 75 mg/m2 day 1
Continuous infusion 5-FU 750 mg/m2/day IV continuous infusion
IV days 1–5 Repeat every 2 weeks • Capecitabine + RT
Repeat every 4 weeks9 Capecitabine 825 mg/m2 PO twice daily on
• Modified DCF12 days 1–5 with RT18-20,a
Docetaxel 40 mg/m2 IV day 1
Cisplatin 40 mg/m2 IV day 1
Fluorouracil 1200 mg/m2/day x 2 days
(total 2400 mg/m2 over 46–48 hours)
Repeat every 2 weeks
a Monday–Friday, on each day that RT is given throughout the duration of RT (typically 28–30 treatment days depending on stage).
b Discontinuation of oxaliplatin should be strongly considered after 3 to 4 months of therapy (or sooner for unacceptable neurotoxicity) while maintaining other agents until time of
progression. Oxaliplatin may be reintroduced if it was discontinued for neurotoxicity rather than for disease progression.
Note: All recommendations are category 2A unless otherwise indicated. References

ANAL-B
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PRINCIPLES OF SYSTEMIC THERAPY

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M, Miwa K, Oka Y, et al. Successful treatment of metastatic anal canal adenocarcinoma with mFOLFOX + bevacizumab. Case Rep Oncol 2016;9:249-
254.
12 Kim S, Francois E, Andre T, et al. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma
(Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol 2018;19:1094-1106.
13 Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicenter, single-arm, phase 2 study.
Lancet Oncol 2017;18:446-453.
14 Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal.
Ann Oncol 2017;28:1036-1041.
15 O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after
curative surgery. N Engl J Med 1994; 331:502-507.
16 Rich TA, Ajani JA, Morrison WH, et al. Chemoradiation therapy for anal cancer: radiation plus continuous infusion of 5-fluorouracil with or without cisplatin. Radiother
Oncol 1993;27:209-215.
17 Charnley N, Choudhury A, Chesser P, et al. Effective treatment of anal cancer in the elderly with low-dose chemoradiotherapy. Br J Cancer 2005; 92:1221-1225.
18 O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from
National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol 2014;32:1927-1934.
19 Hofheinz R, Wenz FK, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: A randomized, multicentre, non-
inferiority, phase 3 trial. Lancet Oncol 2012;13:579-588.
20 Xu WD, Jiang HY, Gao JM, et al. Preliminary results on anal cancer by applying intensity modulated radiotherapy and synchronous capecitabine chemotherapy
simultaneously. Transl Cancer Res 2020; 9:4366-4372.

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PRINCIPLES OF RADIATION THERAPY1

General Principles
• The consensus of the panel is that intensity-modulated RT (IMRT) is preferred over 3D conformal RT (3D-CRT) in the treatment of anal
carcinoma.2 IMRT requires expertise and careful target design to avoid reduction in local control by so-called “marginal-miss.”3 The clinical
target volumes (CTVs) for anal cancer used in the RTOG-0529 trial have been described in detail.2 The outcome results of RTOG-0529
have been reported.4 Also see The RTOG Consensus Panel Contouring Atlas for more details of the contouring atlas defined by RTOG.
The information below provides details regarding simulation, target volume definition, dose prescription, organs at risk (OARs), IMRT
constraints, quality assurance, and image guidance delivery.
• Image-guided RT (IGRT) with kilovoltage (kV) imaging or cone beam CT imaging should be routinely used during the course of treatment
with IMRT and stereotactic body RT (SBRT).
• Consider SBRT for patients with oligometastatic disease.
Treatment Information
• Simulation
After clinical and radiologic staging, CT-based simulation is performed for radiation treatment planning. If available, PET/CT, MRI pelvis, or
PET/MRI (if available) at the time of simulation may be helpful to define local and regional target structures. Patients can be simulated in
the supine or prone position and there are benefits to each approach in the appropriate clinical setting. Prone setup with a false tabletop
allows for improved small bowel avoidance and may be useful in individuals with a large pannus and pelvic node involvement. Supine
setup is usually more reproducible with less setup variability, potentially allowing for reduced planning target volume (PTV) margins and
smaller treatment fields. Patients are typically simulated for anal cancer IMRT planning in the supine position with legs slightly abducted
(frog-legged) with semi-rigid immobilization in vacuum-locked bag or alpha-cradle. Patients are instructed to maintain a full bladder for
simulation and treatment.
In males,* the external genitalia are typically positioned inferiorly such that setup is reproducible. In females,* a vaginal dilator can be
placed to help delineate the genitalia and move the vulva and lower vagina away from the primary tumor. A radiopaque marker should be
placed at the anal verge and perianal skin involvement can be outlined with radio-opaque catheters. It may be helpful to place a catheter
with rectal contrast in the anal canal at the time of simulation for tumor delineation.
In patients with adequate renal function, IV contrast facilitates identification of the pelvic and groin vasculature (which approximates at-risk
nodal regions). Oral contrast identifies small bowel as an avoidance structure during treatment planning. For tumors involving the perianal
skin or superficial inguinal nodes, bolus should be placed as necessary for adequate dosing of gross disease in these areas. Routine
use of bolus may not be necessary as the tangential effect of IMRT may minimize skin sparing. In situations where adequate dosing of
superficial targets is uncertain, in vivo diode dosimetry with the first treatment fraction can ensure appropriate dose at the skin surface.
* NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms
males and females refer to sex assigned at birth.
1 Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and 3 Pepek JM, Willett CG, Czito BG. Radiation therapy advances for treatment of anal
radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal cancer. J Natl Compr Canc Netw 2010;8:123-129.
canal. JAMA 2008;299:1914-1921. 4 Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation
2 Myerson RJ, Garofalo MC, El Naqa I, et al. Elective clinical target volumes of dose-painted intensity modulated radiation therapy in combination with
for conformal therapy in anorectal cancer: a radiation therapy oncology group 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma
consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 2009;74:824-830. of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27-33.
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Treatment Information (continued)
• Target Volume Definition
Target volume definition should be performed per ICRU 50 recommendations. Gross tumor volume (GTV) should include all primary
tumor and involved lymph nodes, using information from physical examination, endoscopic findings, diagnostic imaging, and simulation
planning study for delineation. CTV should include the GTV plus areas at risk for microscopic spread from the primary tumor and at-risk
nodal areas. If the primary tumor cannot be determined with available information (such as after local excision), the anal canal may be used
as a surrogate target.
The pelvic and inguinal nodes should be routinely treated in all patients.
When using IMRT, a separate CTV volume for each planned treatment dose tier is contoured. One approach has been to define three tiers:
a gross disease only volume, a high-risk elective nodal volume (including gross disease), and low-risk elective nodal volume (including
gross disease). These volumes are determined by the presence or absence of tumor based on physical examination, biopsy, diagnostic
and planning studies, and risk of nodal spread depending on tumor stage at presentation. The rationale for this approach is based on the
shrinking fields technique. In RTOG-0529, a gross disease volume with a single elective nodal volume are used to deliver the prescribed
course (dose-painting).
In defining the gross disease CTV around the primary tumor, an approximately 1- to 2-cm margin around GTV should be used with manual
editing to avoid muscle or bone at low risk for tumor infiltration. To define the gross disease CTV around involved nodes, a 1-cm expansion
should be made beyond the contoured involved lymph node with manual editing to exclude areas at low risk for tumor infiltration.
At-risk nodal regions include mesorectal, presacral, internal and external iliac, and inguinal nodes. The mesorectal volume encompasses
the rectum and surrounding lymphatic tissue. The presacral nodal volume is typically defined as an approximately 1-cm strip over the
anterior sacral prominence. To contour the internal and external iliac nodes, it is recommended to generally contour the iliac arteries
and veins with approximately 0.7-cm margin (1- to 1.5-cm anteriorly on external iliac vessels) to include adjacent lymph nodes. In order
to include the obturator lymph nodes, external and internal iliac volume contours should be joined parallel to the pelvic sidewall. The
inguinal node volume extends beyond the external iliac contour along the femoral artery from approximately the upper edge of the superior
pubic rami to approximately 2 cm caudad to saphenous/femoral artery junction. The inguinal node volume should be contoured as a
compartment with general margins. The medial and lateral borders may be defined by adductor longus and sartorius muscles, respectively.
Several recently published atlases are helpful to review when defining elective nodal CTVs.5,6 The above descriptions are generalizations
and each plan should be individualized based on the anatomy of each patient and tumor distribution.
1 Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. JAMA
2008;299:1914-1921.
5 Myerson RJ, Garofalo MC, El Naqa I, et al. Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus
panel contouring atlas. Int J Radiation Oncology Biol Phys 2009;74:824-830.
6 Ng M, Leong T, Chander S, et al. Australasian Gastrointestinal Trials Group (AGITG) contouring atlas and planning guidelines for intensity-modulated radiotherapy in
anal cancer. Int J Radiation Oncology Biol Phys 2012;83:1455-1462.
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• Target Volume Definition
The high-risk elective nodal volume typically includes the gross disease CTV plus the entire mesorectum, presacral nodes, and bilateral
internal and external iliac lymph nodes inferior to the sacroiliac joint. In patients with gross inguinal nodal involvement, the bilateral or
unilateral inguinal nodes may be included in the high-risk elective nodal volume. The low-risk elective nodal volume should include the
gross disease CTV, high-risk elective nodal CTV, and presacral, bilateral internal, and external iliac nodes above the inferior border of the
sacroiliac joint to the bifurcation of the internal and external iliac vessels at approximately L5/S1 vertebral body junction. If there is no
obvious involvement of the bilateral inguinal nodes, these are included in the low-risk elective nodal volume.
PTV should account for effects of organ and patient movement and inaccuracies in beam and patient setup. PTV expansions should
typically be approximately 0.5- to 1.0-cm depending on use of image guidance and physician practice with treatment setup for each
defined CTV. To account for differences in bladder and rectal filling, a more generous CTV to PTV margin is applied in these regions. These
volumes may be manually edited to limit the borders to the skin surface for treatment planning purposes.
• Dose Prescription
With IMRT treatment planning, doses are typically prescribed to PTVs. The dose of radiation required to control disease is extrapolated
from historical studies that show excellent rates of control with concurrent radiation and chemotherapy. Typically prescribed dose varies
by size of the tumor and risk of microscopic spread in elective nodal areas. One approach with “shrinking field technique” is that the low-
risk elective nodal PTV volume is typically prescribed to 30.6 Gy in 1.8 Gy daily fractions. The high-risk elective nodal PTV is sequentially
prescribed an additional 14.4 Gy in 1.8 Gy daily fractions for a total prescribed dose of 45 Gy. Finally, for T1–2 lesions with residual disease
after 45 Gy, T3–4 lesions, or N1 lesions, an additional 5.4–14.4 Gy in 1.8–2 Gy daily fractions is again sequentially prescribed to the gross
disease PTV volume (total dose, 50.4–59.4 Gy).
In RTOG-0529, the prescription parameters are different due to the use of only a single elective nodal volume and slightly different dose
prescriptions depending on tumor stage. Furthermore, delivery of escalating dose to different target volumes was performed using a
simultaneous integrated boost (SIB) dose painting technique with a maximum dose of 1.8 Gy per fraction to the primary tumor and large
volume gross nodal involvement and 1.5 Gy per daily fraction to elective nodal areas. Table 1 outlines dose prescriptions by TNM stage
according to the RTOG-0529 protocol. The SIB approach offers the convenience of developing a single treatment plan with reduced
planning complexity, albeit with a lower biological dose delivered to the elective nodal areas.
For untreated patients presenting with synchronous local and metastatic disease, a platinum-based regimen is standard practice, and
radiation can be considered for local control. The approach to radiation depends on the patient’s performance status and extent of metastatic
disease. If performance status is good and metastatic disease is limited, treat involved fields, 45–54 Gy to the primary tumor and involved
sites in the pelvis, in coordination with plans for a platinum-based regimen. If there is low-volume liver oligometastasis, an SBRT dosing
schema after systemic therapy may be appropriate depending on response. If metastatic disease is extensive and life expectancy is limited,
a different schedule and dose of radiation should be considered, again in coordination with plans for 5-FU/cisplatin or a platinum-based
regimen.
1 AjaniJA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. JAMA
2008;299:1914-1921.
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Table 1: Dose Specification of Primary and Nodal Planning Target Volumes: RTOG-05294
TNM Stage Primary Tumor PTV Dose Involved Nodal PTV Dose Nodal PTV Dose
T1, N0 50.4 Gy (28 fxs at 1.8 Gy/fx) N/A 42 Gy (28 fxs at 1.5 Gy/fx)
T2, N0 50.4 Gy (28 fxs at 1.8 Gy/fx) N/A 42 Gy (28 fxs at 1.5 Gy/fx)
T3–4, N0 54 Gy (30 fxs at 1.8 Gy/fx) N/A 45 Gy (30 fxs at 1.5 Gy/fx)
T any, N+ (≤3 cm) 54 Gy (30 fxs at 1.8 Gy/fx) 50.4 Gy (30 fxs at 1.68 Gy/fx) 45 Gy (30 fxs at 1.5 Gy/fx)
T any, N+ (>3 cm) 54 Gy (30 fxs at 1.8 Gy/fx) 54 Gy (30 fxs at 1.8 Gy/fx) 45 Gy (30 fxs at 1.5 Gy/fx)
• Dose Prescription
The usual scenario of recurrent disease is recurrence in the primary site or nodes after previous RT and chemotherapy. In this setting,
surgery should be performed if possible, and, if not, palliative RT and chemotherapy can be considered based on symptoms, extent of
recurrence, and prior treatment. RT technique and doses are dependent on dosing and technique of prior treatment. In the setting of pure
palliation, doses of 20–25 Gy in 5 fractions to 30 Gy in 10 fractions can be considered. SBRT can also be considered for treatment of
primary and nodal recurrence in the setting of low-volume metastatic disease.
• OARs and IMRT Constraints
It is important to accurately define OARs so that dose to these structures can be minimized during treatment. In anal cancer, 2D and 3D
treatment planning techniques are limited in their ability to spare most pelvic normal tissues due to the location of the target. With IMRT,
dose to small bowel, bladder, pelvic/femoral bones, and external genitalia can be sculpted and minimized despite close proximity of these
organs to target volumes. When contouring these structures, it is typically best to demarcate normal tissues on axial CT at least 2 cm
above and below the PTV. Oral contrast is helpful to delineate the small bowel. While there is significant variability in how to contour the
small bowel, one approach entails contouring the entire volume of peritoneal space in which the small bowel can move. As with elective
nodal volume delineation, contouring atlases offer excellent guidance on defining OARs.7 Once the OARs have been identified, the chief
aim of IMRT planning is to limit the dose to these structures without compromising PTV coverage. The extent to which OARs can be
avoided largely depends on the location and extent of tumor involvement at presentation as well as the extent to which the bowel extends
into the lower pelvis and a given individual’s anatomy.
Given patient variation with respect to OAR position and areas of tumor involvement, practical dose constraint guidelines are challenging.
In tumors without gross nodal involvement it is often possible to limit OAR doses even further. Alternatively, in tumors with gross nodal
involvement within the pelvis, compromise of PTV coverage may be necessary to limit doses to normal tissues, such as small bowel. Table
2 outlines dose constraints in RTOG-0529.
1 AjaniJA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. JAMA
2008;299:1914-1921.
4 Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil
and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27-33.
7 Gay HA, Barthold HJ, O’Meara E, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a radiation therapy oncology group consensus panel atlas. Int
J Radiation Oncol Biol Phys 2012;83:e353-e362.
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Table 2: DP-IMRT Dose Constraints for Normal Tissues8

Organ Dose (Gy) at <5% Volume Dose (Gy) at <35% Volume Dose (Gy) at <50% Volume
Small bowel† 45 (<20 cc) 35 (<150 cc) 30 (<200 cc)
Femoral heads 44 40 30
Iliac crest 50 40 30
External genitalia 40 30 20
Bladder 50 40 35
Large bowel† 45 (<20 cc) 35 (<150 cc) 30 (<200 cc)
Organs are listed in order of decreasing priority.
†Dose constraints are based on absolute volume instead of % volume.
• Quality Assurance and Image-Guided Treatment Delivery

Due to the sophistication and complexity of IMRT planning for anal cancer, comprehensive quality assurance measures must be
implemented to ensure minimal variability between the designed and delivered treatment plans. Each institution should have a quality
assurance program in place for the treatment of patients with anal cancer.
The use of image guidance for radiation treatment delivery has significantly improved confidence in daily treatment setup. This has allowed
for shrinking CTV to PTV expansions during the treatment planning process, which in turn further minimizes dose to OARs.
If it is not possible to achieve the dosimetric goals in Table 2, small bowel max point dose should be limited to 50 Gy, V45 should be <195
cc for a bowel bag avoidance structure, and V15 should be <120cc for individual small bowel loops.9
• Supportive Care
Patients should be considered for vaginal dilators and instructed on the symptoms of vaginal stenosis.
Patients of childbearing potential should be counseled about the effects of premature menopause and consideration should be given to
referral for discussion of hormone replacement strategies.
Patients of childbearing potential should be counseled that an irradiated uterus cannot carry a fetus to term.
Patients should be counseled on sexual dysfunction, potential for future low testosterone levels, and infertility risks and given information
regarding sperm banking or oocyte, egg, or ovarian tissue banking, as appropriate, prior to treatment.
1 Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. JAMA
2008;299:1914-1921.
8 Reprinted from the International Journal of Radiation Oncology, Biology, Physics, Vol. 86/1, Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation
of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal
canal. Int J Radiat Oncol Biol Phys 2013;86:27-33 with permission from Elsevier.
9 Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys 2010;76:S101-107.

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PRINCIPLES OF SURVIVORSHIP
Anal Carcinoma Surveillance: • Urogenital dysfunction after resection and/or pelvic radiation7,8
• Long-term surveillance should be carefully managed with routine Screen for sexual dysfunction, erectile dysfunction, dyspareunia,
good medical care and monitoring, including cancer screening, vaginal stenosis, and vaginal dryness.
routine health care, and preventive care. Screen for urinary incontinence, frequency, and urgency.
Consider referral to urologist or gynecologist for persistent
Survivorship Care Planning: symptoms.
The oncologist and primary care provider should have defined roles • Potential for pelvic fractures/decreased bone density after pelvic
in the surveillance period, with roles communicated to the patient.1 radiation
• Develop survivorship care plan that includes: Consider bone density monitoring.
Overall summary of treatment, including all surgeries, radiation
treatments, and chemotherapy received. Counseling Regarding Healthy Lifestyle and Wellness9:
Description of possible expected time to resolution of acute NCCN Guidelines for Survivorship
toxicities, long-term effects of treatment, and possible late • Undergo all age- and gender-appropriate cancer and preventive
sequelae of treatment. health screenings as per national guidelines.
Surveillance recommendations. • Maintain a healthy body weight throughout life.
Delineation of appropriate timing of transfer of care with specific • Adopt a physically active lifestyle (at least 30 minutes of
responsibilities identified for primary care physician and moderate-intensity activity on most days of the week). Activity
oncologist. recommendations may require modification based on treatment
Health behavior recommendations. sequelae (ie, ostomy, neuropathy).
Fertility counseling. • Consume a healthy diet with an emphasis on plant sources. Diet
Management of Late/Long-term Sequelae of Disease or Treatment2-6: recommendations may be modified based on severity of bowel
• For issues related to distress, pain, neuropathy, fatigue, or sexual dysfunction.
dysfunction, see NCCN Guidelines for Survivorship. • Consider daily aspirin 325 mg for secondary prevention.
• Bowel function changes: chronic diarrhea, incontinence, stool • Drink alcohol sparingly, if at all.
frequency, stool clustering, urgency, and/or cramping • Seek smoking cessation counseling as appropriate.
Consider anti-diarrheal agents, bulk-forming agents, diet
manipulation, pelvic floor rehabilitation, and protective Additional health monitoring and immunizations should be performed
undergarments. as indicated under the care of a primary care physician. Survivors are
Management of an ostomy encouraged to maintain a therapeutic relationship with a primary care
◊ Consider participation in an ostomy support group or physician throughout their lifetime.
coordination of care with a health care provider specializing in
ostomy care (ie, ostomy nurse).
◊ Screen for distress around body changes (NCCN Guidelines
for Distress Management) and precautions around involvement
with physical activity (SPA-A in the NCCN Guidelines for
Survivorship).
References
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PRINCIPLES OF SURVIVORSHIP
REFERENCES
1 Hewitt M, Greenfield S, Stovall E. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, D.C.:The National Academies Press;2006.
2 Schneider EC, Malin JL, Kahn KL, et al. Surviving colorectal cancer. Cancer 2007;110:2075-2082.
3 Sprangers MAG, Taal BG, Aaronson NK, te Velde A. Quality of life in colorectal cancer. Stoma vs. nonstoma patients. Dis Colon Rectum 1995;38:361-369.
4 Gami B, Harrington K, Blake P, et al. How patients manage gastrointestinal symptoms after pelvic radiotherapy. Aliment Pharmacol Ther 2003;18:987-994.
5 DeSnoo L, Faithfull S. A qualitative study of anterior resection syndrome: the experiences of cancer survivors who have undergone resection surgery. Eur J Cancer
Care (Engl) 2006;15:244-251.
6 McGough C, Baldwin C, Frost C, Andreyev HJ. Role of nutritional intervention in patients treated with radiotherapy for pelvic malignancy. Br J Cancer 2004;90:2278-
2287.
7 Lange MM, Marijnen CAM, Mass CP, et al. Risk factors for sexual dysfunction after rectal cancer treatment. Eur J Cancer 2009;45:1578-1588.
8 Lange MM, Mass CP, Marijnen CAM, et al. Urinary dysfunction after rectal cancer treatment is mainly caused by surgery. Brit J Cancer 2008;95:1020-1028.
9 Kushi LH, Byers T, Doyle C, et al and The American Cancer Society 2006 Nutrition and Physical Activity Guidelines Advisory Committee. American Cancer Society
Guidelines on Nutrition and Physical Activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin
2006;56:254-281.

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American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Anal Carcinoma (9th ed., 2022)
Table 1. Definitions for T, N, M Table 2. AJCC Anatomic Stage/Prognostic Groups
T Primary Tumor T N M
TX Primary tumor not assessed Stage I T1 N0 M0
T0 No evidence of primary tumor Stage IIA T2 N0 M0
T1 Tumor less than or equal to 2 cm in greatest dimension Stage IIB T1-T2 N1 M0
T2 Tumor greater than 2 cm but less than or equal to 5 cm in Stage IIIA T3 N0-N1 M0
greatest dimension Stage IIIB T4 N0 M0
T3 Tumor greater than 5 cm in greatest dimension Stage IIIC T4 N1 M0
T4 Tumor of any size invades adjacent organ(s), such as the Stage IV Any T Any N M1
vagina, urethra, or bladder
N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed
N0 No tumor involvement of regional lymph node(s)
N1 Tumor involvement of regional lymph node(s)
N1a Tumor involvement of inguinal, mesorectal, superior rectal,
internal iliac, or obturator lymph node(s)
N1b Tumor involvement of external iliac lymph node(s)
N1c Tumor involvement of N1b (external iliac) with any N1a
node(s)
M Distant Metastasis
cM0 No distant metastasis
cM1 Distant metastasis
pM1 Microscopic confirmation of distant metastasis
© 2022, American College of Surgeons, All Rights Reserved. Used with permission of the American College of Surgeons, Chicago, Illinois. The original
source for this information is the AJCC Cancer Staging System.
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ABBREVIATIONS
APR abdominoperineal resection

CTV clinical target volume
DRE digital rectal examination
FNA fine-needle aspiration
GBCA gadolinium-based contrast agent
GTV gross tumor volume
IMRT intensity-modulated radiation therapy
OAR organs at risk
PET positron emission tomography
PTV planning target volume
RT radiation therapy
SBRT stereotactic body radiation therapy
SIB simultaneous integrated boost
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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 2.2023

Anal Carcinoma
Discussion This discussion corresponds to the NCCN Guidelines

Summary .................................................................................. MS-22
f or Anal Carcinoma. Last updated April 28, 2023
References ............................................................................... MS-23
Table of Contents
Overview..................................................................................... MS-2
Guidelines Update Methodology............................................... MS-2
Literature Search Criteria .......................................................... MS-2
Sensitive/Inclusive Language Usage ........................................ MS-2
Risk Factors ............................................................................... MS-3
Risk Reduction ......................................................................... MS-4
Anatomy/Histology..................................................................... MS-5
Pathology ................................................................................... MS-6
Staging........................................................................................ MS-7
Prognostic Factors .................................................................... MS-8
Management of Anal Carcinoma ............................................... MS-8
Clinical Presentation/Evaluation................................................ MS-8
Primary Treatment of Non-Metastatic Anal Carcinoma.............. MS-9
Surveillance Following Primary Treatment .............................. MS-17
Treatment of Locally Progressive or Recurrent Anal Carcinoma

............................................................................................... MS-18
Treatment of Metastatic Anal Cancer ...................................... MS-19
Survivorship ............................................................................. MS-21
Version 2.2023 © 2023 National Comprehensive Cancer Network© (NCCN© ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1

Anal Carcinoma
Overview Guidelines Update Methodology

An estimated 9760 new cases (3180 male and 6580 female) of anal The complete details of the Development and Update of the NCCN
cancer involving the anus, anal canal, or anorectum will occur in the Guidelines are available at www.NCCN.org.
United States in 2023, accounting for approximately 2.8% of digestive
system cancers.1 1870 deaths due to anal cancer are projected to occur Literature Search Criteria
in the United States in 2023.1 Although considered to be a rare cancer, Prior to the update of this version of the NCCN Guidelines for Anal
the incidence rate of invasive anal carcinoma in the United States Carcinoma, an electronic search of the PubMed database was
increased by approximately 1.9-fold for males and 1.5-fold for females performed to obtain key literature in the field of anal cancer published
between the periods of 1973–1979 to 1994–2000 and has continued to since the previous Guidelines update, using the search terms: anal
increase since that time.2-4 According to an analysis of SEER data, the cancer or anal squamous cell carcinoma. The PubMed database was
incidence of anal squamous carcinoma increased at a rate of 2.9% per chosen because it remains the most widely used resource for medical
year from 1992 to 2001.5 Supporting this, an analysis of the U.S. literature and indexes peer-reviewed biomedical literature.11
Cancer Statistics dataset reported an annual increase of 2.7% between
2001 to 2015 with the greatest increases in age groups ≥50 years,6 The search results were narrowed by selecting studies in humans
while the National Program of Cancer Registries and SEER programs published in English. Results were confined to the following article
showed similar trends from 2001 to 2016, with an annual percent types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial,
change of 2.1 (95% CI, 1.7–2.5) overall, and 2.8 (95% CI, 2.5–3.1) in Phase IV; Practice Guideline; Randomized Controlled Trials; Meta-
those ≥50 years of age.7 Increases in incidence of anal cancer during Analysis; Systematic Reviews; and Validation Studies. The data from
that time frame were especially noted for females ≥50 years. Anal key PubMed articles as well as articles from additional sources deemed
cancer mortality rates (2001–2016) also rose, with an average increase as relevant to these Guidelines as discussed by the panel during the
of 3.1% per year.6 Guidelines update have been included in this version of the Discussion
section. Recommendations for which high-level evidence is lacking are
This Discussion summarizes the NCCN Clinical Practice Guidelines for based on the panel’s review of lower-level evidence and expert opinion.
managing squamous cell anal carcinoma, which represents the most
common histologic form of the disease. Other groups have also Sensitive/Inclusive Language Usage
published guidelines for the management of anal squamous cell NCCN Guidelines strive to use language that advances the goals of
carcinoma.8-10 Other types of cancers occurring in the anal region are equity, inclusion, and representation. NCCN Guidelines endeavor to use
addressed in other NCCN Guidelines; anal adenocarcinoma and anal language that is person-first; not stigmatizing; anti-racist, anti-classist,
melanoma are managed according to the NCCN Clinical Practice anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and
Guidelines (NCCN Guidelines®) Rectal Cancer and the NCCN inclusive of individuals of all sexual orientations and gender identities.
Guidelines® for Melanoma, respectively. NCCN Guidelines incorporate non-gendered language, instead focusing
on organ-specific recommendations. This language is both more
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Anal Carcinoma
accurate and more inclusive and can help fully address the needs of prevalence rates in anal cancer specimens.23,24 A 2012 report from the
individuals of all sexual orientations and gender identities. NCCN U.S. Centers for Disease Control and Prevention (CDC) estimated that
Guidelines will continue to use the terms men, women, female, and 86% to 97% of cancers of the anus are attributable to HPV infection.25
male when citing statistics, recommendations, or data from
organizations or sources that do not use inclusive terms. Most studies Suppression of the immune system by the use of immunosuppressive
do not report how sex and gender data are collected and use these drugs or HIV infection likely facilitates persistence of HPV infection of
terms interchangeably or inconsistently. If sources do not differentiate the anal region.26,27 Studies have shown that people living with HIV
gender from sex assigned at birth or organs present, the information is (PLWH) have an approximately 15- to 35-fold increased likelihood of
presumed to predominantly represent cisgender individuals. NCCN being diagnosed with anal cancer compared with the general
encourages researchers to collect more specific data in future studies population.28-31 In PLWH, the standardized incidence rate of anal
and organizations to use more inclusive and accurate language in their carcinoma per 100,000 person-years in the United States, estimated to
future analyses. be 19.0 in 1992 through 1995, increased to 78.2 during 2000 through
2003.27 This result likely reflects both the survival benefits of modern
Risk Factors antiretroviral therapy (ART) and the lack of an impact of ART on the
Anal carcinoma is associated with human papillomavirus (HPV) progression of anal cancer precursors. The incidence rate of anal
infection (anal-genital warts); a history of receptive anal intercourse or cancer has been reported to be 131 per 100,000 person-years in males
sexually transmitted disease; a history of cervical, vulvar, or vaginal who have sex with males (MSM) with HIV in North America, and in the
cancer; immunosuppression after solid organ transplantation or human range of 3.9 to 30 per 100,000 person years in females living with
immunodeficiency virus (HIV) infection; hematologic malignancies; HIV.32,33 An analysis of the French Hospital Database on HIV showed a
certain autoimmune disorders; and smoking.12-20 highly elevated risk of anal cancer in PLWH, including in those who
were on therapy and whose CD4+ T-cell counts were high.34 The data
The association between anal carcinoma and persistent infection with a also revealed an increasing incidence of anal cancer in the PLWH
high-risk form of HPV (eg, HPV-16; HPV-18) is especially strong.13,21,22 population over time. However, some evidence suggests that prolonged
For example, a study of tumor specimens from more than 60 pathology ART (>24 months) may be associated with a decrease in the incidence
laboratories in Denmark and Sweden showed that high-risk HPV DNA of high-grade anal intraepithelial neoplasia (AIN).35
was detected in 84% of anal cancer specimens, with HPV-16 detected
in 73% of them. In contrast, high-risk HPV was not detected in any of A meta-analysis of anal cancer incidence across risk groups found that
the rectal adenocarcinoma specimens analyzed.13 In addition, results of the incidence of anal cancer in solid organ transplant recipients
a systematic review of 35 peer-reviewed anal cancer studies that increased both by age and years since transplant.20 Incidence rates
included HPV DNA testing results published up until July 2007 showed rose from 0.0 and 3.1 per 100,000 person years in males and females
the prevalence of HPV-16/18 to be 72% in patients with invasive anal >30 years to 13.4 and 25.9 per 100,000 person years in males and
cancer.22 Population and registry studies have found similar HPV females ≥60 years. Years since transplant appeared to identify an even
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Anal Carcinoma
higher risk than age, with an incidence rate of 24.5 and 29.6 per Guidelines for the treatment of AIN have been developed by several
100,000 person years in males and females ≥10 years post-transplant, groups, including the American Society of Colon and Rectal Surgeons
respectively. This study also assessed risk in patients with autoimmune (ASCRS).52,57,59,60 Treatment recommendations vary widely because
diseases and found incidence rates of 10, 6, and 3 per 100,000 person high-level evidence in the field is limited.59 One randomized controlled
years for patients with systemic lupus erythematosus, ulcerative colitis, trial in 246 HIV-positive MSM found that electrocautery was superior to
and Crohn’s disease, respectively. both topical imiquimod and topical fluorouracil in the treatment of AIN
overall.61 The subgroup with perianal AIN, as opposed to intra-anal AIN,
Risk Reduction appeared to respond better to imiquimod. Regardless of treatment,
High-grade AIN can be a precursor to anal cancer,36-39 and treatment of recurrence rates were high, and careful follow-up is likely needed. A
high-grade AIN may prevent the development of anal cancer.40 AIN can large randomized phase III trial compared topical or ablative treatment
be identified by cytology, HPV testing, digital rectal examination (DRE), with active monitoring in 4459 PLWH with high-grade AIN.62 With a
high-resolution anoscopy, and/or biopsy.41,42 The spontaneous median follow-up of 25.8 months, 9 cases of anal cancer were
regression rate of high-grade AIN is not known, and estimates suggest diagnosed in the treatment group compared to 21 cases in the active
that the progression rates of AIN to cancer in MSM might be quite monitoring group. The rate of progression to anal cancer was 57%
low.43-46 However, a prospective cohort study of 550 MSM who were lower with treatment compared to active monitoring (95% CI, 6–80; P =
HIV-positive found the rate of conversion of high-grade AIN to anal .03).
cancer to be 18% (7/38) at a median follow-up of 2.3 years, despite
treatment.39 In this study, screening led to the identification of high- HPV Immunization
grade AIN and/or anal cancer in 8% of the cohort. A quadrivalent HPV vaccine is available and has been shown to be
effective in preventing persistent cervical infection with HPV-6, -11, -16,
Routine screening for AIN in high-risk individuals such as PLWH or or -18 as well as in preventing high-grade cervical intraepithelial
MSM is controversial, because randomized controlled trials showing neoplasia related to these strains of the virus.63-65 The vaccine has also
that such screening programs are efficacious at reducing anal cancer been shown to be efficacious in young males at preventing genital
incidence and mortality are lacking, whereas the potential benefits are lesions associated with HPV-6, -11, -16, or -18 infection.66 A substudy
quite large.47-53 Systematic reviews and meta-analyses have suggested of a larger double-blind study assessed the efficacy of the vaccine for
that anal cytology is effective in detection of AIN, particularly for high- the prevention of AIN and anal cancer related to infection with HPV-6,
risk individuals.54-56 Most guidelines do not recommend anal cancer -11, -16, or -18 in MSM.67 In this study, 602 healthy MSM aged 16 to 26
screening even in individuals who are high risk at this time or state that years were randomized to receive the vaccine or a placebo. While none
there may be some benefit with anal cytology.52,57 Few guidelines of the participants in either arm developed anal cancer during the 3-year
recommend screening for anal cancer with DRE in PLWH.58 follow-up period, there were 5 cases of grade 2/3 AIN associated with
one of the vaccine strains in the vaccine arm and 24 such cases in the
placebo arm in the per-protocol population, giving an observed efficacy
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Anal Carcinoma
of 77.5% (95% CI, 39.6–93.3). Since high-grade AIN is known to have the FDA expanded use of the 9-valent vaccine to include individuals
the ability to progress to anal cancer,36-38 these results suggest that use aged 27 through 45 years,81 and the ACIP voted in 2019 to recommend
of the quadrivalent HPV vaccine in MSM may reduce the risk of anal vaccination, based on shared clinical decision-making, for individuals in
cancer in this population. this age range who are not adequately vaccinated.
A bivalent HPV vaccine against HPV-16 and -18 is also available.68 In a Anatomy/Histology
randomized, double-blind controlled trial of female patients in Costa The anal region is comprised of the anal canal and the perianal region,
Rica, the vaccine was 83.6% effective against initial anal HPV-16/18 dividing anal cancers into two categories. The anal canal is the more
infection (95% CI, 66.7–92.8).69,70 It has also been shown to be effective proximal portion of the anal region. The 9th Edition of the AJCC Cancer
at preventing high-grade cervical intraepithelial neoplasias in young Staging Manual includes a definition of anal canal cancer as tumors that
people.71 The effect on precancerous anal lesions has not yet been develop from mucosa that cannot be entirely seen when the buttocks
reported. are gently pressed.82 The corresponding definition for perianal cancer is
tumors that 1) arise within the skin distal to or at the squamous
A 9-valent HPV vaccine is also now available, protecting against HPV-6,
mucocutaneous junction; 2) can be visualized completely when the
-11, -16, -18, -31, -33, -45, -52, and -58.72 Targeting the additional
buttocks are gently pressed; and 3) are within 5 cm of the anus.82
strains over the quadrivalent vaccine is predicted to prevent an
Various other definitions of the anal canal exist (ie, functional/surgical;
additional 464 cases of anal cancer annually.73 This vaccine was
anatomic; histologic) that are based on particular physical/anatomic
compared to the quadrivalent vaccine in an international, randomized
landmarks or histologic characteristics.
phase IIb–III study that included more than 14,000 female patients.74
The 9-valent vaccine was noninferior to the quadrivalent vaccine for Histologically, the mucosal lining of the anal canal is predominantly
antibody response to HPV-6, -11, -16, and -18 and prevented infection formed by squamous epithelium, in contrast to the mucosa of the
and disease related to the other viral strains included in the vaccine. rectum, which is lined with glandular epithelium.15,83 The anal margin, on
The calculated efficacy of the 9-valent vaccine was 96.7% (95% CI, the other hand, is lined with skin. By the histologic definition, the most
80.9–99.8) for the prevention of high-grade cervical, vulvar, or vaginal superior aspect of the anal canal is a 1- to 2-cm zone between the anal
disease related to those strains. and rectal epithelium, which has rectal, urothelial, and squamous
histologic characteristics.15,83 The most inferior aspect of the anal canal,
The Advisory Committee on Immunization Practices (ACIP)
recommends routine use of the 9-valent vaccine in children aged 11 approximately at the anal verge, corresponds to the area where the
and 12 years, as well as catch-up vaccination for individuals through 26 mucosa, lined with modified squamous epithelium, transitions to an
years of age who have not been previously vaccinated.75-78 The epidermis-lined anal margin.
American Academy of Pediatrics concurs with this vaccination
schedule.79 ASCO released a statement regarding HPV vaccination for
cancer prevention with the goal of increasing vaccine update.80 In 2018,
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Anal Carcinoma
The anatomic anal canal begins at the anorectal ring and extends to the are now considered to be non-keratinizing tumors; it has been reported
anal verge (ie, squamous mucocutaneous junction with the perianal that both keratinizing and non-keratinizing tumors have a similar natural
skin).84 history and prognosis87; and a mixture of cell types frequently
characterize histologic specimens of squamous cell carcinomas of the
Functionally, the anal canal is defined by the sphincter muscles. The anal canal.83,87,89 No distinction between squamous anal canal tumors
superior border of the functional anal canal, separating it from the based on cell type has been made in these guidelines. Other less
rectum, has been defined as the palpable upper border of the anal common anal canal tumors, not addressed in these guidelines, include
sphincter and puborectalis muscles of the anorectal ring. It is adenocarcinomas in the rectal mucosa or the anal glands, small cell
approximately 3 to 5 cm in length, and its inferior border starts at the (anaplastic) carcinoma, undifferentiated cancers, and melanomas.83
anal verge, the lowermost edge of the sphincter muscles, corresponding
to the introitus of the anal orifice.15,83,85 The functional definition of the Perianal squamous cell carcinomas are more likely than those of the
anal canal is primarily used in the radical surgical treatment of anal anal canal to be well-differentiated and keratinizing large-cell types,90
cancer and is used in these guidelines to differentiate between but they are not characterized in the guidelines according to cell type.
treatment options. The anal margin starts at the anal verge and includes The presence of skin appendages (eg, hair follicles, sweat glands) in
the perianal skin over a 5- to 6-cm radius from the squamous perianal tumors can distinguish them from anal canal tumors. However,
mucocutaneous junction.83 Tumors can involve both the anal canal and it is not always possible to distinguish between anal canal and perianal
the anal margin. squamous cell carcinoma since tumors can involve both areas.
Pathology Lymph drainage of anal cancer tumors is dependent on the location of

Most primary cancers of the anal canal are of squamous cell histology.83 the tumor in the anal region: cancers in the perianal skin and the region
The second edition of the WHO classification system of anal carcinoma of the anal canal distal to the dentate line drain mainly to the superficial
designated all squamous cell carcinoma variants of the anal canal as inguinal nodes.82,83 Lymph drainage at and proximal to the dentate line
cloacogenic and identified subtypes as large-cell keratinizing, large-cell is directed toward the anorectal, perirectal, and paravertebral nodes and
non-keratinizing (transitional), or basaloid.86 It has been reported that to some of the nodes of the internal iliac system. More proximal cancers
squamous cell cancers in the more proximal region of the anal canal are drain to perirectal nodes and to nodes of the inferior mesenteric system.
more likely to be non-keratinizing and less differentiated.15 However, the Therefore, distal anal cancers present with a higher incidence of
terms cloacogenic, transitional, keratinizing, and basaloid were removed inguinal node metastases. Because the lymphatic drainage systems
from the third and fourth editions of the WHO classification system of throughout the anal canal are not isolated from each other, however,
anal canal carcinoma,87,88 and all subtypes have been included under a inguinal node metastases can occur in proximal anal cancer as well.83
single generic heading of squamous cell carcinoma.82,87 Reasons for
The College of American Pathologists publishes protocols for the
this change include the following: both cloacogenic (which is sometimes
pathologic examination and reporting of anal tumors following excision
used interchangeably with the term basaloid) and transitional tumors
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Anal Carcinoma
or transabdominal resection. The most recent updates were made in had already spread to regional lymph nodes at diagnosis; these patients
April 2020 and February 2020, respectively.91,92 had a 60% 5-year survival rate. The 12% of patients presenting with
distant metastasis demonstrated a 30.5% 5-year survival rate.94 In a
Staging retrospective study of 270 patients treated for anal canal cancer with
The TNM staging system for anal canal cancer developed by the AJCC radiation therapy (RT) between 1980 and 1996, synchronous inguinal
is detailed in the guidelines.82 Because current recommendations for the node metastasis was observed in 6.4% of patients with tumors staged
primary treatment of anal canal cancer do not involve a surgical as T1 or T2, and in 16% of patients with T3 or T4 tumors.95 In patients
excision, most tumors are staged clinically with an emphasis on the size with N2–3 disease, survival was related to T-stage rather than nodal
of the primary tumor as determined by direct examination and involvement with respective 5-year survival rates of 72.7% and 39.9%
microscopic confirmation. A tumor biopsy is required. Rectal ultrasound for patients with T1–T2 and T3–T4 tumors; however, the number of
to determine depth of tumor invasion is not used in the staging of anal patients involved in this analysis was small.95 An analysis of more than
cancer (see Clinical Presentation/Evaluation, below). 600 patients with non-metastatic anal carcinoma from the RTOG 98-11
trial also found that the tumor and node categories impacted clinical
In the past, these guidelines have used the AJCC TNM skin cancer outcomes such as overall survival (OS), disease-free survival (DFS),
system for the staging of perianal cancer since the two types of cancers and colostomy failure, with the worst prognoses for patients with T4,N0
have a similar biology. However, the 7th edition of the AJCC Cancer and T3–4,N+ disease.96
Staging Manual included substantial changes to the cutaneous
squamous cell carcinoma stagings,93 making them much less By the 8th edition of AJCC Cancer Staging Manual, the former N2 and
appropriate for the staging of perianal cancers. Furthermore, many N3 categories by locations of positive nodes were removed. 97 New
perianal cancers have involvement of the anal canal or have high- categories of N1a, N1b, and N1c were defined and then further refined
grade, pre-cancerous lesions in the anal canal. It is important to look for in the 9th edition.82 N1a now represents metastasis in inguinal,
such anal canal involvement, particularly if conservative management mesorectal, superior rectal, internal iliac, or obturator nodes. N1b
(simple excision) is being contemplated. Many patients, particularly represents metastasis in external iliac nodes. N1c represents
PLWH, could be significantly undertreated. For these reasons, these metastasis in external iliac with any N1a nodes. However, initial therapy
guidelines use the AJCC anus staging system for both anal canal and of anal cancer does not typically involve surgery, and the true lymph
perianal tumors. node status may not be determined accurately by clinical and radiologic
evaluation. Fine-needle aspiration (FNA) biopsy of inguinal nodes can
The prognosis of anal carcinoma is related to the size of the primary be considered if tumor metastasis to these nodes is suspected. In a
tumor and the presence of lymph node metastases.15 According to the series of patients with anal cancer who underwent an abdominoperineal
SEER database,94 between 1999 and 2006, 50% of anal carcinomas resection (APR), it was noted that pelvic nodal metastases were often
were localized at initial diagnosis; these patients had an 80% 5-year less than 0.5 cm,98 suggesting that routine radiologic evaluation with CT
survival rate. Approximately 29% of patients had anal carcinoma that and PET/CT scan may not be reliable in the determination of lymph
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Anal Carcinoma
node involvement (discussed in more detail in Clinical The panel recommends a thorough examination/evaluation, including a
Presentation/Evaluation, below). careful DRE, an anoscopic examination, and palpation of the inguinal
lymph nodes, with FNA and/or excisional biopsy of nodes found to be
Prognostic Factors enlarged by either clinical or radiologic examination. Evaluation of pelvic
Multivariate analysis of data from the RTOG 98-11 trial showed that lymph nodes with CT or MRI of the pelvis is also recommended. These
male sex and positive lymph nodes were independent prognostic methods can also provide information on whether the tumor involves
factors for DFS in patients with anal cancer treated with 5-FU and other abdominal/pelvic organs; however, assessment of T stage is
radiation and either mitomycin or cisplatin.99 Male sex, positive nodes, primarily performed through clinical examination. A CT scan of the
and tumor size greater than 5 cm were independently prognostic for abdomen is also recommended to assess possible disease
worse OS. A secondary analysis of this trial found that tumor diameter dissemination. Since veins of the anal region are part of the venous
could also be prognostic for colostomy rate and time to colostomy.100 network associated with systemic circulation,83 chest CT scan is
These results are consistent with earlier analyses from the EORTC performed to evaluate for pulmonary metastasis. Gynecologic exam,
22861 trial, which found male sex, lymph node involvement, and skin including cervical cancer screening, is suggested due to the association
ulceration to be prognostic for worse survival and local control.101 of anal cancer and HPV.13 A discussion of infertility risks and counseling
Similarly, multivariate analyses of data from the ACT I trial also showed on fertility preservation, if appropriate, should be carried out prior to the
that positive lymph nodes and male sex are prognostic indicators for start of treatment.
higher local regional failure, anal cancer death, and lower OS.102
HIV testing should be performed if the patient’s HIV status is unknown,
Data suggest that HPV- and/or p16-positivity are prognostic for because the risk of anal carcinoma has been reported to be higher in
improved OS in patients with anal carcinoma.103-106 In a retrospective PLWH.17 Furthermore, about 13% of people in the United States who
study of 143 tumor samples, p16-positivity was an independent are infected with HIV are not aware of their infection status,107 and
prognostic factor for OS (hazard ratio [HR], 0.07; 95% CI, 0.01–0.61; P individuals who are unaware of their HIV-positive status do not receive
= .016).104 Another study of 95 patients found similar results.103 the clinical care they need to reduce HIV-related morbidity and mortality
and may unknowingly transmit HIV.108 HIV testing may be particularly
Management of Anal Carcinoma important in patients with cancer, because identification of HIV infection
Clinical Presentation/Evaluation has the potential to improve clinical outcomes.109 The CDC
Approximately 45% of patients with anal carcinoma present with rectal recommends HIV screening for all patients in all health care settings
bleeding, while approximately 30% have either pain or the sensation of unless the patient declines testing (opt-out screening).110
a rectal mass.15 Following confirmation of squamous cell carcinoma by
PET/CT scanning, or PET/MRI if available, can be considered to verify
biopsy, the recommendations of the NCCN Anal Carcinoma Guidelines
staging before treatment. PET/CT scanning has been reported to be
Panel for the clinical evaluation of patients with anal canal or perianal
useful in the evaluation of pelvic nodes, even in patients with anal canal
cancer are very similar.
MS-8

Anal Carcinoma
cancer who have normal-sized lymph nodes on CT imaging.111-116 A simulated scenarios, the authors further conclude that the actual rate of
systematic review and meta-analysis of seven retrospective and five true node-positivity is likely less than 30%, suggesting that it is possible
prospective studies calculated pooled estimates of sensitivity and some patients are being misclassified and overtreated with the
specificity for detection of lymph node involvement by PET/CT to be increased use of highly sensitive imaging.
56% (95% CI, 45–67) and 90% (95% CI, 86–93), respectively.112 A
more recent meta-analysis of 17 clinical studies calculated the pooled Primary Treatment of Non-Metastatic Anal Carcinoma
sensitivity and specificity for detection of lymph node involvement by In the past, patients with invasive anal carcinoma were routinely treated
PET/CT at 93% and 76%, respectively.117 The use of PET or PET/CT with an APR; however, local recurrence rates were high, 5-year survival
led to upstaging in 5% to 38% of patients and downstaging in 8% to was only 40% to 70%, and the morbidity with a permanent colostomy
27% of patients. Another systematic review and meta-analysis found was considerable.15 In 1974, Nigro and coworkers observed complete
PET/CT to change nodal status and TNM stage in 21% and 41% of tumor regression in some patients with anal carcinoma treated with
patients, respectively.118 PET/CT results can also impact radiation preoperative 5-FU–based concurrent chemotherapy and radiation
therapy planning, as systematic reviews and meta-analyses have (chemoRT) including either mitomycin or porfiromycin, suggesting that it
shown that treatment plan modifications occurred in 12% to 59% of might be possible to cure anal carcinoma without surgery and
patients based on PET/CT results.117,119 The panel does not consider permanent colostomy.121 Subsequent nonrandomized studies using
PET/CT to be a replacement for a diagnostic CT. similar regimens and varied doses of chemoRT provided support for this
conclusion.122,123 Results of randomized trials evaluating the efficacy
According to a systematic review and meta-regression, the proportion of and safety of administering chemotherapy with RT support the use of
patients who are node-positive by pretreatment clinical imaging has combined modality therapy in the treatment of anal cancer.18
increased from 15.3% (95% CI, 10.5–20.1) in 1980 to 37.1% (95% CI, Summaries of clinical trials involving patients with anal cancer have
34.0–41.3) in 2012 (P < .0001), likely resulting from the increased use been presented,124,125 and several key trials are discussed below.
of more sensitive imaging techniques.120 This increase in lymph node
positivity was associated with improvements in OS for both the lymph- Chemotherapy
node–positive and the lymph-node–negative groups. Because the A phase III study from the EORTC compared the use of chemoRT (5-
proportion of patients with T3/T4 disease remained constant and FU plus mitomycin) to RT alone in the treatment of anal carcinoma.
therefore disease is not truly being diagnosed at more advanced stages Results from this trial showed that patients in the chemoRT arm had an
over time, the authors attribute the improved OS results to the Will 18% higher rate of locoregional control at 5 years and a 32% longer
Rogers effect: The average survival of both groups increases as colostomy-free interval.101 The United Kingdom Coordinating Committee
patients with worse-than-average survival in the node-negative group on Cancer Research (UKCCCR) randomized ACT I trial confirmed that
migrate to the node-positive group, in which their survival is better than chemoRT with 5-FU and mitomycin was more effective in controlling
average. Thus, the survival of individuals has not necessarily improved local disease than RT alone (relative risk [RR], 0.54; 95% CI, 0.42–0.69;
over time, even though the average survival of each group has. Using P < .0001), although no significant differences in OS were observed at 3
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Anal Carcinoma
years.126 A published follow-up study on these patients demonstrates or an APR. The phase II JROSG 10-2 trial of 31 patients with squamous
that a clear benefit of chemoRT remains after 13 years, including a cell anal cancer treated with concurrent chemoRT with 5-FU and
benefit in OS.127 The median survival was 5.4 years in the RT arm and mitomycin in Japan has reported 2-year DFS, OS, local control, and
7.6 years in the chemoRT arm. There was also a reduction in the risk of colostomy-free survival of 77.4%, 93.5%, 83.9%, and 80.6%,
dying from anal cancer (HR, 0.67; 95% CI, 0.51–0.88; P = .004). A respectively.132
systematic review and meta-analysis comparing outcomes in patients
with stage I anal carcinoma found an increased 5-year OS in patients Capecitabine, an oral fluoropyrimidine prodrug, is an accepted
treated with chemoRT compared to RT alone (RR, 1.18; 95% CI, 1.10– alternative to 5-FU in the treatment of colon and rectal cancer.133-136
1.26; P < .00001) but no significant difference in 5-year DFS (RR, 1.01; Capecitabine has been assessed as an alternative to 5-FU in chemoRT
95% CI, 0.92–1.11; P = 0.87).128 Conversely, a population-based cohort regimens for non-metastatic anal cancer.137-140 Doses throughout the
analysis of Medicare-eligible (>65 years of age or with an eligible radiation course on treatment days may offer improved radiation
disability) patients with stage I anal cancer showed no difference in OS, sensitization compared to two courses of 5-FU infusion during the
cause-specific survival, colostomy-free survival, or DFS with chemoRT chemoRT course. A retrospective study compared 58 patients treated
versus RT alone after adjustment using propensity score methods.129 with capecitabine to 47 patients treated with infusional 5-FU; both
Therefore, this study concludes that radiation alone may allow for groups also received mitomycin and concurrent radiation.139 No
adequate oncologic outcomes for highly selected patients with stage I significant differences were seen in clinical complete response, 3-year
anal cancer, although it is important to note that this study did not locoregional control, 3-year OS, or colostomy-free survival between the
differentiate between anal canal and perianal cancers. Current NCCN two groups of patients. Another retrospective study compared 27
Guideline Recommendations for the Primary Treatment of Anal Canal patients treated with capecitabine to 62 patients treated with infusional
Cancer and Recommendations for the Primary Treatment of Perianal 5-FU; as in the other study, both groups also received mitomycin and
Cancer can be found below. radiation.138 Grade 3/4 hematologic toxicities were significantly lower in
the capecitabine group, with no oncologic outcomes reported. A phase
A few studies have addressed the efficacy and safety of specific II study found that chemoRT with capecitabine and mitomycin was safe
chemotherapeutic agents in the chemoRT regimens used in the and resulted in a 6-month locoregional control rate of 86% (95% CI,
treatment of anal carcinoma.99,130,131 In a phase III Intergroup study, 0.72–0.94) in patients with localized anal cancer.141 Although data for
patients receiving chemoRT with the combination of 5-FU and this regimen are limited, the panel recommends mitomycin/capecitabine
mitomycin had a lower colostomy rate (9% vs. 22%; P = .002) and a plus radiation as an alternative to mitomycin/5-FU plus radiation in the
higher 4-year DFS (73% vs. 51%; P = .0003) compared with patients setting of stage I through III anal cancer.
receiving chemoRT with 5-FU alone, indicating that mitomycin is an
important component of chemoRT in the treatment of anal carcinoma.131 Cisplatin as a substitute for 5-FU was evaluated in a phase II trial, and
The OS rate at 4 years was the same for the two groups, however, results suggest that cisplatin-containing and 5-FU–containing chemoRT
reflecting the ability to treat recurrent patients with additional chemoRT may be comparable for treatment of locally advanced anal cancer.130
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Anal Carcinoma
The efficacy of replacing mitomycin with cisplatin has also been .026).143 In addition, 5-year colostomy-free survival showed a trend
assessed. The phase III UK ACT II trial compared cisplatin with towards statistical significance (65.0% vs. 71.9%; P = .05), again in
mitomycin and also looked at the effect of additional maintenance favor of the mitomycin group. Since the two treatment arms in the
chemotherapy following chemoRT.142 In this study, more than 900 RTOG 98-11 trial differed with respect to use of either cisplatin or
patients with newly diagnosed anal cancer were randomly assigned to mitomycin in concurrent chemoRT as well as inclusion of induction
primary treatment with either 5-FU/mitomycin or 5-FU/cisplatin with chemotherapy in the cisplatin-containing arm, it is difficult to attribute
radiotherapy. A continuous course (ie, no treatment gap) of radiation of the differences to the substitution of cisplatin for mitomycin or to the use
50.4 Gy was administered in both arms, and patients in each arm were of induction chemotherapy.124,144 However, since ACT II demonstrated
further randomized to receive two cycles of maintenance therapy with 5- that the two chemoRT regimens are equivalent, some have suggested
FU and cisplatin or no maintenance therapy. At a median follow-up of that results from RTOG 98-11 suggest that induction chemotherapy is
5.1 years, no differences were observed in the primary endpoint of probably detrimental.145
complete response rate in either arm for the chemoRT comparison or in
the primary endpoint of progression-free survival (PFS) for the Results from ACCORD 03 also suggest that there is no benefit of a
comparison of maintenance therapy versus no maintenance therapy. In course of chemotherapy given prior to chemoRT.146 In this study,
addition, a secondary endpoint, colostomy, did not show differences patients with locally advanced anal cancer were randomized to receive
based on the chemotherapeutic components of chemoRT. These induction therapy with 5-FU/cisplatin or no induction therapy followed by
results demonstrate that replacement of mitomycin with cisplatin in chemoRT (they were further randomized to receive an additional
chemoRT does not affect the rate of complete response, nor does radiation boost or not). No differences were seen between tumor
administration of maintenance therapy decrease the rate of disease complete response, tumor partial response, 3-year colostomy-free
recurrence following primary treatment with chemoRT in patients with survival, local control, event-free survival, or 3-year OS. After a median
anal cancer. follow-up of 50 months, no advantage to induction chemotherapy (or to
the additional radiation boost) was observed, consistent with earlier
Cisplatin as a substitute for mitomycin in the treatment of patients with results. A systematic review of randomized trials also showed no benefit
non-metastatic anal carcinoma was also evaluated in the randomized to a course of induction chemotherapy.147
phase III Intergroup RTOG 98-11 trial. The role of induction
chemotherapy was also assessed. In this study, 682 patients were A retrospective analysis, however, suggests that induction
randomly assigned to receive either: 1) induction 5-FU plus cisplatin for chemotherapy preceding chemoRT may be beneficial for the subset of
two cycles followed by concurrent chemoRT with 5-FU and cisplatin; or patients with T4 anal cancer.148 The 5-year colostomy-free survival rate
2) concurrent chemoRT with 5-FU and mitomycin.99,143 A significant was significantly better in T4 patients who received induction 5-
difference was observed in the primary endpoint, 5-year DFS, in favor of FU/cisplatin compared to those who did not (100% vs. 38 ± 16.4%; P =
the mitomycin group (57.8% vs. 67.8%; P = .006).143 Five-year OS was .0006).
also significantly better in the mitomycin arm (70.7% vs. 78.3%; P =
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Anal Carcinoma
The combination of 5-FU, mitomycin C, and cisplatin has also been assess response rate after chemoRT with cisplatin/5-FU and cetuximab,
studied in a phase II trial, but was found to be too toxic.149 The safety was terminated prematurely because of extremely high rates of serious
and efficacy of capecitabine/oxaliplatin with radiation for the treatment adverse events.158 The 15 evaluable patients from ACCORD 16 had a
of localized anal cancer has been investigated in a phase II study, 4-year DFS rate of 53% (95% CI, 28–79), and two of the five patients
which reported that the regimen was safe, with promising efficacy, who completed the planned treatments had locoregional recurrences.159
although larger trials would be needed to confirm these results.150
For older patients or those who are unlikely to tolerate mitomycin, the
There has also been interest in the use of biologic therapies for the optimal chemotherapy regimen remains uncertain. Some NCCN Panel
treatment of anal cancer. A phase 3 trial is investigating the use of the members have used a combination of weekly cisplatin and daily 5-FU
programmed cell death protein 1 (PD-1) inhibitor, nivolumab, following on days of radiation160 for chemoRT in localized anal cancer. Other
combined modality therapy for high risk anal carcinoma.151 This trial has potential strategies for this patient population may include capecitabine
completed enrollment of 344 participants and results are pending. plus RT or RT alone (without chemotherapy). However, due to a lack of
Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor, data supporting this approach and differing strategies among panel
whose anti-tumor activity is dependent on the presence of wild-type members, there are not yet defined recommendations for patients with
KRAS.152 Because KRAS mutations appear to be very rare in anal anal cancer who are not candidates for intensive therapy. Use of a
cancer,153,154 the use of an EGFR inhibitor such as cetuximab has been geriatric assessment to guide management and elicitation of the
considered to be a promising avenue of investigation. The phase II patient’s goals and objectives with regard to their cancer diagnosis is
ECOG 3205 and AIDS Malignancy Consortium 045 trials evaluated the critical to inform shared decision-making discussions in these situations
safety and efficacy of cetuximab with cisplatin/5-FU and radiation in (See the NCCN Guidelines for Older Adult Oncology).
immunocompetent (E3205) and PLWH (AMC045) with anal squamous
cell carcinoma.155,156 Results from E3205 and AMC045 were published Radiation Therapy
in 2017. In a post hoc analysis of E3205, the 3-year locoregional failure Prior to the start of RT, patients should be counseled on infertility risks
rate was 21% (95% CI, 7–26) by Kaplan-Meier estimate.155 The and given information regarding sperm banking or oocyte, egg, or
toxicities associated with the regimen were substantial, with grade 4 ovarian tissue banking, as appropriate. In addition, patients should be
toxicity occurring in 32% of the study population and three treatment- counseled on risks for early treatment-induced menopause and
associated deaths (5%). In AMC045, the 3-year locoregional failure rate changes to sexual function. See the NCCN Guidelines for Survivorship
was 20% (95% CI, 10–37) by Kaplan-Meier estimate.156 Grade 4 toxicity and the NCCN Guidelines for Adolescent and Young Adult (AYA)
and treatment-associated rates were similar to that seen in E3205, at Oncology for more information. Patients should be considered for
26% and 4%, respectively. Two other trials that have assessed the use vaginal dilators daily during treatment, which can reduce RT doses to
of cetuximab in this setting have also found it to increase toxicity, sexual organs at risk,161 and instructed on the symptoms of vaginal
including a phase I study of cetuximab with 5-fluorouracil, cisplatin, and stenosis.
radiation.157 The ACCORD 16 phase II trial, which was designed to
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Anal Carcinoma
The optimal dose and schedule of RT for anal carcinoma continues to designed for that particular comparison. In addition, the absence of a
be explored and has been evaluated in a number of nonrandomized planned treatment break in the ACT II trial was considered to be at least
studies. In one study of patients with early-stage (T1 or Tis) anal canal partially responsible for the high colostomy-free survival rates observed
cancer, most patients were effectively treated with RT doses of 40 to 50 in that study (74% at 3 years).142 A post hoc analysis from the ACT II
Gy for Tis lesions and 50 to 60 Gy for T1 lesions.162 In another study, in trial revealed worse outcomes if the planned RT dose was extended to
which the majority of patients had stage II/III anal canal cancer, local more than 42 days, with a significant increase in the risk of PFS event
control of disease was higher in patients who received RT doses (P = .01) and worse OS (P = .006).168 Although results of these and
greater than 50 Gy than in those who received lower doses (86.5% vs. other studies have supported the benefit of delivery of chemoRT over
34%; P = .012).163 In a third study of patients with T3, T4, or lymph shorter time periods,169-171 treatment breaks in the delivery of chemoRT
node-positive tumors, RT doses of greater than or equal to 54 Gy are required in up to 80% of patients since chemoRT-related toxicities
administered with limited treatment breaks (<60 days) were associated are common.171 For example, it has been reported that one-third of
with increased local control.164 The effect of further escalation of patients receiving primary chemoRT for anal carcinoma at RT doses of
radiation dose was assessed in the ACCORD 03 trial, with the primary 30 Gy in 3 weeks develop acute anoproctitis and perineal dermatitis,
endpoint of colostomy-free survival at 3 years.146 No benefit was seen increasing to one-half to two-thirds of patients when RT doses of 54 to
with the higher dose of radiation. These results are supported by much 60 Gy are administered in 6 to 7 weeks.83
earlier results from the RTOG 92-08 trial165 and suggest that doses of
greater than 59 Gy provide no additional benefit to patients with anal Some of the reported late side effects of chemoRT include increased
cancer. The randomized, phase 2 DECREASE study (NCT04166318) is frequency and urgency of defecation, chronic perineal dermatitis,
currently looking at how well lower-dose chemoRT works in comparison dyspareunia, and impotence.172,173 In some cases, severe late RT
to standard-dose chemoRT for patients with stage I or IIA anal complications, such as anal ulcers, stenosis, and necrosis, may
cancer.166 Patients on this study are randomized to either 28 fractions necessitate surgery involving colostomy.173 In addition, results from a
(standard-dose) or 20 or 23 fractions (deintensified dose) of intensity- retrospective cohort study of data from the SEER registry showed the
modulated radiation therapy (IMRT). Study completion is expected in risk of subsequent pelvic fracture to be 3-fold higher in female patients
2025. ≥65 years undergoing RT for anal cancer compared with female
patients of the same age with anal cancer who did not receive RT.174
There is evidence that treatment interruptions, either planned or
required by treatment-related toxicity, can compromise the effectiveness An increasing body of literature suggests that toxicity can be reduced
of treatment.115 In the phase II RTOG 92-08 trial, a planned 2-week with advanced radiation delivery techniques.115,175-185 IMRT utilizes
treatment break in the delivery of chemoRT to patients with anal cancer detailed beam shaping to target specific volumes and limit the exposure
was associated with increased locoregional failure rates and lower of normal tissue.184 Multiple pilot studies have demonstrated reduced
colostomy-free survival rates when compared to patients who only had toxicity while maintaining local control using IMRT. For example, in a
treatment breaks for severe skin toxicity,167 although the trial was not cross-study comparison of a multicenter study of 53 patients with anal
MS-13

Anal Carcinoma
cancer treated with concurrent 5-FU/mitomycin chemotherapy and complete response after a median follow-up of 49 months.190 The 4-
IMRT compared to patients in the 5-FU/mitomycin arm of the year OS was 85.5% and the 4-year event-free survival was 75.5%. The
randomized RTOG 98-11 study, which used conventional 3-D RT, the rate of grade greater than or equal to two non-hematologic late toxicities
rates of grade 3/4 dermatologic toxicity were 38%/0% for patients was 15%. In a longer-term follow-up with 52 eligible patients, the 8-year
treated with IMRT compared to 43%/5% for those undergoing OS was 68% and the 8-year disease-free survival was 62%.189 The rate
conventional RT.99,184 No decrease in treatment effectiveness or local of grade 2 late adverse events was 55%, 16% for grade 3, 0 for grade
control rates was observed with use of IMRT, although the small sample 4, and 4% for grade 5 events.
size and short duration of follow-up limit the conclusions drawn from
such a comparison. In one retrospective comparison between IMRT and A retrospective cohort study using the 2014 linkage of the SEER-
conventional radiotherapy, IMRT was less toxic and showed better Medicare database showed that IMRT is associated with higher total
efficacy in 3-year OS, locoregional control, and PFS.186 In a larger costs than 3-D conformal radiation (median total cost, $35,890 vs.
retrospective comparison, no significant differences in local recurrence- $27,262; P < .001), but unplanned health care utilization costs (ie,
free survival, distant metastasis-free survival, colostomy-free survival, hospitalizations and emergency department visits) are higher for those
and OS at 2 years were seen between patients receiving IMRT and receiving conformal radiation (median, $711 vs. $4,957 at 1 year; P =
those receiving 3-D conformal radiotherapy, despite the fact that the .02).191
IMRT group had a higher average N stage.187
Recommendations regarding RT doses follow the multifield technique
RTOG 0529 was a prospective clinical trial investigating if dose-painted used in the RTOG 98-11 trial.99 After clinical and radiologic staging, CT-
IMRT/5-FU/mitomycin could decrease the rate of gastrointestinal and based simulation is performed for radiation treatment planning. If
genitourinary adverse effects compared to patients treated with available, MRI pelvis, PET/CT, or PET/ MRI (if available) at the time of
conventional radiation/5-FU/mitomycin from RTOG 98-11. This trial did simulation may be helpful to define local and regional target structures.
not meet its primary endpoint of reducing grade 2+ combined acute All patients should receive a minimum RT dose of 45 Gy to the primary
genitourinary and gastrointestinal adverse events by 15% compared to cancer. The recommended initial RT dose is 30.6 Gy to the pelvis,
conventional radiation on RTOG 98-11.188 Of 52 evaluable patients, the anus, perineum, and inguinal nodes; there should be attempts to reduce
grade 2+ combined acute adverse event rate was 77%; the rate in the dose to the femoral heads. Field reduction off the superior field
RTOG 98-11 was also 77%. However, significant reductions were seen border and node-negative inguinal nodes is recommended after delivery
in grade 2+ hematologic events (73% vs. 85%; P = .032), grade 3+ of 30.6 Gy and 36 Gy, respectively. For patients treated with an
gastrointestinal events (21% vs. 36%; P = .008), and grade 3+ anteroposterior-posteroanterior (AP-PA) rather than multifield
dermatologic events (23% vs. 49%; P < .0001). Subsequently, long- technique, the dose to the lateral inguinal region should be brought to
term outcomes and toxicities of patients with anal cancer treated with the minimum dose of 36 Gy using an anterior electron boost matched to
dose-painted IMRT as per RTOG 0529 have been reported.189,190 Of 99 the PA exit field. Patients with disease clinically staged as node-positive
eligible patients identified in the 2017 publication, 92% had a clinically or T2–T4 should receive an additional boost of 9 to 14 Gy. The
MS-14

Anal Carcinoma
consensus of the panel is that IMRT is preferred over 3-D conformal RT detection of high-grade squamous intraepithelial lesions (HSIL) in 74%
in the treatment of anal carcinoma.192 IMRT requires expertise and of patients following local excision.194 A retrospective study described
careful target design to avoid reduction in local control by marginal characteristics, treatment, and outcomes of 17 patients with completely
miss.115 The clinical target volumes for anal cancer used in the RTOG excised invasive anal cancer, seven of whom met the criteria for
0529 trial have been described in detail.192 Also see classification as superficially invasive.195 Those with positive margins
https://www.nrgoncology.org/Portals/0/Scientific%20Program/CIRO/Atla (≤2 mm for anal canal cancer and <1 cm for perianal cancer) received
ses/AnorectalContouringGuidelines.pdf for more details of the local radiation, and all patients underwent surveillance. After a median
contouring atlas defined by RTOG. follow-up of 45 months, no differences were seen in 5-year OS (100%
for the entire cohort) or 5-year cancer recurrence-free survival rates
For patients with previously untreated anal cancer who present with (87% for the entire cohort) between the superficially invasive and
synchronous local and metastatic disease, chemoRT to the primary site invasive groups.
can be considered for local control following first-line chemotherapy, as
described in these guidelines. For recurrence in the primary site or Local excision is also used for T1,N0, well-differentiated or select T2,N0
nodes after previous chemoRT, surgery should be performed if perianal (anal margin) cancer that does not involve the sphincter (also
possible, and, if not, palliative chemoRT can be considered based on see Recommendations for the Primary Treatment of Perianal Cancer,
symptoms, extent of recurrence, and prior treatment. below). In these cases, a 1-cm margin is recommended. A retrospective
cohort study that included 2243 adults from the National Cancer
Surgical Management Database diagnosed with T1,N0 anal canal cancer between 2004 and
Local excision is used for anal cancer in two situations. The first is for 2012 found that the use of local excision in this population increased
superficially invasive squamous cell carcinoma (SISCCA), which is over time (17.3% in 2004 to 30.8% in 2012; P < .001).196 No significant
defined as anal cancer that has been completely excised, with less than difference in 5-year OS was seen based on management strategy
or equal to 3-mm basement membrane invasion and a maximal (85.3% for local excision; 86.8% for chemoRT; P = .93). Many patients
horizontal spread of less than or equal to 7 mm (T1,NX).193 SISCCA are with T1 or selected T2 perianal cancers will have concomitant HSIL of
generally found incidentally in the setting of a biopsy or excision of what the anal canal, therefore it is important to look for such anal canal
is thought to be a benign lesion such as a condyloma, hemorrhoid, or involvement when conservative management (local excision) is being
anal skin tag. Such lesions are being seen with increasing frequency considered.
because anal cancer screening in high-risk populations is becoming
more common. For SISCCA that are noted to have histologically Radical surgery in anal cancer (APR) is reserved for local recurrence or
negative margins in carefully selected patients followed by an disease persistence (see Treatment of Locally Progressive or Recurrent
experienced provider and/or team, local excision alone with a structured Anal Carcinoma, below).
surveillance plan may represent adequate treatment. A careful
surveillance plan is necessary as observational studies have reported
MS-15

Anal Carcinoma
Treatment of Anal Cancer in Patients Living with HIV/AIDS the efficacy or toxicity of chemoRT.207 A population-based study of
As discussed above (see Risk Factors), PLWH have been reported to almost 2 million patients with cancer, including 6459 PLWH, found no
be at increased risk for anal carcinoma.18,28-31 Some evidence suggests increase in cancer-specific mortality for anal cancer in PLWH.209
that ART may be associated with a decrease in the incidence of high- Although the numbers of PLWH in these studies have been small, the
grade AIN and its progression to anal cancer.35,197 However, the efficacy and safety results appear similar regardless of HIV status.
incidence of anal cancer in PLWH has not decreased much, if at all,
over time.27,29,31,34 Overall, the panel believes that PLWH who have anal cancer should be
treated as per these guidelines and that modifications to treatment of
Most evidence regarding outcomes in PLWH with anal cancer comes anal cancer should not be made solely based on HIV status. Additional
from retrospective comparisons, a few of which found worse outcomes considerations for PLWH who have anal cancer are outlined in the
in PLWH.198-200 For example, a cohort comparison of 40 PLWH with anal NCCN Guidelines for Cancer in People Living with HIV, including the
canal cancer and 81 patients who were HIV-negative with anal canal use of normal tissue-sparing radiation techniques, the consideration of
cancer found local relapse rates to be four times higher in PLWH at 3 non-malignant causes for lymphadenopathy, and the need for more
years (62% vs. 13%) and found significantly higher rates of severe frequent post-treatment surveillance anoscopy for PLWH. Poor
acute skin toxicity for PLWH.199 However, no differences in rates of performance status in PLWH and anal cancer may be from HIV, cancer,
complete response or 5-year OS were observed between the groups in or other causes. The reason for poor performance status should be
that study. Another systematic review and meta-analysis of 40 studies considered when making treatment decisions. Treatment with ART may
including 3720 patients with localized squamous cell carcinoma of the improve poor performance status related to HIV.
anus who were treated with chemoRT, 34% of whom were HIV-positive,
found a greater risk of grade 3 and higher cutaneous toxicities (RR = Recommendations for the Primary Treatment of Anal Canal Cancer
1.34), and worse 3-year DFS (RR = 1.32) and OS (RR = 1.77) rates, in Currently, concurrent chemoRT is the recommended primary treatment
PLWH compared to those who were HIV-negative.200 for patients with non-metastatic anal canal cancer as well as for patients
with positive para-aortic lymph nodes that can be included in the
Most studies, however, have found outcomes to be similar in PLWH and radiation field, although only limited retrospective data support use in
patients who were HIV-negative.201-208 In a retrospective cohort study of this setting.210 Mitomycin/5-FU or mitomycin/capecitabine is
1184 veterans diagnosed with squamous cell carcinoma of the anus administered concurrently with radiation.99,138-140 Alternatively, 5-
between 1998 and 2004 (15% of whom tested positive for HIV), no FU/cisplatin can be given with concurrent radiation (category 2B).211
differences with respect to receipt of treatment or 2-year survival rates Most studies have delivered 5-FU as a protracted 96- to 120-hour
were observed when the group of PLWH was compared with the group infusion during the first and fifth weeks of RT, and bolus injection of
of patients testing negative for HIV.203 Another study of 36 consecutive mitomycin is typically given on the first or second day of the 5-FU
patients with anal cancer including 19 immunocompetent and 17 infusion.83 Capecitabine is given orally, Monday through Friday, on each
patients who were immunodeficient (14 PLWH) showed no difference in
MS-16

Anal Carcinoma
day that RT is given, for 4 or 6 weeks, with bolus injection of mitomycin Surveillance Following Primary Treatment
and concurrent radiation.138,140 Following primary treatment of non-metastatic anal cancer, the
surveillance and follow-up treatment recommendations for perianal and
An analysis of the National Cancer Database found that only 61.5% of
anal canal cancer are the same. Patients are re-evaluated by DRE
patients with stage I anal canal cancer received chemoRT as
between 8 and 12 weeks after completion of chemoRT. Following re-
recommended in these guidelines.212 Patients who were male, aged ≥70
evaluation, patients are classified according to whether they have a
years, had smaller or lower-grade tumors, or who had been evaluated
complete remission of disease, persistent disease, or progressive
at academic facilities were more likely than others to be treated with
disease. Patients with persistent disease but without evidence of
excision alone. In a separate analysis of the National Cancer Database,
progression may be managed with close follow-up (in 4 weeks) to see if
88% of patients with stage II/III anal canal cancer received chemoRT.213
further regression occurs.
Males, Black patients, those with multiple comorbidities, and those
treated in academic facilities were less likely to receive combined The National Cancer Research Institute’s ACT II study compared
modality treatment. different chemoRT regimens and found no difference in OS or PFS.142
Interestingly, 72% of patients in this trial who did not show a complete
RT is associated with significant side effects. Patients should be
response at 11 weeks from the start of treatment had achieved a
counseled on infertility risks and given information regarding sperm,
complete response by 26 weeks. 5-year survival was superior in
oocyte, egg, or ovarian tissue banking prior to treatment. In addition,
patients who achieved complete response at 26 weeks.214 Based on
patients should be considered for vaginal dilators and should be
these results, the panel believes it may be appropriate to follow patients
instructed on the symptoms of vaginal stenosis.
who have not achieved a complete clinical response with persistent anal
Recommendations for the Primary Treatment of Perianal Cancer cancer for up to 6 months after completion of radiation and
Perianal lesions can be treated with either local excision or chemoRT chemotherapy, as long as there is no evidence of progressive disease
depending on the clinical stage. Primary treatment for patients with during this period of follow-up. Persistent disease may continue to
T1,N0 well-differentiated or select smaller T2,N0 perianal (anal margin) regress for up to 6 months from the start of treatment, and APR can
cancer that does not involve the sphincter is by local excision with thereby be avoided in some patients. In these patients, observation and
adequate margins. The ASCRS defines an adequate margin as 1 cm.57 re-evaluation should be performed at 3-month intervals. The panel
If the margins are not adequate, re-excision is the preferred treatment recommends against the use of PET/CT imaging as part of this re-
option. Local RT with or without continuous infusion 5-FU/mitomycin, evaluation strategy due to concerns for false-positivity from local
mitomycin/capecitabine, or 5-FU/cisplatin (category 2B) can be inflammation from RT leading to unnecessary surgeries. If biopsy-
considered as alternative treatment options when surgical margins are proven disease progression occurs, further intensive treatment is
inadequate. For all other perianal cancers, the treatment options are the indicated (see Treatment of Locally Progressive or Recurrent Anal
same as for anal canal cancer (see above).99,138-140,211 Carcinoma, below).
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Anal Carcinoma
Although a clinical assessment of progressive disease requires incidence rates for tumor-specific and therapy-specific colostomy were
histologic confirmation, patients can be classified as having a complete 26% (95% CI, 21–32) and 8% (95% CI, 5–12), respectively. Larger
remission without biopsy verification if clinical evidence of disease is tumor size (>6 cm) was a risk factor for tumor-specific colostomy, while
absent. The panel recommends that these patients undergo evaluation local excision prior to radiotherapy was a risk factor for therapy-specific
every 3 to 6 months for 5 years, including DRE and inguinal node colostomy. However, it should be noted that these patients were treated
palpation. Anoscopic evaluation is recommended every 6 to 12 months with older chemotherapy and RT regimens, which could account for
for 3 years. Annual chest, abdominal, and pelvic CT with contrast or these high colostomy rates.219
chest CT without contrast and abdominal/pelvic MRI with contrast is
recommended for 3 years for patients who initially had stage II–III In studies involving a minimum of 25 patients undergoing an APR for
disease. anal carcinoma, 5-year survival rates of 39% to 66% have been
observed.215,216,220-224 Complication rates were reported to be high in
Treatment of Locally Progressive or Recurrent Anal Carcinoma some of these studies. Factors associated with worse prognosis
Despite the effectiveness of chemoRT in the primary treatment of anal following APR include an initial presentation of node-positive disease
carcinoma, rates of locoregional failure of 10% to 30% have been and RT doses less than 55 Gy used in the treatment of primary
reported.215,216 Some of the disease characteristics that have been disease.216
associated with higher recurrence rates following chemoRT include
The general principles for APR technique are similar to those for distal
higher T stage and higher N stage (also see the section on Prognostic
rectal cancer and include the incorporation of meticulous total
Factors, above).217
mesorectal excision (TME). However, APR for anal cancer may require
Evidence of progression found on DRE should be followed by biopsy as wider lateral perianal margins than are required for rectal cancer. A
well as restaging with CT and/or PET/CT imaging. Patients with biopsy- retrospective analysis of the medical records of 14 patients who
proven locally progressive disease are candidates for radical surgery received intraoperative radiation therapy (IORT) during APR revealed
with an APR and colostomy.216 In an attempt to avoid surgery, the use that IORT is unlikely to improve local control or to give a survival
of immunotherapy with nivolumab or pembrolizumab may be considered benefit.225
prior to APR (category 2B) as some patients may have a good
Because of the necessary exposure of the perineum to radiation,
response, however it should be noted that this approach is based on
patients with anal cancer are prone to poor perineal wound healing. It
institutional experience only and there are currently no published data
has been shown that for patients undergoing an APR that was
supporting its use in this setting of otherwise curative intent surgery.
preceded by RT, closure of the perineal wound using rectus abdominis
A multicenter retrospective cohort study looked at the cause-specific myocutaneous flap reconstruction results in decreased perineal wound
colostomy rates in 235 patients with anal cancer who were treated with complications.226,227 Reconstructive tissue flaps for the perineum, such
radiotherapy or chemoRT from 1995 to 2003.218 The 5-year cumulative as the vertical rectus or local myocutaneous flaps, should therefore be
considered for patients with anal cancer undergoing an APR.
MS-18

Anal Carcinoma
Inguinal node dissection is recommended for recurrence in that area Treatment of Metastatic Anal Cancer
and for patients who require an APR but have already received groin It has been reported that the most common sites of anal cancer
radiation. Inguinal node dissection can be performed with or without an metastasis outside of the pelvis are the liver, lung, and extrapelvic
APR depending on whether disease is isolated to the groin or has lymph nodes.230 Since anal carcinoma is a rare cancer and only 10% to
occurred in conjunction with recurrence or persistence at the primary 20% of patients with anal carcinoma present with extrapelvic metastatic
site. disease,230 only limited data are available on this population of patients.
Despite this fact, evidence indicates that systemic therapy has some
Patients who develop inguinal node metastasis who do not undergo an
benefit in patients with metastatic anal carcinoma.
APR can be considered for palliative RT to the groin with or without 5-
FU/mitomycin or mitomycin/capecitabine if no prior RT to the groin was Palliative chemoRT to the primary site can be administered following
given. Radiation therapy technique and doses are dependent on dosing upfront chemotherapy for local control of a symptomatic bulky primary.
and technique of prior treatment (see the guidelines above). If RT was In fact, an analysis of the National Cancer Database reported that
given previously, 5-FU/cisplatin chemotherapy may be given (category patients with newly diagnosed metastatic anal cancer who received
2B). definitive pelvic RT in addition to chemotherapy had longer median OS
than those who received chemotherapy alone (21.3 vs. 15.9 months;
Surveillance Following Treatment of Recurrence
HR, 0.70; 95% CI, 0.61–0.81; P < .001).231 A retrospective analysis of
Following APR, patients should undergo re-evaluation every 3 to 6
106 patients with squamous cell carcinoma reported that resection or
months for 5 years, including clinical evaluation for nodal metastasis (ie,
ablation of liver metastases can result in long-term survival and that
inguinal node palpation). In addition, it is recommended that these
patients with anal cancer had better outcomes than those with non-anal
patients undergo annual chest, abdominal, and pelvic CT with contrast
squamous cell carcinoma, although this approach is not currently
or chest CT without contrast and abdominal/pelvic MRI with contrast for
included in the NCCN Guidelines for Anal Carcinoma.232
3 years. In one retrospective study of 105 patients with anal canal
carcinoma who had an APR between 1996 and 2009, the overall First-Line Treatment of Metastatic Anal Cancer
recurrence rate following APR was 43%.228 Those with T3/4 tumors or Based on results from the phase II International Multicentre InterAACT
involved margins were more likely to experience recurrence. The 5-year study, carboplatin in combination with paclitaxel has been noted as the
survival rate after APR has been reported to be 60% to 64%.228,229 preferred regimen for first-line treatment of metastatic anal cancer by
the NCCN Panel.233 In this trial, 91 patients with previously untreated,
Following treatment of inguinal node recurrence, patients should have a
unresectable, locally recurrent or metastatic anal squamous cell
DRE and inguinal node palpation every 3 to 6 months for 5 years. In
carcinoma were randomized to either carboplatin plus paclitaxel or
addition, anoscopy every 6 to 12 months and annual chest, abdominal,
cisplatin plus 5-FU. While response rates were similar between
and pelvic CT with contrast or chest CT without contrast and
carboplatin plus paclitaxel and cisplatin plus 5-FU (59% and 57%,
abdominal/pelvic MRI with contrast are recommended for 3 years.
respectively), carboplatin plus paclitaxel showed lower toxicity
MS-19

Anal Carcinoma
compared to cisplatin plus 5-FU (71% vs. 76% grade ≥3 toxicity and carcinoma. This trial demonstrated the efficacy of DCF (both standard
36% vs. 62% [P = .016] serious adverse events). Median PFS and OS and modified regimens) in this setting and reported better tolerability of
were 8.1 months and 20 months for carboplatin plus paclitaxel and 5.7 modified DCF compared to the standard regimen.242 The median PFS
months and 12.3 months for cisplatin plus 5-FU (HR for OS, 2.0; 95% was 10.7 months for the standard DCF regimen and 11.0 months for the
CI, 1.15–3.47; P = .014).233 The results from the InterAACT trial are in modified regimen. For the standard regimen, 83% of patients had at
agreement with older studies that showed that chemotherapy with a least one grade 3–4 AE, while 53% had at least one grade 3–4 adverse
fluoropyrimidine-based regimen plus cisplatin211,234-236 or a platinum- event when treated with modified DCF. The most common grade 3–4
based therapy plus paclitaxel235,237,238 benefited some patients with adverse events were neutropenia, diarrhea, asthenia, anemia,
metastatic anal carcinoma. lymphopenia, mucositis, and vomiting. Based on these results, the
panel added modified DCF as an option for metastatic anal cancer, with
Other recommended treatment options include 5-FU, leucovorin, and the category 2B designation reflecting concerns voiced by some panel
cisplatin (FOLFCIS); 5-FU, leucovorin, and oxaliplatin (FOLFOX); 5-FU members about potentially higher toxicity with modified DCF compared
plus cisplatin (category 2B reflecting its similar efficacy, but higher to the other regimens recommended for metastatic anal cancer.
toxicity, when compared to carboplatin plus paclitaxel in a randomized
trial); or modified docetaxel, cisplatin, and 5-FU (DCF, category 2B). A Several ongoing clinical trials are investigating whether checkpoint
retrospective study of 53 patients with advanced anal squamous cell inhibitors could have a role in the first-line treatment of metastatic anal
carcinoma who received FOLFCIS as first-line therapy showed that this cancer. NCT04444921 is a randomized, phase 3 trial comparing
regimen was safe and effective in this patient population. The response chemotherapy alone (carboplatin and paclitaxel) to chemotherapy plus
rate was 48%, PFS was 7.1 months, and OS was 22.1 months.239 The nivolumab for treatment-naïve metastatic anal cancer.244 This study is
safety of FOLFOX in patients with anal cancer has been demonstrated expected to enroll 205 participants and complete in 2023. POD1UM-
in a case report.240 Despite the limited data for FOLFOX in this setting, 303/InterAACT2 is a similar, phase 3 global study (NCT04472429)
the panel added it based on consensus and its current use as a investigating the addition of the checkpoint inhibitor, retifanlimab, to
standard option at many NCCN Member Institutions. With use of carboplatin/paclitaxel chemotherapy and comparing it to chemotherapy
FOLFOX, the panel recommends strong consideration of alone.245 This trial expects to enroll 300 participants with previously
discontinuation of oxaliplatin after 3 to 4 months (or sooner for untreated metastatic anal carcinoma and expected completion is in
unacceptable neurotoxicity) while maintaining other agents until time 2024.
of disease progression.241 Oxaliplatin may be reintroduced if it was
discontinued for neurotoxicity rather than for disease progression. Second-Line Treatment of Metastatic Anal Cancer
A single-arm, multicenter phase 2 trial assessed the safety and efficacy
DCF is another regimen that has been evaluated for metastatic anal of the anti-PD-1 antibody nivolumab for refractory metastatic anal
cancer.242,243 A single-arm phase II trial evaluated this regimen in cancer.246 Two complete responses and seven partial responses were
patients with previously untreated, advanced anal squamous cell seen among the 37 enrolled participants who received at least one
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dose, for a response rate of 24% (95% CI, 15–33). The KEYNOTE-028 Although further studies of PD-1/PD-L1 inhibitors are warranted, the
trial is a multi-cohort, phase 1b trial of the anti-PD-1 antibody panel added nivolumab and pembrolizumab as preferred options for
pembrolizumab in 24 patients with programmed cell death ligand 1 (PD- patients with metastatic anal cancer who have progressed on first-line
L1)–positive advanced squamous cell carcinoma of the anal canal.247 chemotherapy in the 2018 version of these guidelines. Microsatellite
Four partial responses were seen, for a response rate of 17% (95% CI, instability (MSI)/mismatch repair (MMR) testing is not required. MSI is
5–37), and 10 patients (42%) had stable disease, for a disease control uncommon in anal cancer,252 and as discussed above, responses to
rate of 58%. In both trials, toxicities were manageable, with 13% and PD-1/PD-L1 inhibitors occur in 20% to 24% of patients.246,247 Anal
17% experiencing grade 3 adverse events with nivolumab and cancers may be responsive to PD-1/PD-L1 inhibitors because they
pembrolizumab, respectively.246,247 The phase II KEYNOTE-158 study often have high PD-L1 expression and/or a high tumor mutational load
investigated the use of pembrolizumab in patients with noncolorectal despite being microsatellite stable (MSS).252
microsatellite instability-high (MSI-H)/ deficient mismatch repair (dMMR)
cancers, including patients with anal cancer (cohort A).248,249 A total of The panel also notes that platinum-based chemotherapy should not be
112 patients with anal cancer were enrolled and treated, 67% of whom given in second line if disease progressed on platinum-based therapy in
had PD-L1-positive disease249. A total of 11% of patients (95% CI, 6– first line.
18) had an objective response, with responses in 15% (95% CI, 8–25)
Survivorship
of patients with PD-L1-positive disease and in 3% (95% CI, 0–17) with
PD-L1-negative disease. Serious treatment-related adverse events The panel recommends that a prescription for survivorship and transfer
were noted in 11% of patients, with 25% of patients having immune- of care to the primary care physician be written.253 The oncologist and
mediated events. This study demonstrated the clinical benefit of primary care provider should have defined roles in the surveillance
pembrolizumab for patients with previously treated advanced anal period, with roles communicated to the patient. The care plan should
squamous cell carcinoma. include an overall summary of treatments received, including surgeries,
radiation treatments, and chemotherapy. The possible expected time to
A phase 2 clinical trial (NCT02314169) is also underway investigating resolution of acute toxicities, long-term effects of treatment, and
the efficacy and safety of nivolumab, with or without ipilimumab, for possible late sequelae of treatment should be described. Finally,
patients with refractory metastatic anal canal cancer.250 This trial has an surveillance and health behavior recommendations should be part of
estimated enrollment of 137 participants and is expected to complete in the care plan.
February 2024. Other trials are investigating novel second-line agents
for metastatic anal cancer, including the phase 2 PODIUM-202 trial of Disease-preventive measures, such as immunizations; early disease
retifanlimab for advanced or metastatic squamous cell carcinoma of the detection through periodic screening for second primary cancers (eg,
anal canal that progressed following platinum-based chemotherapy.251 breast, cervical, prostate cancers); and routine good medical care and
monitoring are recommended (see the NCCN Guidelines for
Survivorship). Additional health monitoring should be performed as
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Anal Carcinoma
indicated under the care of a primary care physician. Survivors are Recommendations for the primary treatment of perianal cancer and anal
encouraged to maintain a therapeutic relationship with a primary care canal cancer are very similar and include chemoRT in most cases. The
physician throughout their lifetime.254 exception is small, well or moderately differentiated perianal lesions and
superficially invasive lesions, which can be treated with margin-negative
Other recommendations include monitoring for late sequelae of anal local excision alone. Follow-up clinical evaluations are recommended
cancer or the treatment of anal cancer. Late toxicity from pelvic for all patients with anal carcinoma because additional curative-intent
radiation can include bowel dysfunction (ie, increased stool frequency, treatment is possible. Patients with biopsy-proven evidence of locally
fecal incontinence, flatulence, rectal urgency), urinary dysfunction, and recurrent or persistent disease following primary treatment should
sexual dysfunction (ie, impotence, dyspareunia, vaginal stenosis, undergo an APR with groin dissection if there is clinical evidence of
vaginal dryness, reduced libido).255-259 Anal cancer survivors also report inguinal nodal metastasis. Patients with a regional recurrence in the
significantly reduced global quality of life, with increased frequency of inguinal nodes can be treated with an inguinal node dissection, with
somatic symptoms including fatigue, dyspnea, nausea, appetite loss, consideration of RT with or without chemotherapy if no prior RT to the
pain, and insomnia.255,259-261 Therefore, survivors of anal cancer should groin was given. Patients with evidence of extrapelvic metastatic
be screened regularly for distress. disease should be treated with systemic therapy. The panel endorses
the concept that treating patients in a clinical trial has priority over
The NCCN Guidelines for Survivorship provide screening, evaluation,
standard or accepted therapy.
and treatment recommendations for common consequences of cancer
and cancer treatment to aid health care professionals who work with
survivors of adult-onset cancer in the post-treatment period, including
those in specialty cancer survivor clinics and primary care practices.
These guidelines include many topics with potential relevance to
survivors of anal cancer, including anxiety, depression, and distress;
cognitive dysfunction; fatigue; pain; sexual dysfunction; sleep disorders;
healthy lifestyles; and immunizations. Concerns related to employment,
insurance, and disability are also discussed.
Summary
The NCCN Anal Carcinoma Guidelines Panel believes that a
multidisciplinary approach including physicians from gastroenterology,
medical oncology, surgical oncology, radiation oncology, and radiology
is necessary for treating patients with anal carcinoma.
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Anal Carcinoma
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines for Patients® available at www.nccn.org/patients

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

*Al B. Benson, III, MD/Chair † William Jeck, MD ≠ Hitendra Patel, MD †

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

CLINICAL WORKUP CLINICAL PRIMARY TREATMENTg

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

CLINICAL WORKUP CLINICAL STAGE PRIMARY TREATMENTg

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

FOLLOW-UP SURVEILLANCE TREATMENT SURVEILLANCEo

e Principles of Surgery (ANAL-A). m Palliative RT may be considered in symptomatic patients. Records of

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

m Palliative RT may be considered in symptomatic patients. Records of previous

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF SYSTEMIC THERAPY – LOCALIZED CANCER

Chemo/RT for Localized Cancer

Systemic Therapy Regimens and Dosing – Localized Cancer

• 5-FU + mitomycin + RT1,2

• Capecitabine + mitomycin + RT3,4

• 5-FU + cisplatin + RT5

Note: All recommendations are category 2A unless otherwise indicated. References

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF SYSTEMIC THERAPY – METASTATIC CANCER

First-Line Therapy for Metastatic Cancer Subsequent Therapy Chemo/RT to the

Systemic Therapy Regimens and Dosing – Metastatic Cancer

Note: All recommendations are category 2A unless otherwise indicated. References

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF SYSTEMIC THERAPY

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF RADIATION THERAPY1

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF RADIATION THERAPY1

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF RADIATION THERAPY1

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF RADIATION THERAPY1

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

PRINCIPLES OF RADIATION THERAPY1

Table 2: DP-IMRT Dose Constraints for Normal Tissues8

• Quality Assurance and Image-Guided Treatment Delivery

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

American Joint Committee on Cancer (AJCC)

N Regional Lymph Nodes

NCCN Guidelines Version 2.2023 NCCN Guidelines Index

APR abdominoperineal resection

NCCN Guidelines Version 2.2023 NCCN Guidelines Index