Professional Documents
Culture Documents
Anal Cancer
Anal Cancer
Related Summaries
● Anal ssure
General Information
Description
Also called
● anal carcinoma
Definitions
● anal canal 5
⚬ begins at anorectal junction at upper portion of pelvic oor (upper border of anal sphincter is the
puborectalis muscle), passes through anal ring, and ends at merging of skin and anal margin
⚬ anatomic anal canal is region from dentate line to anal verge
⚬ surgical anal canal is area from anorectal junction extending to anal verge
● anal margin is area from anal verge that extends 5 cm onto perineum 5
● anal verge - junction of anal canal and hair-bearing skin 5 , see Squamous cell carcinoma for cancer of
perianal skin
● dentate line - line separating simple columnar epithelium of rectum from strati ed squamous
Types
● squamous cell carcinoma makes up majority of anal carcinomas 5
Epidemiology
● women
⚬ estimated 2,750 new cases in women vs. 1,910 in men in United States in 2006
⚬ Reference - CA Cancer J Clin 2006 Mar-Apr;56(2):106 full-text
Incidence/Prevalence
● age-adjusted incidence of anal cancer in persons ≥ 20 years old 1.5 per 100,000 in United States from
2000-2004
⚬ based on data from Surveillance, Epidemiology, and End Results (SEER) program
⚬ Reference - National Cancer Institute Fact Sheet on Cancer of Anus, Anal Canal and Anorectum
● age-adjusted incidence of anal cancer in persons ≥ 20 years old 1.7 per 100,000 person-years in
United States from 1973-2000
⚬ based on data from Surveillance, Epidemiology, and End Results (SEER) program
⚬ incidence increased during this period in men and women (p < 0.01 for both)
⚬ incidence of invasive disease increased over time in men and women, but women had higher
annual rates
⚬ incidence of in situ disease increased more over time in men than women
⚬ higher incidence of anal cancer in women ≥ 65 years old than men ≥ 65 years old
⚬ Reference - Cancer 2004 Jul 15;101(2):281 PDF
● up to 35 per 100,000 population per year for men who practice anoreceptive sexual intercourse 6
● 1.5% of all gastrointestinal tract cancers in United States (CA Cancer J Clin 2000 Jan-Feb;50(1):7 full-
text )
STUDY
● SUMMARY
HIV infection associated with increased risk of anal cancer
Details
⚬ based on cohort study
⚬ 86,620 persons with HIV and 196,987 uninfected adults from the United States and Canada
followed between 1996 and 2009
⚬ cumulative incidence of anal cancer by age 75 years 1.5% for persons with HIV infection vs. 0.05%
for uninfected persons (p < 0.05)
⚬ Reference - Ann Intern Med 2015 Oct 6;163(7):507
● HIV associated with increased risk of squamous cell carcinoma of the anus (World J Gastroenterol
2011 Jul 7;17(25):2987 full-text )
STUDY
● SUMMARY
risk factors for anal cancer
Details
⚬ based on case-control study with 306 men and women diagnosed with anal cancer 1986-1998 and
1,700 population-based controls in Seattle, Washington
⚬ men not being exclusively heterosexual (adjusted odds ratio [OR] 17.3, 95% CI 8.2-36.1)
⚬ history of ≥ 15 lifetime sexual partners
⚬ anoreceptive intercourse
⚬ cigarette smoking
STUDY
● SUMMARY
receptive anal intercourse, other sexually transmitted disease, and higher numbers of sexual
partners appear to be risk factors for anal cancer
Details
⚬ based on case-control study with 324 women and 93 men with invasive or in situ anal cancer 1991-
1994 compared to 534 controls with rectal adenocarcinoma and 554 population controls in
Denmark and Sweden
⚬ Reference - N Engl J Med 1997 Nov 6;337(19):1350 , editorial can be found in N Engl J Med 1997
Nov 6;337(19):1386 , commentary can be found in N Engl J Med 1998 Mar 26;338(13):921
STUDY
● SUMMARY
risk factors for anal and rectal squamous cell carcinoma
Details
⚬ based on case-control study with 126 patients and 372 controls in San Francisco, California
⚬ history of homosexual activity in men (relative risk [RR] 12.4, p < 0.001) but not signi cant in
adjusted analysis
⚬ history of genital warts
⚬ history of > 12 episodes of hemorrhoids (RR 2.6 in heterosexual men and women, p < 0.001)
⚬ cigarette smoking in men who have sex with men
STUDY
● SUMMARY
history of lower genital tract neoplasia may increase risk for abnormal anal cytology, high-risk
HPV in anal canal, and anal intraepithelial neoplasia
Details
⚬ based on cross-sectional cohort study
⚬ 273 HIV-negative women ≥ 18 years old evaluated for history of HPV-related genital neoplasia and
had anal cytologic testing
⚬ 190 women (70%) had history of high-grade cervical, vulvar, or vaginal cytology, dysplasia, or cancer
(high-risk group)
⚬ women in high-risk group were younger than those in low-risk group (median 47 years vs. 57 years,
p < 0.001) and more likely to be current smokers (30% vs. 12%, p = 0.002)
⚬ comparing high-risk group vs. women with no history of high-grade anogenital dysplasia or cancer
STUDY
● SUMMARY
higher incidence of anal cancer reported in women with history of cervical cancer or cervical
intraepithelial neoplasia 3 and in women with HIV infection
Details
⚬ based on systematic review of observational studies
⚬ systematic review of 60 observational studies evaluating epidemiology of anal HPV infection, anal
intraepithelial neoplasia, and anal cancer in women
⚬ meta-analyses not performed due to heterogeneity in HPV testing and study types
⚬ incidence of anal cancer (per 100,000 person-years)
– 0.8-63.8 in women with history of cervical cancer or cervical intraepithelial neoplasia 3 (the study
reporting 63.8 per 100,000 person-years included rectal and anal cancers)
– 3.9-30 in women with HIV infection
– 0.55-2.4 in general female population
STUDY
● SUMMARY
risk of anal HPV infection in women associated with cervical HPV infection
Details
⚬ based on a cohort of 431 women followed for mean 1.3 years
⚬ 70% were positive for anal HPV
⚬ incidence of high-risk anal HPV infections 19.5 per 1,000 woman-months (95% CI 16-23.6)
⚬ risk of incident high-risk anal HPV infection associated with high-risk cervical HPV infection at
baseline (odds ratio 1.81, 95% CI 1.09-3.02)
⚬ Reference - J Infect Dis 2008 Apr 1;197(7):957 PDF
STUDY
● SUMMARY
high-risk cervical HPV associated with increased high-risk anal HPV, and high-risk anal HPV
associated with increased risk of abnormal anal cytology
Details
⚬ based on prospective cohort study
⚬ 196 women ≥ 21 years old with 1 of the following conditions had standard colposcopy with possible
biopsy and cervical human papillomavirus (HPV) testing as well as anal swab testing for anal HPV
and anal cytology
– atypical squamous cells of undetermined signi cance with HPV
– atypical squamous cells, cannot rule out high-grade dysplasia
– low-grade squamous intraepithelial lesions
– high-grade squamous intraepithelial lesions
● organ transplant associated with increased risk of anal cancer (incidence 11.6/100,000 person-years,
excess absolute risk 9.6/100,000 person-years [95% CI 7.3-12.3]) based on cohort study of 175,732
patients with solid organ transplants (JAMA 2011 Nov 2;306(17):1891 full-text )
STUDY
● SUMMARY
benign anal lesions may be associated with increased risk for anal cancer
Details
⚬ based on 2 retrospective cohort studies
⚬ 68,549 patients hospitalized with benign anal lesions between 1977-1989 were followed for median
6.2 years (427,922 person-years of follow-up)
– 23 patients developed anal cancer
● higher than expected 5.25 cases of anal cancer for general population
● standardized incidence ratio (SIR) 4.4 (95% CI 2.8-6.6)
● 5.4 (95% CI 2-11.7) for anal ssure (based on 6 cases of anal cancer)
● 8.1 (95% CI 2.2-20.8) for anal stula (based on 4 cases of anal cancer)
● 6.4 (95% CI 2.1-14.8) for perianal abscess (based on 5 cases of anal cancer)
● 3.8 (95% CI 2-6.5) for hemorrhoids (based on 13 cases of anal cancer)
– Reference - N Engl J Med 1994 Aug 4;331(5):300 , commentary can be found in N Engl J Med
1995 Jan 19;332(3):190
⚬ 45,186 patients hospitalized for in ammatory anal lesions (anal ssures, stulas, or perianal
abscesses) and 79,808 hemorrhoid patients from 1965 to 2002 were evaluated
– anal squamous cell carcinoma determined from medical record linkages through 2002
– patients with in ammatory anal lesions had higher than expected incidence of anal squamous
cell carcinoma
● 6 cases in rst year (13.3 per 100,000) or standardized incidence ratio (SIR) 24 (95% CI 8.8 -
52.3)
● 4 cases in second year (8.85 per 100,000) or SIR 16.3 (95% CI 4.4 - 41.7)
● 13 cases during 3-37 years of follow-up (28.7 per 100,000) or SIR 3.3 (95% CI 1.8 - 5.7)
– hemorrhoids associated with increased risk in rst year (SIR 14.9) and no signi cant increased
risk in subsequent years
– colorectal cancer only associated with in increased risk in rst year after hospitalization for both
patients with in ammatory anal lesions and patients with hemorrhoids
– Reference - Gut 2006 May;55(5):703 full-text
Associated conditions
● HIV infection 2
● condyloma acuminatum 2
STUDY
● SUMMARY
model with 3 risk factors may help to predict anal intraepithelial neoplasia in women with
genital dysplasia
Details
⚬ based on cohort study without independent validation
⚬ 327 women with biopsy-con rmed diagnosis of genital intraepithelial neoplasia (vulvar, vaginal, or
cervical) had both anal cytology and anoscopy
⚬ 19.6% had anal intraepithelial neoplasia
⚬ 3 risk factors associated with anal intraepithelial neoplasia
– sensitivity 47%
– speci city 86.2%
– positive predictive value 43.1%
– negative predictive value 88.2%
⚬ Reference - Obstet Gynecol 2013 Aug;122(2 Pt 1):218 , commentary can be found in Obstet
Gynecol 2014 Jan;123(1):183
⚬ prevalence of anal intraepithelial neoplasia 12.2% in women with genital intraepithelial
neoplasia
– based on cohort study
– 205 women aged 14-83 years (mean 40 years) with con rmed genital intraepithelial neoplasia
had anal cytology and high-resolution anoscopy
– biopsy-proven anal intraepithelial neoplasia in 12.2%
● abnormal anal cytology in 5.9% (8% sensitive, 94% speci c for anal intraepithelial neoplasia)
● abnormal anoscopy ndings in 38% (100% sensitive, 71% speci c for anal intraepithelial
neoplasia)
– comparing anal cytology vs. anoscopy
– Reference - Obstet Gynecol 2010 Sep;116(3):578 , editorial can be found in Obstet Gynecol
2010 Sep;116(3):566
⚬ presence of human papillomavirus-related gynecologic neoplasms associated with increased
risk of anal cancer
– based on retrospective cohort study
– 189,206 cases of in situ or invasive cervical, vulvar, or vaginal neoplasm followed for 138,553,519
person-years for development of primary anal cancer compared with expected ratios in
una ected matched controls from the general population
– anal cancer developed in 255 women with gynecologic neoplasm (aggregate standardized
incidence ratio 13.6, 95% CI 11.9-15.3)
– standardized incidence ratio for anal cancer among women with
STUDY
● SUMMARY
previous HPV-related cancers associated with increased risk of primary HPV-related anal cancer
Details
⚬ based on systematic review of observational studies
⚬ systematic review of 32 cohort studies evaluating incidence of second HPV-related cancer in
3,759,726 patients with previous preinvasive or invasive HPV-related cancer
⚬ increased risk of primary HPV-related anal cancer associated with previous HPV-related
– anal cancer (standardized incidence ratio [SIR] 30.81, 95% CI 23.5-40.39) in analysis of 2 studies
– vaginovulval cancer (SIR 13.69, 95% CI 8.56-21.89) in analysis of 6 studies, results limited by
signi cant heterogeneity
– cervical intraepithelial neoplasia (SIR 4.47, 95% CI 2.66-7.51) in analysis of 9 studies, results
limited by signi cant heterogeneity
– cervical cancer (SIR 3.82, 95% CI 2.35-6.2) in analysis of 8 studies, results limited by signi cant
heterogeneity
– oropharyngeal cancer (SIR 2.7, 95% CI 1.17-6.23) in analysis of 5 studies
⚬ Reference - Br J Cancer 2018 Nov 28 early online
Causes
STUDY
● SUMMARY
high-risk HPV detected in anal carcinomas in 90% of women and 63% of men
Details
⚬ based on histologic evaluation of tumor tissue from 331 patients with invasive anal cancer
⚬ polymerase chain reaction assay used to test for HPV type 16 and 13 other high-risk HPV types
⚬ high-risk HPV detected in anal carcinomas in 90% of women and 63% of men
⚬ among high-risk HPVs identi ed
– 87% HPV-16
– 7% HPV-18
– 6% HPV-33
– 1% HPV-31
– 2% untyped high-risk HPV
– 7 patients had HPV infection with 2 subtypes
⚬ 100% of men reporting homosexual activity vs. 58% without homosexual activity had high-risk HPV
types identi ed (p = 0.006)
⚬ Reference - Cancer Res 1999 Feb 1;59(3):753 full-text
● HPV DNA detected in 88% of tumors from 306 men and women diagnosed with anal cancer 1986-
1998
⚬ HPV-16 detected in 73% of all tumors
⚬ HPV-18 detected in 6.9% of all tumors
⚬ HPV detected in tumors from 89% of women and 86% of men (98% men who were not exclusively
heterosexual, 78% of exclusively heterosexual men)
⚬ Reference - Cancer 2004 Jul 15;101(2):270 PDF
Pathogenesis
● HPV infection associated with development of premalignant anal squamous intraepithelial lesions
⚬ weight loss
⚬ constipation
⚬ change in stool caliber
⚬ inguinal adenopathy
⚬ rectovaginal stula
⚬ HIV infection
⚬ human papillomavirus (HPV) infection
⚬ tobacco use
⚬ hemorrhoids
⚬ anal ssures (based on weak evidence)
⚬ organ transplant
Physical
Lungs
Abdomen
Extremities
Rectal
⚬ mass, lesions 2
⚬ genital warts 5
● metastatic colorectal carcinoma within thrombosed hemorrhoids in case report (J Med Case Reports
2008 Apr 28;2:128 full-text )
Pelvic
Differential diagnosis
● palpable masses
⚬ condyloma
⚬ molluscum contagiosum
⚬ hemorrhoids
⚬ polyps
⚬ anal ssure
⚬ hemorrhoids
⚬ regional enteritis (Crohn disease)
⚬ ulcerative colitis
⚬ infectious colitis
⚬ polyps
⚬ arteriovenous malformation
⚬ intussusception
⚬ stula
⚬ chronic ulcer
Testing overview
● proctosigmoidoscopy 5
● ne-needle aspiration and cytology for suspicious palpable lymphadenopathy (NCCN Category 2A) 7
● imaging studies for staging
⚬ endoanal ultrasound 5 , 6
– computed tomography (CT) of pelvis, abdomen and chest (NCCN Category 2A)
– magnetic resonance imaging (MRI) of pelvis and abdomen (NCCN Category 2A)
– stage II-IV disease without lymph node involvement (NCCN Category 2A)
– any stage disease with lymph node involvement (NCCN Category 2A)
Staging system
● American Joint Committee on Cancer (AJCC) staging for anal cancer, eighth edition
Stage T N M
0 Tis N0 M0
I T1 N0 M0
IIA T2 N0 M0
IIB T3 N0 M0
IIIA T1 N1 M0
T2 N1 M0
IIIB T4 N0 M0
IIIC T3 N1 M0
T4 N1 M0
IV Any T Any N M1
● de nitions of staging abbreviations
– M0 - no distant metastasis
– M1 - distant metastasis
● Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this
information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International
Publishing.
Imaging studies
⚬ anorectal endosonography reported to be better for staging of anal carcinoma than classical TNM
classi cation alone (Scand J Gastroenterol Suppl 2006 May;(243):165 )
⚬ 3-dimensional anal endosonography more sensitive than 2-dimensional anal endosonography in
prospective study of 38 patients with history of anal carcinoma being evaluated for recurrent anal
cancer (Dis Colon Rectum 2006 Oct;49(10):1527 )
⚬ review of endoanal ultrasound for evaluation of anorectal disease can be found in Eur J Radiol
2007 Mar;61(3):480
⚬ retrospective series of 30 patients who had endoscopic ultrasound for squamous cell carcinoma of
anal canal can be found in Endoscopy 1999 Jun;31(5):359
⚬ MRI may be more accurate than CT in di erentiating tumor from normal pelvic structures 6
⚬ retrospective series of MRI imaging in 27 cases of primary or recurrent anal carcinoma can be
found in Clin Radiol 2005 Oct;60(10):1111
⚬ review of postoperative anatomic and pathologic ndings on pelvic MRI can be found in
Radiographics 2006 Sep-Oct;26(5):1391 full-text
STUDY
● SUMMARY
FDG-PET scanning may be more sensitive than CT in identification of disease DynaMed Level 2
COHORT STUDY: Int J Radiat Oncol Biol Phys 2006 Jul 1;65(3):720
COHORT STUDY: Mol Imaging Biol 2005 Jul;7(4):309
Details
⚬ based on 2 small cohort studies
⚬ 41 consecutive patients with anal carcinoma had staging evaluation including physical examination,
CT, and 2-FDG-PET/CT
– PET detected 91% and CT detected 59% of nonexcised primary tumors
– PET identi ed abnormal nodal uptake in 17% of groins not identi ed by either CT or physical
examination
– Reference - Int J Radiat Oncol Biol Phys 2006 Jul 1;65(3):720
⚬ 21 patients with anal cancer had pre-treatment and follow-up PET and CT scanning
– PET identi ed metastases (lymphoid and omental) not observed by CT scan in 24% (5 of 21)
patients
– post treatment PET may not be accurate for prognosis
● 3 of 9 patients (33%) with minimal residual activity at primary site had recurrence
● 3 of 6 patients (50%) with negative post treatment PETs had recurrence
● review of imaging for investigating perianal pain of uncertain cause can be found in BMJ 2008 Feb
16;336(7640):387 full-text
● American College of Radiology (ACR) Appropriateness Criteria for anal cancer can be found at ACR
2013 PDF
● special stains and immunohistochemical markers for poorly di erentiated neoplasms include 1
⚬ mucin
⚬ S100
⚬ CK7/20
⚬ NSE/chromogranin/synaptophysin
⚬ CD20/EBV
⚬ CK5/6 and p63
⚬ keratin AE1/AE3
● limited evidence regarding use of sentinel lymph node biopsy to guide treatment (Ann Surg Oncol
2010 Oct;17(10):2656 full-text )
● intraepithelial neoplasia 8
Management
Management overview
● for patients with well-di erentiated stage I anal margin lesion without lymph node involvement 7
● for patients with anal margin lesion that is T2-T4, N0 or any T N-positive disease, or in patients with
nonmetastatic anal canal cancer, consider concurrent chemoradiation (NCCN Category 2A; ASCRS
Grade 1A [ASCRS Grade 1C for lymph node disease]) 7 , 8
⚬ for radiation therapy
● for patients with metastatic anal margin lesion or anal canal cancer, consider systemic chemotherapy
● for patients with HIV infection, consider basing treatment approach on CD4 counts (ASCRS Grade
2C) 8
⚬ if CD4 counts > 200 cells/mL, use similar approach as in patients without HIV infection
⚬ if CD4 counts < 200 cells/mL, individualize treatment (may require lower doses of chemoradiation
and/or may have wound healing de ciencies after surgery)
● three-dimensional conformal radiation therapy (3D-CRT) may improve survival and freedom from
relapse compared to conventional radiation therapy DynaMed Level 2
● pelvic irradiation associated with increased risk of pelvic fracture in older women DynaMed Level 2
Medications
⚬ for patients with metastatic disease, recommended regimen is 5-FU plus cisplatin
STUDY
● SUMMARY
addition of 5-FU plus mitomycin to radiation therapy may reduce local failure and colostomy
rates DynaMed Level 2
Details
⚬ based on 2 randomized trials without blinding
⚬ UKCCCR trial
– 585 patients aged 26-88 years with epidermoid anal cancer were randomized to chemoradiation
(radiation plus mitomycin plus 5-FU) vs. radiation therapy alone and followed for median 42
months
● external beam radiation with 45 Gy as central axis dose given for 4-5 weeks
● chemotherapy given with rst course of radiation therapy
⚬ initial chemotherapy was 5-FU (1,000 mg/m2 IV for 4 days or 750 mg/m2 for 5 days) plus
– 110 patients with locally advanced anal cancer were randomized to chemoradiation (5-FU plus
mitomycin plus radiation) vs. radiation alone and followed for median 42 months
● radiation therapy consisted of 45 Gy given in 5 weeks (daily dose 1.8 Gy), additional
treatment given at 6 weeks if partial (20 Gy) or complete (15 Gy) response
● chemotherapy (given with rst course of radiation therapy) consisted of uorouracil 750
mg/m2 IV continuously on days 1-5 and 29-33 plus mitomycin 15 mg/m2 as single dose on
day 1
– comparing chemoradiation vs. radiation alone
– no signi cant di erences in severe side e ects but anal ulcers more frequent with combination
therapy
– Reference - J Clin Oncol 1997 May;15(5):2040 , commentary can be found in J Clin Oncol 1998
Feb;16(2):802
STUDY
● SUMMARY
addition of mitomycin to chemoradiation with 5-FU may improve colostomy-free survival
DynaMed Level 2
Details
⚬ based on randomized trial with allocation concealment and blinding not stated
⚬ 310 patients with anal canal cancer were given chemoradiation with 5-FU (1,000 mg/m2 on days 1
and 29) plus radiation therapy (45-50 Gy over 5 weeks) and then randomized to mitomycin (10
mg/m2 on days 1 and 29) vs. no additional treatment and followed for median 3 years
⚬ patients with residual tumor had salvage treatment with radiation 9 Gy, 5-FU, and cisplatin 100
mg/m2
⚬ 291 patients (94%) were analyzed
⚬ comparing chemoradiation with vs. without mitomycin at 4 years
⚬ grade 4-5 toxicity occurred in 23% of patients with mitomycin vs. 7% without (p < 0.001, NNH 7)
⚬ Reference - RTOG 87-04 trial (J Clin Oncol 1996 Sep;14(9):2527 )
STUDY
● SUMMARY
chemoradiation with mitomycin associated with higher 5-year survival but greater hematologic
toxicity than chemoradiation with cisplatin for patients with anal cancer DynaMed Level 2
Details
⚬ based on randomized trial without blinding
⚬ 682 patients with anal cancer were given radiation and were randomized to 5-FU plus mitomycin
vs. 5-FU plus cisplatin
– 5-FU plus mitomycin group treated with
⚬ 644 (94.4%) patients were analyzed at median follow-up 2.5 years in original publication
⚬ 3-year outcomes comparing chemoradiation with mitomycin vs. chemoradiation with cisplatin
⚬ References - RTOG 98-11 trial (JAMA 2008 Apr 23;299(16):1914 ), commentary can be found in
JAMA 2008 Sep 24;300(12):1410
⚬ follow-up study (J Clin Oncol 2012 Dec 10;30(35):4344 full-text )
STUDY
● SUMMARY
chemoradiation with mitomycin associated with similar rates of complete response but
increased hematologic toxicity compared to chemoradiation with cisplatin; addition of
maintenance therapy to either chemoradiation regimen does not appear to improve
progression-free survival DynaMed Level 2
Details
⚬ based on randomized trial without blinding
⚬ 940 patients (median age 58 years) with squamous cell carcinoma of anus without metastasis
randomized to
– uorouracil 1,000 mg/m2/day IV on days 1-4 and 29-32 plus radiotherapy 50.4 Gy in 28 fractions
plus mitomycin 12 mg/m2 IV on day 1 vs. cisplatin 60 mg/m2 IV on days 1 and 29
– maintenance chemotherapy with uorouracil plus cisplatin on days 71-74 and days 92-95 vs. no
maintenance chemotherapy
⚬ median follow-up 5.1 years
⚬ complete response de ned as disappearance of clinically or radiologically overt disease
⚬ comparing mitomycin vs. cisplatin
⚬ 3-year progression-free survival 74% with maintenance chemotherapy vs. 73% with no
maintenance chemotherapy (not signi cant)
⚬ no signi cant di erences in overall survival among groups
⚬ Reference - ACT II trial (Lancet Oncol 2013 May;14(6):516 ), editorial can be found in Lancet Oncol
2013 May;14(6):443 , commentary can be found in Nat Rev Clin Oncol 2013 Jun;10(6):306
STUDY
● SUMMARY
longer treatment duration associated with increased local failure in patients with anal cancer
treated with radiation therapy (RT) plus fluorouracil (FU) and mitomycin or cisplatin
DynaMed Level 2
Details
⚬ based on post hoc analysis of 2 randomized trials (RTOG 98-11 and RTOG 87-04) above
⚬ 937 patients receiving any combination of treatment (RT plus FU plus mitomycin vs. RT plus FU plus
cisplatin vs. RT plus FU) evaluated for total duration of treatment
⚬ longer overall total treatment duration associated with
STUDY
● SUMMARY
addition of induction chemotherapy to radiochemotherapy may not improve survival in patients
with locally advanced anal canal carcinoma DynaMed Level 2
Details
⚬ based on randomized trial without blinding
⚬ 307 patients aged 18-80 years with locally advanced anal canal carcinoma randomized to 1 of 4
treatments and followed for median 50 months
– induction chemotherapy of uorouracil 800 mg/m2 IV on days 1-4 and 29-32 plus cisplatin 80
⚬ overall survival
– 74.5% with induction chemotherapy plus radiochemotherapy vs. 71% with radiochemotherapy
(not signi cant)
– 71% with standard boost vs. 74% with high-dose boost (not signi cant)
Radiation therapy
STUDY
● SUMMARY
three-dimensional conformal radiation therapy (3D-CRT) may improve survival and freedom
from relapse compared to conventional radiation therapy DynaMed Level 2
COHORT STUDY: Int J Radiat Oncol Biol Phys 2007 Apr 1;67(5):1394
Details
⚬ based on prospective cohort study
⚬ 62 consecutive patients with anal cancer had 3D-CRT 54 Gy in 30 fractions continuously and were
compared to 60 historical controls having conventional radiation therapy with median 54 Gy in split
course
⚬ all patients had concurrent chemotherapy with 5- uorouracil plus either mitomycin-C or cis-
platinum
⚬ comparing 3D-CRT vs. conventional radiation at 5 years
STUDY
● SUMMARY
external radiation therapy without chemotherapy reported to be effective for T1 and T2 lesions
DynaMed Level 3
CASE SERIES: Int J Radiat Oncol Biol Phys 2003 Aug 1;56(5):1259
CASE SERIES: Radiother Oncol 1992 Nov;25(3):196
CASE SERIES: Cancer 1993 Mar 1;71(5):1736
Details
⚬ based on 3 case series
⚬ case series of 305 patients with cancer of anal canal
– 305 patients with anal cancer had curative-intent radiation therapy (median dose 45 Gy) and
were followed for mean 103 months
● 279 patients had EBRT 20 Gy boost after rest period of 4-6 weeks
● 17 had interstitial (192)Ir brachytherapy boost after rest period of 4-6 weeks
● 7 patients had only 1 course of EBRT
● 2 patients had interstitial (192)Ir brachytherapy only
● 19 patients had concomitant chemotherapy with 5-FU plus either cisplatin or mitomycin-C
– all patients treated with external beam radiation (commonly 5,000 centigray over 4 weeks)
– 5-year outcomes
– all had radiation 45-50 Gy in 25-28 fractions, 16 had additional radiation increasing total dose to
55-67 Gy
– follow-up ranged from 2.5-11.2 years
– 94% projected survival at 5 years
– 100% projected freedom from local recurrence at 5 years
– no patient required permanent colostomy or had permanent sphincter function loss
– Reference - Cancer 1993 Mar 1;71(5):1736
STUDY
● SUMMARY
chemotherapy plus external beam radiation followed by interstitial implant reported to have
84% loco-regional control in patients with T3 and T4 anal cancer DynaMed Level 3
Details
⚬ based on case series
⚬ 31 patients with T3 or T4 anal cancer had external beam radiation 30 Gy plus 5-FU plus mitomycin-
C followed by interstitial (192)Ir implant boost (median implant dose 31.3 Gy at 0.5 cm delivered at
mean 0.52 Gy/hour)
⚬ 6 patients had local persistence
⚬ 4 developed local recurrence
⚬ 8 patients had abdominoperineal resection (APR)
⚬ 84% local regional control after initial treatment and APR
⚬ Reference - Brachytherapy 2004;3(2):95
STUDY
● SUMMARY
pelvic irradiation associated with increased risk of pelvic fracture in older women
DynaMed Level 2
⚬ cumulative 5-year fracture rate (after adjusting for length of follow-up) in women who had pelvic
irradiation vs. women who did not have pelvic irradiation
– 14% vs. 7.5% in women with anal cancer
– 8.2% vs. 5.9% in women with cervical cancer
– 11.2% vs. 8.7% in women with rectal cancer
⚬ Reference - JAMA 2005 Nov 23-30;294(20):2587 , editorial can be found in JAMA 2005 Nov 23-
30;294(20):2635
⚬ anterior tumor
⚬ perineum involvement
⚬ vaginal-mucosal involvement (may indicate risk for rectovaginal stula with chemoradiation)
Follow-up
● computed tomography (CT) of pelvis, abdomen and chest (NCCN Category 2A)
● magnetic resonance imaging (MRI) of pelvis and abdomen (NCCN Category 2A)
⚬ if local recurrence, APR with groin dissection if positive inguinal lymph nodes (NCCN Category 2A) 7
Category 2A) 7
Surveillance
– inguinal node palpation every 3-6 months for 5 years (NCCN Category 2A)
– annual chest/abdominal/pelvic CT or MRI for 3 years (NCCN Category 2A)
⚬ perform examination (digital rectal exam, anoscopy, and inguinal palpation) (ASCRS Grade 1C)
⚬ consider imaging (such as endoanal ultrasound, computed tomography [CT], magnetic resonance
imaging, and FDG-PET/CT) to assess for persistent or recurrent disease (ASCRS Grade 1C)
Complications
⚬ about 10% incidence of nodal metastases reported at presentation, but may be higher (20-60%) for
⚬ up to 25% incidence of distant metastases reported in patients with inguinal adenopathy or with
lesions > 5 cm 3
● complications of chemoradiation 2
– diarrhea
– mucositis
– skin erythema and desquamation
– myelosuppression
– anal ulcers
– stricture/stenosis
– stulae
– necrosis
● patients with CD4 count < 200 cells/mm3 had increased risk for complications in cohort of 17 patients
with HIV infection with anal canal cancer (Int J Radiat Oncol Biol Phys 1999 Apr 1;44(1):127 )
Prognosis
● tumor size > 5 cm associated with increased risk of colostomy (J Clin Oncol 2009 Mar 1;27(7):1116
full-text )
STUDY
● SUMMARY
relative 5-year survival improving for women but worsening for black men in United States
Details
⚬ based on data from Surveillance, Epidemiology, and End Results (SEER) program from 1973-2000
⚬ relative 5-year survival rates
– 58% overall for men (relatively unchanged from 60% [1973-1979] to 61% [1994-2000])
– 64% overall for women (increased from 59% [1973-1979] to 73% [1994-2000])
– 38% overall for black men (decreased from 45% [1973-1979] to 27% [1994-2000])
⚬ age ≥ 65 years at diagnosis associated with poorer survival in men and women
⚬ Reference - Cancer 2004 Jul 15;101(2):281 PDF
STUDY
● SUMMARY
larger tumor size and poor response to first course of radiation associated with worse 5-year
prognosis
Details
⚬ based on cohort study with full-text in English not available
⚬ 286 patients with anal cancer were treated at one institution 1976-2005 and followed for mean 65
months (range 1.3-250 months)
– 180 had radiation therapy
– 106 had chemoradiation
– 233 had brachytherapy boost following either radiation therapy or chemoradiation
– 24 had external beam radiation therapy boost following either radiation therapy or
chemoradiation
⚬ staging on presentation
– 43 stage I
– 154 stage II
– 31 stage IIIA
– 53 stage IIIB
– tumor size ≥ 40 mm
– node involvement
– poor response (< 75%) to rst course of irradiation
– local relapse
– distant metastases
⚬ 71% overall sphincter conservation at 5 years, prognosis associated with tumor size and response
to rst course of radiation
⚬ Reference - Cancer Radiother 2007 Jun;11(4):169 [French]
STUDY
● SUMMARY
more advanced tumor node category associated with decreased 5-year overall survival in
patients with nonmetastatic anal cancer who received chemoradiation
COHORT STUDY: Int J Radiat Oncol Biol Phys 2013 Nov 15;87(4):638
Details
⚬ based on cohort analysis of data from RTOG 98-11 trial
⚬ 620 patients with nonmetastatic anal cancer who received chemoradiation were analyzed by tumor
node (TN) category
⚬ 5-year overall survival
⚬ compared to patients with T2-3N0 disease, T4N0/T2-4N+ disease associated with decreased overall
and disease-free survival, and higher rates of local-regional failure and distant metastasis at 5 years
(p < 0.0001 for each)
⚬ Reference - Int J Radiat Oncol Biol Phys 2013 Nov 15;87(4):638
STUDY
● SUMMARY
well-differentiated tumors have higher 5-year survival than poorly differentiated tumors
Details
⚬ based on small cohort study
⚬ 47 patients with anal squamous cell carcinoma had specimens evaluated for stage (43), grade (41)
and DNA content (31) and were followed 4-7 years (median 5.5 years)
⚬ 5-year survival 75% for well-di erentiated vs. 24% for poorly-di erentiated tumors
⚬ signi cant increase in mortality with higher grade and more advanced stage lesions
⚬ Reference - Dis Colon Rectum 1987 Jun;30(6):444 as referenced in 6
STUDY
● SUMMARY
local failure rates about 35% with chemoradiation and 53% with radiation therapy alone
Details
⚬ based on retrospective cohort study
⚬ 254 patients with non-metastatic epidermoid anal cancer were treated with radiation alone (127
patients) or chemoradiation (127 patients)
⚬ 99 patients (39%) had local disease failure
– higher T stage
– increased age
– total radiation dose < 50 Gy
STUDY
● SUMMARY
adenocarcinoma associated with lower survival and higher recurrence rate compared to
epidermoid carcinoma
COHORT STUDY: Int J Radiat Oncol Biol Phys 2003 Mar 1;55(3):669
Details
⚬ based on retrospective cohort study comparing
– 16 patients with localized adenocarcinoma of anal canal had radiation therapy (median dose 55
Gy) with curative intent, 11 patients had concurrent 5-FU-based chemotherapy
– 92 patients with epidermoid cancer treated with chemoradiation (radiation median dose 55 Gy,
5-FU plus cisplatin)
⚬ median follow-up 44-45 months
⚬ 5-year actuarial outcomes comparing adenocarcinoma vs. epidermoid lesions
STUDY
● SUMMARY
primary anorectal melanoma associated with poor 5-year survival
Details
⚬ based on retrospective cohort study
⚬ 40 patients (mean age 58 years, 70% women) with primary anorectal melanoma were assessed
⚬ median overall survival 17 months, 5-year overall survival 17%
⚬ median disease-free survival 10 months, 5-year disease-free survival 14%
⚬ 5-year survival 24% for stage I and 0% for stage II or III disease
⚬ Reference - Br J Surg 2004 Sep;91(9):1183
Prevention
● intraepithelial neoplasia
⚬ monitor AIN on-going follow-up at 3- to 6-month intervals with (ASCRS Grade 2C) 8
– digital rectal examination, anoscopic exam, with or without magni cation or topical acetic acid
and Lugol solution
– anorectal cytology and/or biopsy for suspicious areas
STUDY
● SUMMARY
electrocautery may be more effective in clearing anal intraepithelial neoplasia (AIN) than
fluorouracil, and imiquimod and electrocautery appear similarly effective for clearing AIN
DynaMed Level 2
Details
⚬ based on randomized trial without blinding
⚬ 156 men who have sex with men (MSM), HIV positivity, and anal intraintraepithelial neoplasia (AIN)
randomized to 1 of following treatments
– imiquimod 6.25 mg topical 3 times weekly for 16 weeks
– uorouracil 2% topical applied once in morning and once in evening twice weekly for 16 weeks
– electrocautery of AIN monthly for 4 months (up to 5 sessions)
⚬ no signi cant di erence in incidence of adverse e ects (mostly pain, irritation, or bleeding)
between groups
⚬ Reference - Lancet Oncol 2013 Apr;14(4):346
STUDY
● SUMMARY
imiquimod might clear anal canal high-grade anal intraepithelial neoplasia DynaMed Level 2
Details
⚬ based on small randomized trial
⚬ 53 patients with HIV positivity and anal canal high-grade anal intraepithelial neoplasia (AIN)
randomized to imiquimod topically 3 times weekly for 4 months
⚬ resolution of AIN in 4 (14%) with imiquimod vs. 1 (4%) with placebo
⚬ AIN downgraded to low-grade squamous intraepithelial lesion (LSIL) in 8 (29%) with imiquimod vs. 0
with placebo
⚬ Reference - AIDS 2010 Sep 24;24(15):2331
⚬ no additional randomized trials evaluating treatment for AIN identi ed in systematic review in
Cochrane Database Syst Rev 2012 Dec 12;12:CD009244
Screening
● recommendations
⚬ United States Preventive Services Task Force (USPSTF), American Cancer Society (ACS), Centers for
Disease Control and Prevention, and the Infectious Diseases Society of America (IDSA) make no
recommendations regarding screening for anal cancer (Managing HPV: A New Era in Patient Care
)
⚬ New York State Department of Health AIDS Institute recommends
– at baseline and as part of annual physical exam for all adults with HIV infection, regardless of
age, clinicians should
● inquire about anal symptoms, such as itching, bleeding, diarrhea, or pain
● perform a visual inspection of the perianal region
● perform a digital rectal examination
– clinicians should refer women with cervical high-grade squamous intraepithelial lesion (HSIL)
and any patient with abnormal anal physical ndings, such as warts, hypopigmented or
hyperpigmented plaques/lesions, lesions that bleed, or any other lesions of uncertain etiology,
for high-resolution anoscopy and/or examination with biopsy of abnormal tissue
– clinicians should obtain anal cytology at baseline and annually in the following HIV-infected
populations
● men who have sex with men
● any patient with a history of anogenital condylomas
● women with abnormal cervical and/or vulvar histology
– Reference - New York State Department of Health AIDS Institute 2007 Jul
⚬ screening for anal cancer in high-risk population with HIV infection may not be cost-e ective
(Health Technol Assess 2010 Nov;14(53):iii PDF )
⚬ American Society of Colon and Rectal Surgeons (ASCRS) recommends anal Papanicolaou smear
may be useful for detection and follow-up of low-grade anal intraepithelial neoplasia (LGAIN) and
high-grade anal intraepithelial neoplasia (HGAIN) (ASCRS Grade 1C) 8
STUDY
● SUMMARY
anal cytology may not rule out anal cancer or precursor lesions DynaMed Level 2
Details
⚬ based on systematic review of mostly moderate quality studies
⚬ systematic review of 44 studies comparing cytologic sampling of cervical or anal tissues with
histology on magni cation-directed punch biopsy for detection of high-grade squamous
intraepithelial lesions
⚬ 11 studies comparing anal cytology to histology (reference standard) in 2,384 patients
⚬ anal cytology criteria for detection of histopathology-con rmed high-grade squamous
intraepithelial lesions included
– high-grade squamous intraepithelial lesion (HSIL)
– atypical squamous cells, cannot rule out high grade (ASC-H)
– low-grade squamous intraepithelial lesion (LSIL)
– atypical squamous cells of uncertain signi cance (ASCUS)
– no atypical or malignant cells (normal)
● anorectal cytology appears to have high sensitivity but low speci city for anal squamous
intraepithelial lesions DynaMed Level 2
STUDY
⚬ SUMMARY
anorectal cytology reported to have 92% sensitivity and 50% specificity for detecting anal
squamous lesions
Details
– based on retrospective cohort study with limited use of reference standard
– 78 consecutive anorectal cytology specimens (75 ThinPrep, 3 conventional smears) from 51
patients were stained with Pap stain
● 32 patients also had anoscopy
● 30 patients with anoscopy also had anorectal biopsy specimens
STUDY
● SUMMARY
anal HPV infection may occur in men with HIV infection without history of anoreceptive
intercourse
Details
⚬ based on cross-sectional study of 117 men with HIV infection
⚬ 50 had history of injection drug use but no history of anoreceptive intercourse
⚬ 67 had anoreceptive intercourse
⚬ comparing men with vs. without history of anoreceptive intercourse
● self-collected anal swab may be almost as adequate as clinician-collected anal swab for liquid-
based cytology
⚬ 222 young men who have sex with men (mostly HIV-1 seronegative) had paired self- and clinician-
collected anorectal Dacron swabs for liquid-based (ThinPrep) cytology
⚬ 83% self-collected specimens vs. 92% clinician-collected specimens were adequate for cytological
evaluation (p < 0.001)
⚬ both groups had 21% rate of detection of cytological abnormalities (with fair agreement, kappa =
0.4) including 5% atypical squamous cells of undetermined signi cance (ASC-US), 13% low-grade
squamous intraepithelial lesions and 3% high-grade squamous intraepithelial lesions
⚬ Reference - Cytojournal 2006 Mar 20;3:4 full-text
STUDY
● SUMMARY
patient-collected anal cytology samples may have lower sensitivity for anal intraepithelial
neoplasia (AIN) than clinician-collected samples
Details
⚬ based on cross-sectional study with 126 men who have sex with men
⚬ 38 (30%) were patients with HIV infection (by self-report)
⚬ biopsy-proven AIN in 57% of patients with HIV infection vs. 35% of patients without HIV infection (p
= 0.04)
⚬ patient-collected samples
– sensitivity 75% for patients with HIV infection and 48% for patients without HIV infection
– speci city 50% for patients with HIV infection and 86% for patients without HIV infection
⚬ clinician-collected samples
– sensitivity 90% for patients with HIV infection and 62% for patients without HIV infection
– speci city 64% for patients with HIV infection and 85% for patients without HIV infection
⚬ Reference - Ann Intern Med 2008 Sep 2;149(5):300 , commentary can be found in Ann Intern Med
2009 Feb 17;150(4):283
Guidelines
● American College of Radiology (ACR) Appropriateness Criteria for anal cancer can be found at ACR
2013 PDF
● American Society of Colon and Rectal Surgeons (ASCRS) clinical practice guideline on anal squamous
cell cancers can be found in Dis Colon Rectum 2018 Jul;61(7):755 PDF
● American Society of Colon and Rectal Surgeons (ASCRS) clinical practice guideline on ambulatory
anorectal surgery can be found in Dis Colon Rectum 2015 Oct;58(10):915 PDF
● National Comprehensive Cancer Network (NCCN) clinical practice guideline on anal carcinoma be
found at NCCN website (free registration required) or in J Natl Compr Canc Netw 2010 Jan;8(1):106
● Association of Coloproctology of Great Britain and Ireland (ACPGBI) position statement on anal cancer
can be found in Colorectal Dis 2011 Feb;13 Suppl 1:1
● Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines for management of
anal intraepithelial neoplasia can be found in Colorectal Dis 2011 Feb;13 Suppl 1:3
Canadian guidelines
● Cancer Care Ontario (CCO) guideline on PET imaging in anal canal cancer can be found at CCO 2017
Jan
● Alberta Health Services (AHS) clinical practice guideline on anal canal cancer can be found at AHS 2010
Mar PDF
European guidelines
● German S1 guideline on anal intraepithelial neoplasia (AIN) and perianal intraepithelial neoplasia
(PAIN) can be found in J Dtsch Dermatol Ges 2011 Mar;9(3):256
● Spanish Society for Medical Oncology (SEOM) clinical guideline on treatment of anal cancer can be
found in Clin Transl Oncol 2011 Aug;13(8):525
Asian guidelines
● Korean Academy of Medical Sciences (KAMS) guideline on rating system for digestive system
impairments can be found in J Korean Med Sci 2009 May;24 Suppl 2:S271 full-text
Review articles
● review of diagnosis and management of anal intraepithelial neoplasia and anal cancer can be found in
BMJ 2011 Nov 4;343:d6818
● review of diagnosis, treatment and prevention of anal cancer can be found in Curr Infect Dis Rep 2012
Feb;14(1):61
● review of treatment for localized anal carcinoma can be found in Curr Opin Oncol 2007 Jul;19(4):396
● review of evaluation and management of common anorectal conditions can be found in Am Fam
Physician 2012 Mar 15;85(6):624 full-text
● review of common anorectal conditions can be found in Am Fam Physician 2001 Jun 15;63(12):2391
MEDLINE search
● to search MEDLINE for (Anal cancer) with targeted search (Clinical Queries), click therapy , diagnosis
, or prognosis
Patient Information
ICD Codes
ICD-10 codes
References
General references used
1. Balachandra B, Marcus V, Jass JR. Poorly di erentiated tumours of the anal canal: a diagnostic strategy
for the surgical pathologist. Histopathology. 2007 Jan;50(1):163-74
2. Uronis HE, Bendell JC. Anal cancer: an overview. Oncologist. 2007 May;12(5):524-34 full-text
3. Rousseau DL Jr, Thomas CR Jr, Petrelli NJ, Kahlenberg MS. Squamous cell carcinoma of the anal canal.
Surg Oncol. 2005 Nov;14(3):121-32
4. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000 Mar 16;342(11):792-
800 , summary can be found in Am Fam Physician 2000 Sep 1;62(5):1173
5. Eng C. Anal cancer: current and future methodology. Cancer Invest. 2006 Aug-Sep;24(5):535-44
6. Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol. 2004 Mar;5(3):149-57
7. Benson AB, Venook AP, Bekaii-Saab T, et al. Anal Carcinoma. Version 2.2015. In: National
Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines).
NCCN 2014 Dec from NCCN website (free registration required)
8. American Society of Colon and Rectal Surgeons (ASCRS) practice parameter on anal squamous
neoplasms. Dis Colon Rectum 2012 Jul;55(7):735 PDF , commentary can be found in Dis Colon
Rectum 2013 Feb;56(2):e18
● American Society of Colon and Rectal Surgeons (ASCRS) grading system for recommendations based
on Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) System
⚬ strength of recommendation grades
– Grade 1 - strong recommendation - bene ts clearly outweigh risks and burdens (or vice versa)
for most, if not all, patients
– Grade 2 - weak recommendation - bene ts and risks closely balanced and/or uncertain
– Level A - high-quality evidence - randomized trials without factors that reduce quality of
evidence, or well-done observational studies with very large magnitude of e ect
– Level B - moderate-quality evidence - downgraded randomized trials or upgraded observational
studies
– Level C - low- or very low-quality evidence - observational studies or case series
⚬ Reference - ASCRS practice parameter on anal squamous neoplasms (Dis Colon Rectum 2012
Jul;55(7):735 )
⚬ Category 1 - based on high-level evidence, there is uniform NCCN consensus that intervention is
appropriate
⚬ Category 2A - based on lower-level evidence, there is uniform NCCN consensus that intervention is
appropriate
⚬ Category 2B - based on lower-level evidence, there is NCCN consensus that intervention is
appropriate
⚬ Category 3 - based on any level of evidence, there is major NCCN disagreement that intervention is
appropriate
⚬ Reference - NCCN Categories of Evidence and Consensus
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