The American Society of Colon and Rectal Surgeons Clinical

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DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

he American Society of Colon and Rectal Surgeons

is dedicated to ensuring high-quality patient care

by advancing the science, prevention, and manage-

ment of disorders and diseases of the colon, rectum, and

anus. The Clinical Practice Guidelines Committee is com-

posed of society members who are chosen because they

have demonstrated expertise in the specialty of colon and

rectal surgery. This committee was created to lead interna-

tional efforts in deﬁning quality care for conditions related

to the colon, rectum, and anus. This is accompanied by

developing clinical practice guidelines based on the best

available evidence. These guidelines are inclusive and not

prescriptive. The purpose of this guideline is to provide

information on which decisions can be made rather than

to dictate a speciﬁc form of treatment. These guidelines

are intended for use by all practitioners and healthcare

workers, as well as by patients who desire information

about the management of the conditions addressed by the

topics covered in these guidelines. It should be recognized

that these guidelines should not be deemed inclusive of all

proper methods of care or exclusive of methods of care

reasonably directed toward obtaining the same results.

The ultimate judgment regarding the appropriateness of

any speciﬁc management decision must be made by the

treating physician in light of all of the circumstances pres-

ent in the care of the patient in question.

STATEMENT OF THE PROBLEM

Squamous cell cancers of the anal canal and perianal re-

gion remain one of the least common malignancies aris-

ing from the alimentary tract. As of 2016, it is estimated

that 8200 new cases of squamous cell cancers of the anus

were diagnosed in the United States, with 1.7 times as

many women as men affected.

Within this same time pe-

riod, ≈1100 patients were estimated to have died of anal

cancer, with cancer deaths among women being 1.4 times

the number observed among men. Although squamous

cancers of the anus remain relatively rare GI malignan-

cies, 2 factors have nonetheless focused greater attention

toward this disease. The ﬁrst is the observation that the

frequency of squamous cancers of the anus has increased

in the United States from the 1970s through the 2000s,

with a notable increase in incidence among men, and, in

particular, black men.

In addition, given the inverse re-

lationship between stage of disease and survival,

studies

using population-level data suggest that earlier detection

may improve survival from anal cancer, which makes anal

cancer an important and treatable public health concern.

Supplemental digital content is available for this article. Links to the

digital ﬁles are provided in the HTML and PDF versions of this article

on the journal’s Web site (www.dcrjournal.com).

Earn Continuing Education (CME) credit online at cme.lww.com.

Links to search strategies: See search strategies for anal dysplasia, HPV

vaccination, chemoradiation for squamous cell cancer of the anus, sal-

vage APR, and metastatic disease in supplemental digital content at

http://links.lww.com/DCR/A639.

Funding/Support: None reported.

Financial Disclosure: None reported.

Correspondence: Scott R. Steele, M.D., Department of Colorectal

Surgery, Cleveland Clinic, 9500 Euclid Ave, A30, Cleveland, OH 44915.

E-mail: [email protected]

The American Society of Colon and Rectal Surgeons

Clinical Practice Guidelines for Anal Squamous Cell

Cancers (Revised 2018)

David B. Stewart, M.D.

• Wolfgang B. Gaertner, M.D., M.Sc.

• Sean C. Glasgow, M.D.

Daniel O. Herzig, M.D.

• Daniel Feingold, M.D.

• Scott R. Steele, M.D.

Prepared on Behalf of the Clinical Practice Guidelines Committee of the American Society of Colon and Rectal Surgeons

1 Department of Surgery, University of Arizona, Tucson, Arizona

2 Division of Colorectal Surgery, University of Minnesota, Minneapolis, Minnesota

3 Division of Colorectal Surgery, Washington University School of Medicine, St. Louis, Missouri

4 Division of Colorectal Surgery, Columbia University, New York, New York

5 Division of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio

Dis Colon Rectum 2018; 61: 755–774

DOI: 10.1097/DCR.0000000000001114

CLINICAL PRACTICE GUIDELINES

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

756

The second factor that has resulted in a paradigm shift in

understanding the etiology of anal cancer is the discovery

that the human papilloma virus (HPV), especially HPV

serotypes 16 and 18,

is the primary cause of squamous

cancers of the anus,

6,7

making anal cancer a sequela of a

sexually transmitted disease. This aspect of anal carcino-

genesis reinforces the concept that it is a potentially pre-

ventable disease and that if evidence-based screening and

preventative measures were developed and consistently

applied, decreases in cancer-related deaths would follow.

The modiﬁable risk of death from anal cancer is further

underscored by large studies that have documented that

≈50% of patients with anal cancer present with localized,

node-negative disease, which is associated with high cure

rates; one third of patients will present with node-positive

disease, whereas only 10% to 15% will present with dis-

tant metastases.

Thus, even without effective preventative

measures, the majority of patients with anal cancer are po-

tentially curable at the time of diagnosis and treatment.

The multiple risk factors associated with developing

squamous cancers of the anus are well documented and

can be grouped into the 2 broad categories of HPV and

immunosuppression, although there is also an association

between these categories as well. Among the HPV-related

risk factors include lifetime number of sexual partners,

a history of previous sexually transmitted diseases of any

kind,

a history of anogenital warts,

anoreceptive in-

tercourse,

and a history of cervical, vaginal, or vulvar

cancer.

Risk factors related to immunity include a di-

agnosis of HIV,

autoimmune disorders such as lupus

and sarcoidosis,

and being the recipient of a solid organ

transplant.

Female sex

and cigarette smoking

are also

associated with developing anal malignancies.

ANATOMIC CONSIDERATIONS AND TERMINOLOGY

The management of anal cancers requires a multidisci-

plinary approach, and the unfamiliarity of nonsurgical

disciplines with anorectal anatomy can create ambiguity

in describing the location and the clinical stage of anal

cancers across disciplines. The anal canal, as viewed by

colorectal surgeons, is ≈4 to 5 cm in length beginning at

the distal rectum, where the mucosa blends into the anal

transitional zone (ATZ) epithelium, which then transi-

tions to nonkeratinized squamous epithelium as it further

transitions into keratinized perianal skin at the anal verge.

An ATZ, located several millimeters proximal to the den-

tate line and extending for 0.5 to 1.5 cm in length, repre-

sents a region of naturally occurring intestinal metaplasia,

representing a transition from the columnar epithelium of

the distal rectum to the modiﬁed squamous epithelium of

the anal canal, referred to as anoderm. Because of the pres-

ence of metaplasia in the ATZ, this region is particularly

susceptible to HPV infection.

In addition, the variety of

tissue types in the ATZ have been associated with a num-

ber of subtypes of squamous cancers of the anus of both

keratinizing and nonkeratinizing histologies. Although

there were previous efforts to distinguish between histo-

logical subtypes of anal cancer, all of these subtypes are

now grouped together, because multiple histological vari-

ants can exist within the same malignancy,

and because

the natural history and survival of these subtypes are simi-

lar when stratiﬁed by treatment and cancer stage.

Because the anatomic landmarks of the anus will not

be easily identiﬁable by nonsurgical providers who are also

untrained in techniques such as anoscopy and proctosco-

py, a simpliﬁed taxonomy

has been suggested. An anal

canal cancer would be any lesion that cannot be complete-

ly visualized with distraction of the gluteal cheeks, whereas

a perianal (which replaces the term anal margin) lesion

can be completely visualized with distraction of the gluteal

cheeks, and that is still within 5 cm of the anal oriﬁce. Any

lesion >5 cm from the anal oriﬁce would be classiﬁed as a

skin lesion and would not be considered related to the GI

tract.

Confusion often arises over the various pathology

terms commonly used to describe lesions involving the

anus and perianal skin. The Lower Anogenital Squa-

mous Terminology project uniﬁed terminology for all

HPV-related squamous precursor lesions with a 2-tiered

nomenclature system.

22,23

This system simply designates

noninvasive pathology as either low-grade or high-grade

squamous intraepithelial lesions (LSILs and HSILs) based

on histological ﬁndings such as mitotic activity, depth of

dermal involvement, and abnormalities in squamous cell

differentiation. LSILs include anal intraepithelial neopla-

sia (AIN) 1, whereas HSILs encompass AIN-2 and AIN-

3 designations. The distinction between condylomas and

LSILs is somewhat arbitrary; condylomas generally appear

as bland exophytic, papillary proliferations with viral cy-

topathic changes, whereas LSILs tend to be ﬂat lesions.

Older terms such as Bowen’s disease should no longer be

used. Throughout this Clinical Practice Guideline, the

terms LSIL and HSIL will be used, although reference to

AIN may appear when directly quoting published research

ﬁndings.

This guideline only discusses the management of

premalignant and malignant squamous neoplasms of the

anus and perianal region, excluding other, rarer malignan-

cies. The abbreviation SCC will be used to refer to squa-

mous cell cancers.

METHODS

These guidelines were built on the most recent Ameri-

can Society of Colon and Rectal Surgeons Practice Pa-

rameters for Anal Squamous Neoplasms, published in

2012.

An organized search of MEDLINE, PubMed,

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

757

Embase, and the Cochrane Database of Collected Re-

views was queried June 2015 through January 2018,

searching for relevant publications with no limitations

regarding date of publication. Retrieved publications

were limited to the English language, but no limits on

year of publication were applied. The search strate-

gies were based on the key words anal cancer and anal

squamous cancer as primary search terms, with addi-

tional, key-word searches including AIN, anal intraep-

ithelial neoplasia, Nigro protocol, anal HPV, LSIL, and

HSIL. Searches were also performed based on various

treatments for anal cancers, including “anal cancer

AND radiation,” “anal cancer AND chemoradiother-

apy,” “anal cancer AND surgery,” “anal cancer AND

abdominoperineal resection,” “anal cancer AND anal

dysplasia,” and “anal cancer and lymphadenectomy.”

Directed searches of the embedded references from

the primary articles were also performed in certain

circumstances. Prospective randomized controlled tri-

als (RCTs) and meta-analyses were given preference in

developing these guidelines. The final grade of recom-

mendation was performed using the Grades of Recom-

mendation, Assessment, Development, and Evaluation

system (Table 1).

Premalignant Neoplasms of the Anal Canal and

Perianal Region

Patients at increased risk for anal squamous neoplasms

should be identiﬁed by history, physical examination,

and laboratory testing, noting that the risk is higher in

HIV-positive individuals, men who have sex with men

(MSM), and women with a history of cervical dysplasia.

Grade of Recommendation: Strong recommendation

based on moderate-quality evidence, 1B.

Multiple large (300- to 1200-patient) cohort studies have

identiﬁed risk factors for anal dysplasia and cancer.

26,27

A systematic review and meta-analysis noted that the

pooled prevalence of HPV-16 in HIV-positive MSM was

35.4%.

The prevalence of AIN was 29.1%, and the inci-

dence of anal cancer was 45.9 per 100,000 men. For HIV-

negative MSM, the prevalence of HPV-16 was 11.8%, the

prevalence of AIN was 21.5%, and the incidence of anal

cancer was 5.1 per 100,000 men. A cohort of 171 HIV-

positive women noted that 12.9% had HSILs.

Cervi-

cal dysplasia can also guide risk assessment in women; a

population-based study of 89,018 women with cervical

HSILs matched with control subjects without cervical

dysplasia demonstrated an increased rate of anal cancer

TABLE 1. Grade scoring system

Description Benet vs risk and burdens

Methodologic quality of

supporting evidence Implications

1A Strong recommendation,

High-quality evidence

Benets clearly outweigh risk

and burdens or vice versa

RCTs without important

limitations or overwhelming

evidence from observational

studies

Strong recommendation, can

apply to most patients in

most circumstances without

reservation

1B Strong recommendation,

Moderate-quality

evidence

Benets clearly outweigh risk

and burdens or vice versa

RCTs with important limitations

(inconsistent results,

methodologic aws, indirect

or imprecise) or exceptionally

strong evidence from

observational studies

Strong recommendation, can

apply to most patients in

most circumstances without

reservation

1C Strong recommendation,

Low- or very-low–quality

evidence

Benets clearly outweigh risk

and burdens or vice versa

Observational studies or case

series

Strong recommendation but

may change when higher-

quality evidence becomes

available

2A Weak recommendation,

High-quality evidence

Benets closely balanced with

risks and burdens

RCTs without important

limitations or overwhelming

evidence from observational

studies

Weak recommendation, best

action may dier depending

on circumstances or patient

or societal values

2B Weak recommendations,

Moderate-quality

evidence

Benets closely balanced with

risks and burdens

RCTs with important limitations

(inconsistent results,

methodologic aws, indirect

or imprecise) or exceptionally

strong evidence from

observational studies

Weak recommendation, best

action may dier depending

on circumstances or patient

or societal values

2C Weak recommendation,

Low- or very-low–quality

evidence

Uncertainty in the estimates of

benets, risks, and burdens;

benets, risks, and burdens

may be closely balanced

Observational studies or case

series

Very weak recommendations;

other alternatives may be

equally reasonable

Adapted with permission from Chest 2006;129:174–181.

RCT = randomized controlled trial.

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

758

(relative risk = 6.68 (95% CI, 3.64–12.25)) and HSILs

(relative risk = 4.97 (95% CI, 3.26–7.57)).

Standardized nomenclature with a 2-tiered system

should be used. Biomarkers, including p16, should be

used selectively to clarify equivocal high-grade lesions.

Grade of Recommendation: Strong recommendation

based on low- or very-low–quality evidence, 1C.

There are advantages in standardizing terminology in de-

ﬁning the disease and treatments. The 2-tiered system

22,23

deﬁned in 2012 provides the most appropriate system for

standardizing deﬁnitions. Two retrospective studies have

shown that there can be inconsistent interrater reliability

when examining histology specimens.

Evidence support-

ing this 2-tiered system is based in part on 1 prospective

blinded study that reported that interrater reliability for

cytology using a 2-tiered system was 85% and that p16

staining and HPV oncogene messenger RNA analysis im-

proved the ability to come to a diagnostic consensus.

Individuals with anal dysplasia should be followed

at regular intervals with a history, physical examina-

tion, and a discussion of screening options. Grade of

Recommendation: Weak recommendation based on

moderate-quality evidence, 2B.

Prevention of cervical cancer with screening for precan-

cerous lesions has been proven effective.

Whether a simi-

lar program of screening and destruction of precancerous

anal lesions will lead to reductions in anal cancer is a mat-

ter of considerable debate. A 2012 systematic review and

meta-analysis suggested that, as part of their natural his-

tory, rates of progression to anal cancer are substantially

lower than those observed for cervical cancer.

Regardless

of which, if any, intensive screening program is selected,

individuals with anal dysplasia should have a periodic of-

ﬁce visit to assess for any new or modiﬁable risk factors,

including a digital anorectal examination. Even in an in-

tensive screening program, nearly all the cancers that de-

veloped were detectable on digital examination.

It is not clear that screening will prevent a cancer from

occurring, but there is evidence that cancers detected dur-

ing a screening program are identiﬁed at an early stage.

Multiple cohort studies have shown progression from low-

grade to high-grade dysplasia and from dysplasia to cancer

even under regimented surveillance. A cohort of 91 HIV-

positive patients treated for anal dysplasia followed for >1

year showed that 75.8% had recurrent dysplasia, 46.0%

progressed to high-grade dysplasia, and 2.3% developed

anal cancer.

Studies of 4 cohorts of patients in intensive

treatment programs have separately estimated the devel-

opment of cancer despite treatment, although all recorded

the risk differently. One estimated the rate of progression

to cancer at 6.9 cases per 100 person-years of follow up,

another estimated the Kaplan–Meier probability of SCC

at 3 years at 1.97%,

a third estimated the duration to de-

velopment of SCC at 57 to 62 months,

and a fourth esti-

mated the 5-year cumulative incidence of SCC at 1.70%.

There is consensus among experts that an HSIL is the

precursor to invasive cancer.

33,38

What remains unclear

is whether screening to identify and ablate premalignant

lesions will decrease the incidence of SCC. Nevertheless,

even if the progression to cancer cannot be halted, early

diagnosis of a cancer justiﬁes follow-up, and a history and

examination to identify and treat visible and palpable le-

sions and/or a discussion of screening options is justiﬁed.

Screening with anal cytology (or anal Papanicolaou (Pap)

tests) may be considered in high-risk populations as part

of a comprehensive screening program, but the sensitivity

and speciﬁcity of the test do not support its use for uni-

versal screening. Grade of Recommendation: Weak rec-

ommendations based on moderate-quality evidence, 2B.

Similar to cervical Pap smear cytology, a swab or brush

sample from the anal canal to include the ATZ can be

evaluated for cytological evidence of dysplasia. Although

the data demonstrating effectiveness for cervical cancer

screening and prevention are well founded, substantial

efforts to prove its role in anal cancer screening have not

been conclusive. Because screening tests perform better as

the prevalence of a condition is higher, screening a higher-

risk population will be more effective. Most studies screen

high-risk individuals, including MSM, HIV-positive per-

sons, and/or women with a history of cervical dysplasia.

Results from studies that have performed both anal cytol-

ogy and histologic evaluation are shown in Table 2.

12,29,39–52

The sensitivity and speciﬁcity are limited, because the gold

standard is the ﬁnding of HSILs on biopsies. Currently

the ability of anal cytology to identify patients at risk for

dysplasia is inconclusive, and an association between anal

cytology and reduced rates of anal cancer has not been dem-

onstrated. The decision to perform anal Pap tests should be

a shared decision with the patient, including a discussion

about how abnormal tests will be further evaluated.

HPV testing may be used as an adjunct to screening for

anal cancer. Grade of Recommendation: Weak recom-

mendations based on moderate-quality evidence, 2B.

The presence of HPV, especially subtypes 16 and 18, is

associated with the majority of anal cancers. Biomarkers

screen for the presence of high-risk HPV to estimate the

risk of dysplasia. The main limitation to this strategy is

the high prevalence of HPV in the high-risk population.

Currently available options include HPV DNA testing,

HPV DNA genotyping for HPV-16 and HPV-18, HPV-E6/

E7 mRNA testing, and p16/Ki-67 immunostaining based

on either anal cytology or biopsy. P16 is a tumor suppres-

sor gene product that indicates HPV integration into the

host genome. The Lower Anogenital Squamous Terminol-

ogy guidelines recommend the use of p16 in borderline

HSIL/LSIL cases, with strong positive staining leading to

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

759

Table 2. Studies of anal cytology and histologic evaluation for squamous intraepithelial lesions

Study Location

No./type of

patient

Anal cytology

ndings

Anal biopsy

ndings

Sensitivity/specicity for

cytology detecting HSIL

Jin et al,

2017 Sydney, NSW, Australia 617 MSM Negative 41.0%

ASC-US 17.5

LSIL 8.0%

ASC-H 15.0%

HSIL 18.5%

Negative 29.6%

LSIL 31.0%

HSIL 39.0%

SCC 0.2%

Sensitivity 83.2%

Specicity 52.4%

PPV 45.8%

NPV 86.6%

Schoeld et al,

2016

Manchester,

United Kingdom

284 MSM Negative 56%

Inadequate 2.1%

LSIL 31.4%

HSIL 10.5%

Normal 4.5%

AIN-1 54.9%

AIN-2 31.7%

AIN-3 7.6%

SCC 1.3%

Sensitivity 76.5%

Specicity 54.6%

PPV 45.8%

NPV 86.6%

Heard et al,

2015 Multicenter 171 HIV-positive women Negative 70.7%

ASC-US or LSIL 18.7%

ASC-H or HSIL 10.0%

SCC 0.6%

Normal 59.2%

Benign 20.7%

LG-AIN 10.7%

HG-AIN 5.9%

SCC 0.6%

Cheng et al,

2015 Taiwan 196 HIV-positive men Negative 63.8%

ASC-US 16.8%

LSIL 14.8%

HSIL 4.6%

HG-AIN 7.1% Sensitivity 64.0%

Specicity 66.0%

PPV 12.7%

NPV 96.0%

Sendagorta

et al,

2014

Spain 298 HIV-positive MSM Negative 60.2%

ASC-US 5.7%

LSIL 24.1%

HSIL 10%

Normal 19.3%

Benign 10.9%

AIN-1 14.3%

AIN-2 35.3%

AIN-3 20.2%

Incomplete data

Botes et al,

2013 Australia 262 HIV-positive MSM Negative 23.0%

ASC-US 15.8%

ASC-H 9.6%

LSIL 39.9%

HSIL 4.5

No biopsy 11.9%

Benign 19.7%

LG-AIN 13.9%

HG-AIN 54.5%

Incomplete data

Wentzensen

et al,

2012

San Francisco, California 363 HIV-positive patients Negative 30.8%

ASC-US 20.1%%

ASC-H 7.4%

LSIL 18.5%

HSIL 16.5%

No biopsy 19.3%

Benign 23.4%

AIN-1 34.7%

AIN-2 15.2%

AIN-3 6.9%

Williams et al,

2010 Australia 154 patients Negative 5.4%

ASC-US 18.7%

ASC-H 1.2%

LSIL 47.3%

HSIL 27.4%

Benign 11.6%

LSIL 50.0%

HSIL 38.6

Sensitivity 96.0%

Specicity 14.0%

PPV 89.0%

NPV 31.0%

Salit et al,

2010 Toronto, Ontario,

Canada

401 HIV-positive MSM Negative 33.0%

ASC-US 12.0%

LSIL 43.0%

HSIL 12.0%

Normal 59.2%

Benign 32.0%

LG-AIN 43.0%

HG-AIN 25.0%

Sensitivity 84.0%

Specicity 39.0%

NPV 88.0%

PPV 31.0%

Nathan et al,

2010 London,

United Kingdom

395 patients Negative 32.6%

ASC-US 26.7%

LSIL 32.6%

HSIL 8.0%

Normal 24.2%

LG-AIN 50.2%

HG-AIN 25.6%

Sensitivity 81.0%

Specicity 37.0%

NPV 85.0%

PPV 30.0%

Fox et al,

2005 London,

United Kingdom

99 MSM Negative 26.0%

LSIL 59.0%

HSIL 15.0%

Normal 16.0%

AIN-1 18.0%

AIN-2 37.0%

AIN-3 26.0%

Sensitivity 83.0%

Specicity 38.0%

NPV 86.0%

PPV 33.0%

Arain et al,

2005 Los Angeles, California 198 patients Negative 31.7%

ASC-US or LSIL 55.2%

ASC-H or HSIL 13.1%

Normal 18.3%

AIN-1 21.1%

AIN-2 35.2%

AIN-3 25.4%

Sensitivity 98.0%

Specicity 50.0%

(Continued)

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

760

an HSIL diagnosis and weak or absent staining supporting

an LSIL diagnosis. The use of p16 staining, or any of the

biomarkers, in a screening setting is less clear.

Two prospective studies have compared anal cytology

with HPV testing, as have multiple retrospective cohorts.

The ANALOGY trial prospectively evaluated screen-

ing with cytology, high-risk HPV typing, and high-reso-

lution anoscopy (HRA). With HPV testing only 59% of

HSILs would have been detected.

The Australian study

used high-risk HPV viral load and high-risk HPV-E6/E7

mRNA, as well as cytology and HRA.

Compared with

cytology for the detection of HSIL, HPV testing showed

similar sensitivity and improved speciﬁcity for the detec-

tion of HSILs, especially in the HIV-negative group.

HRA may be considered as a screening option for pa-

tients at high risk for cancer when performed by cli-

nicians with appropriate training in the procedure.

Recommendation: Weak recommendation based on

moderate-quality evidence, 2B.

HRA is a procedure performed in the ofﬁce or in the op-

erating room using magniﬁcation and topical agents such

as acetic acid and Lugol’s solution to identify, biopsy, and

ablate lesions not visible by conventional examination or

anoscopy. The procedure can be more cost-effective if per-

formed in the ofﬁce. In addition, because it is superior to

cytology or HPV testing in identifying HSILs, HRA may

be more cost-effective than other strategies; the cost per

HSIL found has been estimated to be $809.39. A prospec-

tive screening study of high-risk MSM evaluated all 3

modalities of HPV testing, cytology, and HRA.

In a co-

hort of 284 MSM, AIN-3 was detected in 17 patients, with

screening HRA ﬁnding 16, HPV-16/18 testing ﬁnding 10,

any HPV testing ﬁnding 16, high-grade cytology detecting

3, and any abnormal cytology detecting 12 subjects. How-

ever, only 15% of the cohort tested negative for HPV, rep-

resenting a methodologic weakness in this study. Cytology

missed nearly one third of high-risk lesions, suggesting

that HRA would have the most clinical use for screening.

The effectiveness of HRA to prevent the progression

of dysplasia or development of cancer has been evaluated

in retrospective cohort studies. A retrospective review of

246 patients treated with HRA-targeted destruction of

HSIL/LSIL over a 10-year period was published in 2008.

A recurrent HSIL was seen in 57% of patients at an aver-

age of 19 months. Despite treatment, 1.2% progressed to

invasive cancer.

A cohort of 727 MSM followed for a median of 2.2 years

was published in 2014. With ablation of all HRA-identiﬁed

lesions and with regular follow-up, the rate of recurrence at

1 year was 53% in HIV-positive patients and 49% in HIV-

negative patients. Over the follow-up period, 5 patients devel-

oped cancer, with the probability of cancer 1.97% at 3 years.

There are few comparisons of HRA with other treatment

strategies. A retrospective review of 424 patients compared

HRA with expectant management in 2 cohorts, one treated

by 3 clinicians who followed patients with expectant man-

agement and the other treated by 2 clinicians who followed

patients with HRA.

Anal cancer occurred in 1 of the HRA

patients and 2 of the expectant management patients. The

5-year progression rate was similar in the 2 cohorts. Selection

bias and the possibility for type II error limit these ﬁndings.

Papaconstantinou

et al,

2005

Dallas, Texas 47 patients Negative 23.4%

ASC-US or LSIL 57.4%

ASC-H or HSIL 14.9%

SCC 4.3%

Normal 42.6%

AIN-1 17.0%

AIN-2 12.8%

AIN-3 21.3%

SCC 6.4%

Sensitivity 42.0%

Specicity 96.0%

Mathews et al,

2004 San Diego, California 1732 patients Negative 43.2%

ASC-US 34.1

LSIL 15.3%

HSIL 7.5%

Incomplete data Sensitivity 85.0%

Specicity 56.0%

Panther et al,

2004 Boston, Massachusetts 153 MSM Negative 12.4%

ASC-US 19.6%

LSIL 47.1%

HSIL 20.9%

Normal 21.6%

AIN-1 37.3%

AIN-2 14.4%

AIN-3 25.5%

SCC 1.3%

Sensitivity 47.0%

Specicity 90.0%

Palefsky et al,

1997 San Francisco, California 407 patients Negative 72.4%

ASC-US 15.1%

LSIL 12.1%

HSIL 0.4%

Normal 11.9%

LG-AIN 79.3%

HG-AIN 8.9%

Sensitivity 69.0%

Specicity 59.0%

MSM = men who have sex with men; ASC-US = atypical squamous cells of undetermined signicance; ASC-H = atypical squamous cells, cannot exclude high-grade squa-

mous intraepithelial lesion; LSIL = low-grade squamous intraepithelial lesion; HSIL = high-grade squamous intraepithelial lesion; SCC = squamous cell cancers; AIN = anal

intraepithelial neoplasia; LG = low-grade; HG = high-grade; PPV = positive predictive value; NPV = negative predictive value.

Table 2. Continued

Study Location

No./type of

patient

Anal cytology

ndings

Anal biopsy

ndings

Sensitivity/specicity for

cytology detecting HSIL

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

761

Performing HRA requires specialized training and on-

going practice to perform good-quality examinations.

55,56

In addition, patient compliance, patient tolerance, and the

risk of over treatment have led some clinicians to wait to

start performing HRA until additional data are available.

Although HRA effectively identiﬁes HSIL, whether HRA

with ablation of HSIL can reduce the incidence of cancer

or whether it can do so more consistently than conven-

tional anoscopy remains unclear.

Topical imiquimod, ﬂuorouracil, trichloroacetic acid

and cidofovir with close long-term follow-up are each

options for the treatment of LSIL or HSIL. Grade of

Recommendation: Weak recommendation based on

moderate-quality evidence, 2B.

Two randomized trials and 1 prospective cohort study have

evaluated imiquimod. A placebo-controlled RCT of 64 HIV-

positive patients with HSILs who were followed with HRA

suggested superior clearance of HSILs with imiquimod

(42.9% vs 4.0%).

With a median follow-up of 33 months,

61% showed a sustained absence of HSILs. An RCT compar-

ing imiquimod with topical ﬂuorouracil and electrocautery

found that 24% of HSILs had resolved and 11% had a partial

response with imiquimod.

Although electrocautery had a

statistically signiﬁcant improvement in response when the

p value was calculated for the 3 treatment options, the dif-

ference was not signiﬁcant if imiquimod and electrocautery

were compared head to head. A third prospective cohort

study evaluated imiquimod 5 days per week and found that

the overall response rate for HSILs was 66%.

Two retrospective studies have evaluated topical ﬂuoro-

uracil. A retrospective review of 46 patients with HSILs or

LSILs showed that 57% responded to topical ﬂuorouracil,

with 39% having a complete response.

A second review

of 11 patients with dysplasia (although only 5 had HSILs)

showed a decrease in dysplasia in 6 (55%) of 11 patients.

Two retrospective cohort studies have examined the use

of trichloroacetic acid. A review of 98 HSILs from 72 patients

demonstrated that 28.7% of lesions had resolution or down-

grading to LSILs on follow-up, although recurrence occurred

in 20.8% of the lesions.

A review of 54 men showed that,

on a per-lesion basis, 72% of HSILs cleared to LSIL or less.

Cidofovir has been evaluated in 1 prospective pilot

study and 1 retrospective cohort study. The pilot study in-

cluded 16 HIV-positive patients with HSILs and revealed

a complete response rate of 10 (62.5%) of 16, although

2 (20.0%) of 10 had recurrent HSILs at the 24-week end

point of the study.

A small cohort of 24 patients with

HSILs demonstrated that 51% had responsive disease,

with a complete response observed in 15% of patients.

Ablative treatments with conventional anoscopy or

HRA are appropriate therapies for HSILs. Grade of

Recommendation: Weak recommendation based on

moderate-quality evidence, 2B.

If HRA is used as the primary screening modality, ablative

therapies can be used as ﬁrst-line treatment for dysplasia.

A prospective cohort of 98 patients with HSILs treated

with infrared coagulation (IRC) showed that 74% had no

additional evidence of HSILs on short-term follow-up.

There was a comparison to expectant management in that

study, but the control group was derived from patients who

delayed or declined treatment, and patients who missed

follow-up were excluded. In light of these limitations, the

ﬁndings in this study are best viewed as a cohort treated

with IRC. Three reviews have been published from a single

center, and it is unclear how much overlap exists.

67–69

Find-

ings from the most recent review, a retrospective review

of 96 MSM with HSILs treated with ≥1 IRC showed that

82% of HIV-positive and 90% of HIV-negative individu-

als were free from HSILs, but recurrence rates were high

in the study, and nearly one third of patients were lost to

follow-up.

A retrospective review of 78 HSILs in 68 HIV-

positive MSM showed 64% efﬁcacy per treated lesion.

retrospective review of 66 patients with HSILs treated with

IRC reported that only 13% had recurrent HSILs at 1 year

of follow-up.

Electrocautery ablation was reviewed in a cohort of

232 MSM with HSIL.

Initial clearance rates were high

(75%–80%), but recurrences were common (53%–61%),

and 1 patient in the cohort developed cancer despite treat-

ment. A cohort of 83 patients treated for HSIL with elec-

trocautery found a complete or partial response in 66.2%.

With a mean follow-up of 12.1 months, 25.4% of patients

had a high-grade recurrence. A single-center review of

3 ablative techniques, electrocautery, IRC, or laser treat-

ments, showed no differences in the rate of recurrence.

One prospective RCT compared imiquimod, topical

ﬂuorouracil, and electrocautery in HIV-positive MSM

with conﬁrmed AIN.

Resolution of AIN was achieved

in 24% of patients in the imiquimod group, 17% of the

topical ﬂuorouracil group, and 39% of the electrocautery

group (p = 0.008 for electrocautery vs ﬂuorouracil; p =

0.10 for electrocautery vs imiquimod).

Vaccination against HPV in men and women under

age 26 years for primary prevention is typically recom-

mended. Vaccination of individuals with anal dysplasia

for secondary prevention of dysplasia and cancer is not

recommended. Grade of Recommendation: Weak rec-

ommendation based on high-quality evidence, 2A.

The availability of bivalent, quadrivalent, and now non-

avalent vaccines has created considerable promise that the

next generation of individuals will be largely exempt from

HPV-related neoplasms. Although there are convincing

data for use of the vaccine in pre-exposure young individ-

uals, the off-label use of the vaccine in those with anal dys-

plasia is of considerable interest. A systematic review and

meta-analysis of the efﬁcacy of the vaccine in cervical dys-

plasia showed that it had no effect.

A systematic review

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

762

including all of the sites reported that 9 of 12 studies per-

formed in patients with active disease showed decreased

disease recurrence, but no study reported improved out-

comes without clinical disease.

However, enthusiasm for

the vaccine for secondary prevention or regression of dys-

plasia gained attention after a study of 602 MSM who were

randomly assigned to receive either the quadrivalent HPV

vaccine or placebo. Those who received the vaccine had

a lower rate of intraepithelial neoplasia, and the rate of

HSILs was reduced by 54%.

A comparative cohort study

of 202 patients with previous HSILs treated with or with-

out the quadrivalent vaccine demonstrated that vaccine

treatment was associated with decreased risk of recurrent

HSILs.

A prospective, randomized, National Institutes of

Health–funded trial including 574 patients has been com-

pleted and presented in abstract form, and the results are

available at clinicaltrials.gov (NCT01461096). The num-

ber of participants with biopsy-proven HSIL occurrences

and recurrences at 1 year or abnormal cytology at 1, 2, or

3 years was the same.

Patients who have been treated for anal dysplasia may

be observed without regular cytology, HPV testing, or

HRA; however, treatment of visible or palpable disease

should be offered. Grade of Recommendation: Weak

recommendation based on low or very low-quality

evidence, 2C.

Although it is generally accepted that HSIL is a precursor to

invasive cancer, there remain no studies that compare more

intensive screening and/or HRA protocols with ofﬁce exami-

nations, conventional anoscopy, and treatment of visible or

palpable disease. A review of 574 patients in an HRA pro-

gram showed that 24% of patients with HSIL had spontane-

ous regression to LSIL.

The progression to cancer is often

multifactorial, including contributions from medication

compliance, immunosuppression, HIV viral load, ongoing

exposure to HPV, smoking, and a variety of other factors.

In the largest prospective randomized US trial, which is

currently enrolling, the control arm of the study includes no

treatment of HRA-identiﬁed HSILs. The Topical or Ablative

Treatment in Preventing Anal Cancer in Patients With HIV

and Anal High-Grade Squamous Intraepithelial Lesions

trial (NCT02135419) will screen HIV-positive patients with

HRA and targeted biopsies. Previously untreated individu-

als who have HSILs identiﬁed will be randomly assigned to

treatment or monitoring. For patients who are treated, the

clinician decides whether the patient should have topical

treatment or ablative treatment. Patients with topical treat-

ment may receive imiquimod, ﬂuorouracil, or trichloro-

acetic acid. Patients with ablative treatment may have IRC,

electrocautery, or laser ablation. In the study, number and

frequency of the treatments is left to the discretion of the

treating physician. For patients who are observed, examina-

tions and cytology are performed every 6 months, with bi-

opsies of any visible lesions. Therefore, although screening

and preventative treatment remain controversial, expectant

management with treatment of visible or palpable disease

remains an option unless or until emerging evidence sug-

gests that screening and ablation of subclinical lesions are

beneﬁcial to reduce the incidence of anal cancer.

MALIGNANT NEOPLASMS OF THE ANAL CANAL

AND PERIANAL REGION

Pretreatment Evaluation

A disease-speciﬁc history and physical examina-

tion should be performed, emphasizing symptoms,

risk factors, and signs of advanced disease. Grade of

Recommendation: Strong recommendation based on

low-quality evidence, 1C.

Most patients present with a slow-growing mass involv-

ing either the anal canal or the perianal skin.

Pain and

bleeding are common, occurring in approximately half

of patients, although <20% of patients may be asymp-

tomatic.

10,79

Diagnosis of anal SCC may often be delayed,

mainly because of nonspeciﬁc anorectal symptoms, which

are frequently attributed to benign anorectal pathology,

such as hemorrhoids, in <70% to 80% of patients.

78,80

Pa-

tients with locally advanced anal cancers may also pres-

ent with foreign body sensation, symptoms related to

anal stenosis, and inguinal pain (commonly representing

inguinal lymph node metastases). Risk factors associated

with anal SCC include HPV infection; HIV seropositiv-

ity; a history of other HPV-related genital neoplasias,

such as cervical cancer; cervical intraepithelial neoplasia;

vulvar cancer; vulvar intraepithelial neoplasia; previous

sexually acquired diseases; cigarette smoking; anoreceptive

intercourse; multiple sexual partners; a history of solid-

organ transplant; and other forms of immunosuppres-

sion.

9,11,81–86

Because the incidence of anal cancer is higher

among men practicing anoreceptive intercourse, as well as

among patients positive for HIV, a high index of suspicion

should be maintained in these patients who present with

anorectal complaints.

Additional historical factors such

as previous radiation and inadequately controlled HIV

may limit chemoradiotherapy (CRT) and radical surgery

and are important variables to investigate at the time of

diagnosis.

Physical examination should focus primarily on ano-

rectal examination and evaluation of the inguinofemoral

nodes.

Digital anorectal examination should be performed

to identify the lesion location and to evaluate for ﬁxation

and/or the presence of invasion of local structures, such as

the vagina or the anal sphincter mechanism. Anoscopy or

proctoscopy with biopsy is essential to establish the size of

the lesion, to determine its location within the anal canal,

and to conﬁrm diagnosis. The presence of palpable inguinal

lymphadenopathy can suggest the need for ﬁne-needle aspi-

ration or core biopsy to conﬁrm malignant involvement and

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

763

to help guide radiation planning. In general, metastatic dis-

ease is difﬁcult to detect on physical examination, although a

complete physical examination should be performed to help

identify any potential sites of distant spread that may war-

rant additional evaluation. All patients with a new diagnosis

of anal SCC should undergo basic laboratory studies, in-

cluding a complete blood count, renal and hepatic function

tests, and an assessment of their HIV status if not already

known. Women should undergo a cervical Pap test, and men

should undergo penile examination to exclude premalignant

or malignant lesions. Although the immunohistochemical

expression of p16 and Ki-67 has been shown to correlate

with the degree of anal intraepithelial neoplasia,

their role

in the evaluation of anal SCC is still being deﬁned.

Endoscopic and radiologic evaluation should be per-

formed to help determine tumor extension and assess for

metastatic disease. Grade of Recommendation: Strong

recommendation based on low-quality evidence, 1C.

Biopsy should be performed under direct vision or with

anoscopy. Although anal cancer is not a risk factor for the de-

velopment of colon cancer, colorectal neoplasms have been

demonstrated in <15% of patients with anal cancer; there-

fore, colonoscopy should be performed to rule out synchro-

nous colorectal neoplasms.

88,89

A CT of the chest, abdomen,

and pelvis with intravenous contrast enhancement should

be performed to evaluate for distant metastatic disease and

lymphadenopathy, including evaluating the inguinal lymph

nodes, which may warrant biopsy in the setting of clinical or

radiographic abnormalities.

Because SCC can metastasize

to the brain, a CT of the head may be performed if the patient

has symptoms or signs of central nervous system involve-

ment. With CRT being the mainstay of treatment for anal

SCC, accurate anatomic imaging of the primary tumor is

highly recommended, because it enables optimal radiother-

apy planning and allows for posttreatment comparisons. En-

doanal ultrasound (EAUS) and MRI are at present the 2 most

accepted modalities for determining primary tumor depth,

anal sphincter involvement, and perirectal lymph node in-

volvement.

91,92

There is only 1 study to date

that directly

compares EAUS (using 2-dimensional imaging) with MRI in

the primary staging of anal SCC, with comparable results in

assessing primary tumor size and perirectal lymph node sta-

tus. Although EAUS is traditionally considered to be superior

to MRI for small superﬁcial tumors, this has not been report-

ed in the current literature. Additional considerations with

EAUS include that it is operator dependent and may cause

signiﬁcant discomfort in patients with anal stenosis.

2-[

F] Fluoro-2-deoxy-D-glucose positron emission to-

mography (PET)/CT may be considered as an adjunct

radiologic study in the staging of anal SCC, although it

does not replace CT scanning for clinical staging. Grade

of Recommendation: Strong recommendation based on

low-quality evidence, 1C.

Staging for SCC of the anal canal focuses on size of the pri-

mary lesion and locoregional lymph node involvement. As

such, clinical evaluation including size is critically impor-

tant to determine proper staging. The most widely used

clinical staging system is the American Joint Committee

on Cancer and International Union Against Cancer TNM

classiﬁcation (Table 3), which deﬁnes T stage by maxi-

mum tumor diameter. This staging system does not take

into account sphincter muscle and perianal skin involve-

ment or the presence of a perianal or anovaginal ﬁstula,

which are important prognostic factors that have not been

well studied in the era of modern CRT.

94–96

Although not typically a part of the routine evalua-

tion, 2-[

F] ﬂuoro-2-deoxy-D-glucose PET/CT has been

shown to identify distant metastases that are not detected

by physical examination or other imaging modalities in

17% to 25% of patients,

97,98

resulting in a reported change

in treatment (ie, radiotherapy) in <19% of cases.

99–101

addition, retrospective studies evaluating the role and im-

pact of PET/CT in anal SCC have shown that metabolic

tumor volume at the primary tumor site, as well as hy-

permetabolic inguinal lymphadenopathy, correlates with

overall survival.

102–104

The measurement of metabolic

tumor volume at the primary cancer site, as well as with

potential pelvic and inguinal lymph node metastases, also

inﬂuences preradiation planning by radiation oncologists.

The primary treatment for all squamous cell cancers of

the anal canal, and for most perianal squamous cell can-

cers, is CRT. Grade of Recommendation: Strong recom-

mendation based on high-quality evidence, IA.

Before the initial case series by Nigro et al

105

describing

patients with squamous anal cancers treated with mul-

timodal neoadjuvant therapy, patients with these malig-

nancies were treated with abdominoperineal resection

(APR). The outcomes associated with primary APR were

dismal,

106,107

with locoregional recurrence rates as high

as 50% and 5-year survival rates ranging from 40% to

70%.

108,109

In addition, the morbidity of an APR during

this time period was signiﬁcant. By contrast, even with

the limitations of delivering radiotherapy in his day, Ni-

gro and colleagues provided follow-up data to his original

series,

110,111

culminating in an evaluation of 104 patients

with squamous cancers of the anus who were treated with

30 Gy of radiotherapy combined with 5-ﬂuorouracil (5-

FU) and mitomycin-C (MMC). In 97 patients, no gross

tumor remained. In this same series there were 31 patients

who underwent an APR regardless of whether there was

clinical evidence of tumor persistence, and 22 of these pa-

tients were completely free of any histological evidence of

cancer.

Currently, CRT is the standard of care for the treat-

ment of all anal canal squamous cell cancers and for all

perianal squamous cell cancers that are not well-differen-

tiated, node-negative, T1 lesions amenable to wide local

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

764

excision. Although there are slight variations in how ra-

diation is administered, there are certain principles that

should be followed for every patient.

112,113

A multiﬁeld

technique should be used to deliver a minimum radiation

dose of 45.0 Gy, which is typically delivered to the primary

cancer in 25 fractions, each of 1.8 Gy over an ≈5-week time

interval. The radiation ﬁeld should initially extend from

the border of L5 to S1, spreading distally to incorporate

the entire pelvis, including the anus and the inguinofemo-

ral nodes, terminating onto the perianal skin 2.5 cm distal

to the anus. Radiation oncologists should also make ef-

forts to reduce radiation exposure to the femoral heads be-

cause of the risk of avascular necrosis.

114

After the ﬁrst 30.6

Gy is administered, the additional 14.4 Gy of scheduled

radiation should be delivered with the cephalad aspect of

the radiation ﬁeld lowered to the distal aspect of the sac-

roiliac joints while also sparing the inguinal nodes from

additional treatment for those patients with no inguinal

nodal disease. In addition, for any lesions larger than a T1

cancer or for those that are node positive, a boost of 9 to

14 Gy to the primary tumor and to the involved nodes is

recommended. In this setting, the total dose of radiation

delivered would be 54 to 59 Gy.

The selection and doses of chemotherapeutic agents

for CRT can vary from among several options. Classically,

5-FU is infused at 1000 mg/m

on days 1 to 4 and days 29

to 32, with MMC administered in bolus form at 10 mg/

on days 1 and 29.

112

Alternatively, capecitabine, an oral

ﬂuoropyrimidine prodrug, can be substituted for 5-FU at

a dose of 825 mg/m

twice daily.

115,116

When capecitabine is

selected, the dose of MMC is often increased to 12 mg/m

at the discretion of the treating medical oncologist.

CRT is associated with signiﬁcant rates of acute toxic-

ity. In the Radiation Therapy Oncology Group (RTOG)

9811 study,

112

a total of 90% of patients treated with

MMC-based CRT experienced some form of GI toxicity,

ranging from nausea to vomiting and diarrhea. The inci-

dence of grade III or IV nonhematologic toxicity was 74%

in this group, whereas the incidence of severe long-term

toxic effects was 11%. This high incidence of signiﬁcant

toxicities has prompted investigations into alternative

CRT regimens, as discussed below.

Patients preparing for CRT need to be counseled re-

garding sexual and reproductive health choices. Both men

and women of child-producing ages should be counseled

regarding sperm and ova banking before the onset of

therapy. Women should be asked if they have undergone

a recent gynecologic examination with screening for cer-

vical HPV, given the frequent association between ano-

rectal HPV and HPV of the cervix. Female patients who

are planning on sexual activity at any point after CRT

should be counseled regarding the use of vaginal dilators

to prevent vaginal stenosis resulting in the inability for

coitus. These issues are easily and frequently overlooked

and should typically be included in pretherapy counsel-

ing to preserve quality of life for long-term survivors of

anal cancer.

Multimodal therapy involving chemotherapy combined

with radiotherapy provides superior locoregional con-

trol compared with treatment with radiotherapy alone.

Grade of Recommendation: Strong recommendation

based on high-quality evidence, IA.

Cancers with squamous histology are typically radiosensi-

tive, and with the initial implementation of radiation as

monotherapy for squamous cancers of the anus, a high rate

of locoregional disease control and avoidance of surgery

was documented with smaller, earlier-stage cancers.

117,118

With larger, bulkier cancers, however, persistence and

recurrence rates were frequently encountered, and this

raised questions regarding a possible role for chemothera-

py in combination with radiotherapy. The ﬁrst large study

to evaluate the role of multimodality therapy in anal can-

TABLE 3. American Joint Committee on Cancer and International

Union Against Cancer TNM classication of anal cancer

Primary tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis High-grade squamous intraepithelial lesion (previously

termed carcinoma in situ, Bowen disease, anal

intraepithelial neoplasia II–III, high-grade anal

intraepithelial neoplasia)

Tumor ≤2 cm

Tumor >2 cm but ≤5 cm

T3 Tumor >5 cm

T4 Tumor of any size invading adjacent organ(s), such as

the vagina, urethra, or bladder

Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in inguinal, mesorectal, internal iliac, or

external iliac nodes

N1a Metastasis in inguinal, mesorectal, or internal iliac lymph

nodes

N1b Metastasis in external iliac lymph nodes

N1c Metastasis in external iliac with any N1a nodes

Distant metastasis (M)

MX Distant metastasis cannot be assessed

cM0 No distant metastasis

cM1 Distant metastasis

pM1 Distant metastasis, microscopically conrmed

When T is... And N is... And M is...

Then the stage

group is...

Tis N0 M0 0

T1 N0 M0 I

T1 N1 M0 IIIA

T2 N0 M0 IIA

T2 N1 M0 IIIA

T3 N0 M0 IIB

T3 N1 M0 IIIC

T4 N0 M0 IIIB

T4 N1 M0 IIIC

Any T Any N M1 IV

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

765

cer was the United Kingdom Coordinating Committee on

Cancer Research Anal Cancer Trial (ACT I) Working Par-

ty.

119

In this trial, 585 patients were randomly assigned to

receive either 45 Gy of radiation in 20 to 25 fractions over

4 to 5 weeks or to receive the same form of radiotherapy

but with the addition of 5-FU and MMC. With a median

follow-up time of 42 months, 59% of the radiotherapy pa-

tients had experienced a local failure compared with 36%

of the CRT group, amounting to a 46% reduction in local

failure associated with the use of CRT. Similar rates of tu-

mor response were observed in both treatment groups at

6 weeks. Although the risk of death in the CRT arm was

lower, there was no difference in overall survival between

the 2 arms at 3 years after treatment. Not unexpectedly,

the CRT cohort was associated with a higher incidence

of early morbidity, whereas late adverse events related to

treatment occurred with similar frequency. This study was

instrumental in establishing CRT as the ﬁrst-line therapy

for squamous cancers of the anal canal. A recent analysis

of this original study population

120

has provided 13-year

follow-up, demonstrating that CRT is associated with 25.3

fewer locoregional recurrences and 12.5 fewer anal can-

cer–related deaths for every 100 patients treated with CRT

compared with every 100 patients treated with radiation

alone. In addition, although there was a 9.1% increase in

deaths unrelated to anal cancer during the ﬁrst 5 years af-

ter CRT, this increased risk of noncancer-related mortality

disappeared after 10 years. Local failure rates favored CRT

(57% vs 32%) at 5 years, as did colostomy-free survival at

5 years (37% vs 47%).

The year following ACT I, the European Organization

for Research and Treatment of Cancer Radiotherapy and

Gastrointestinal Cooperative Groups published a study

(22861)

121

evaluating the role of multimodality therapy

as compared with radiation alone for anal cancer. In this

randomized study, 110 patients were assigned to either 45

Gy followed by a boost of variable dosing depending on

tumor response versus the same radiation regimen com-

bined with 5-FU and MMC, the latter of which was pro-

vided as a bolus only on the ﬁrst treatment day. Patients in

the CRT arm experienced a complete response rate of 80%

compared with 54% in the radiation arm, with improved

locoregional control and with superior progression-free

and colostomy-free survival rates. As with the United

Kingdom Coordinating Committee on Cancer Research

study, there were no differences in overall survival rates at

3 years after treatment.

The combination of 5-FU and MMC in conjunction

with radiotherapy remains as ﬁrst-line multimodal

therapy for the treatment of squamous cancers of the

anus. Grade of Recommendation: Strong recommenda-

tion based on high-quality evidence, IA.

MMC has a significant toxicity profile, including he-

matologic toxicity in the form of bone marrow sup-

pression with neutropenia and thrombocytopenia,

pulmonary toxicity, and acute kidney injuries.

122

Be-

cause of earlier, albeit small, studies suggesting com-

parable oncologic outcomes and lower rates of toxicity

associated with omission of MMC, the RTOG 8704 tri-

123

was performed by the RTOG and the Eastern Co-

operative Oncology Group to evaluate whether MMC

could be removed from CRT while maintaining the

same disease control and cure rates. During this trial,

310 patients were randomly assigned to receive either

radiotherapy (ranging from 45.0 to 50.4 Gy) with 5-FU

infused for 4 days versus the same radiotherapy regi-

men combined with 5-FU and MMC at 10 mg/m

a bolus over 2 days. After treatment, biopsies yielding

histology positive for cancer did not differ to a statisti-

cally significant degree between either treatment arm

(15.0% vs 7.7%; p = 0.135). At 4 years after treatment,

colostomy rates (9% vs 22%; p = 0.002), colostomy

free-survival (71% vs 59%; p = 0.14), and disease-free

survival (73% vs 51%; p = 0.0003) favored the cohort

that received MMC. There was no difference in overall

survival, whereas toxicity was significantly higher in

the MMC cohort (23% vs 7% for grade 4 and 5 toxic-

ity; p < 0.001). Although toxicity with MMC was high-

er, the results of the study nonetheless supported the

inclusion of MMC in CRT compared with the use of

5-FU and radiation alone.

Although the net beneﬁt of including MMC with

5-FU and radiation was established early in the evolution

of multimodality anal cancer therapy, lingering concerns

regarding MMC-related toxicity lead to attempts to sub-

stitute MMC with other agents. Several important clinical

trials have evaluated whether cisplatin might offer im-

proved toxicity rates while providing comparable, or su-

perior, disease control. The ACT II trial,

124

which remains

the largest clinical trial on anal cancer to date, enrolled

patients with squamous cancers of the anus from a total

of 59 centers across the United Kingdom. Patients were

randomly assigned to 1 of 4 groups, receiving either MMC

or cisplatin, with 5-FU and radiotherapy (50.4 Gy) with or

without 2 infusions of maintenance chemotherapy con-

sisting of 5-FU and cisplatin provided at weeks 11 and 14.

A total of 940 patients were enrolled, with a median fol-

low-up of 5.1 years. Complete response rates were similar

in both MMC and cisplatin treatment groups at 26 weeks

after therapy, with similar incidences of treatment-related

toxicities. There was no signiﬁcant difference in 3-year

progression-free survival between the MMC and cisplatin

cohorts, and colostomy rates were similar between MMC-

and cisplatin-treated patients. Because of similar rates of

grade 3 and 4 adverse events, with no signiﬁcant difference

in complete response rates or progression-free survival,

this study concluded that ﬁrst-line therapy for squamous

cancers of the anus should continue as 5-FU and MMC

combined with radiotherapy.

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

766

A second major study investigating the benefit of

MMC versus cisplatin was published by Ajani et al

112

in the RTOG 9811 study, a multicenter RCT. Study

patients were randomly assigned to receive 5-FU and

MMC with 45 to 59 Gy of radiotherapy or to receive

induction 5-FU with cisplatin followed by CRT with

5-FU and cisplatin. A total of 644 patients were evaluat-

ed with a median follow-up time of 2.5 years. There was

no significant difference between the treatment arms

in terms of 5-year disease-free survival or 5-year over-

all survival; 5-year locoregional recurrence rates and

distant metastasis rates were also similar between the

groups. A significantly higher colostomy rate was asso-

ciated with the cisplatin treatment arm (10% vs 19%;

p = 0.02), whereas the MMC arm experienced a higher

incidence of hematologic toxicity. This study conclud-

ed that the routine use of cisplatin in place of MMC is

not recommended. A subsequent analysis of this same

study population was undertaken by Gunderson et al,

125

published in 2012, to determine the long-term effects

of MMC versus cisplatin on recurrence and survival. In

this analysis, both disease-free and overall survival were

actually improved in the MMC-treated group compared

with the cisplatin group, with a trend toward improved

colostomy-free survival and locoregional control. These

results strengthened the recommendations to include

MMC in first-line multimodality therapy for anal squa-

mous cancers.

The European Organization for Research and Treat-

ment of Cancer 22011-40014 trial

126

evaluated the role

of cisplatin not as a replacement for MMC but as a

substitute for 5-FU. In this study, 88 patients with ei-

ther node-negative cancers >4 cm in diameter or those

with node-positive disease were randomly assigned to

radiotherapy totaling 59.4 Gy, with a 2-week gap in ra-

diotherapy deliberately introduced in the middle of the

therapy period, combined with either MMC/cisplatin or

MMC/5-FU. The cisplatin-treated patients demonstrat-

ed a trend toward lower compliance with receipt of CRT.

Toxicity rates were similar between the groups, with the

exception of a higher incidence of grade 3 hematologic

toxicity in the cisplatin group. Survival analyses with

this trial were made difﬁcult because of median event-

free, overall, and progression-free survivals not being

reached. Despite this study concluding that the combi-

nation of MMC and cisplatin is promising, additional

data regarding this form of CRT are required before its

role can be determined.

The use of induction chemotherapy before CRT

has also been evaluated, with disappointing results.

The UNICANCER ACCORD 03 study

127

was a 4-arm,

prospective randomized trial designed to assess both

the role of induction chemotherapy consisting of 5-FU

on days 1 through 4 and days 29 through 32, and cis-

platin on days 1 and 29, before CRT, as well as to test

the effect of a higher dose applied to a radiation boost.

Patients were randomly assigned to the following: 1)

receive 2 cycles of induction chemotherapy, CRT, and

a standard-dose boost (15 Gy); 2) receive 2 cycles of

induction chemotherapy, CRT, and a high-dose boost

(20–25 Gy); 3) receive CRT and a standard-dose boost;

or 4) receive CRT and a high-dose boost. Of the 307

patients enrolled, 283 received a complete treatment

course, with a median follow-up of 50 months. No

benefit to either induction chemotherapy or high-dose

boost radiation was observed, with comparable partial

and complete tumor response rates, locoregional fail-

ure rates, and 3-year colostomy-free, event-free, and

overall survival. A recent small retrospective study (n =

38)

128

of patients with T4 anal cancers treated with 45

Gy of radiotherapy with concurrent 5-FU and cisplatin

(n = 27) versus patients treated with induction chemo-

therapy with 5-FU and cisplatin followed by CRT (n =

11) was conducted. There was no statistically signifi-

cant difference between the 2 groups based on 5-year

overall, disease-free, or relapse-free survival, although

5-year colostomy-free survival was much higher in the

group receiving induction chemotherapy (100% vs

38%; p = 0.0006), leading the authors to suggest that

induction chemotherapy has a role in the management

of T4 anal cancers. At this time, there is insufficient

high-quality data to support the use of induction che-

motherapy outside of a clinical trial.

No oncologic beneﬁt exists for providing radiation dos-

es >59 Gy. Grade of Recommendation: Strong recom-

mendation based on moderate-quality evidence, IB.

Once doses of radiotherapy exceed 40 Gy, the incidence

of radiation-related toxicities increases. There is good

evidence that the minimum dose of radiation for anal

squamous cancers should be 45 Gy, although the op-

timal dose is a matter of debate, in large part because

of different radiation delivery techniques and differ-

ent tumor stages included in the studies on this sub-

ject, all of which influence toxicity and response rates.

The data on optimal radiation dosing have either been

the subject of smaller and nonrandomized studies or

have been evaluated in randomized studies looking at

such issues as adjusting the dose of boost radiation to

the total dosage. The number of studies dedicated to

the subject are few, although 1 such study

129

consisted

of a small number (n = 69) of early stage Tis and T1

cancers. The study population was extremely hetero-

geneous, with 26 subjects undergoing local excision

before radiotherapy and with varying doses of exter-

nal beam radiotherapy, with or without brachytherapy,

with 8 patients treated with brachytherapy alone. The

study concluded, on the basis of local control and tox-

icity rates, that for T1 cancers a radiation dosing range

of 50 to 60 Gy was optimal. One of the only other ret-

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

767

rospective studies on this subject

130

included patients

with stage I to III disease, although with a study popu-

lation of only 43 subjects and with a median follow-up

of only 42 months. Locoregional control was improved

for patients who received >50 Gy (86.5% vs 34.0%; p =

0.012), although no dosage ceiling was suggested from

these data.

An older study, the RTOG 9208 trial,

131

was a clini-

cal trial that enrolled only 47 patients with at least T1

squamous anal cancers who received CRT with 5-FU

and MMC with 59.6 Gy of radiation, which included a

2-week rest period during CRT. The study patients were

compared with patients enrolled in the previous RTOG

8704 trial who had received 40.0 to 50.4 Gy of radia-

tion. Despite a higher dose of radiation, patients in the

9208 trial actually had a higher colostomy rate at 1 and

2 years after treatment, without an improvement in lo-

coregional control. No beneﬁt to higher doses exceeding

59 Gy was noted, although concerns for escalating inci-

dences in toxicity were raised. The lack of efﬁcacy with

higher doses of radiation is also echoed in the results

of the previously mentioned ACCORD 03 trial, which

found no beneﬁt to increasing radiation dosing by using

high-dose boost treatments.

Missed treatments should be avoided, because they are

strongly associated with inferior disease control. Grade

of Recommendation: Strong recommendation based on

moderate-quality evidence, IB.

The ACT II trial primarily evaluated the role of cispla-

tin with CRT, and the use of maintenance chemotherapy

with 5-FU and cisplatin in addition to CRT, ﬁnding no

advantage to either of these alternative approaches. This

study touted a high rate of complete response (90%),

with similar 3-year progression-free survival in the

MMC and cisplatin groups, and with an overall 3-year

colostomy-free survival of 74%, with 75% of patients

having locoregional control with organ preservation.

The authors of this study attributed these excellent re-

sults in part to high compliance rates with the 50.4 Gy

of planned radiation and in part because of the ability

to provide CRT in a shorter time interval by avoiding

a planned treatment gap, which was a common feature

of CRT before this study. A similar observation can be

gleaned from the Eastern Cooperative Oncology Group

E4292 trial,

132

a study of 33 patients designed to evalu-

ate whether cisplatin could replace MMC as part of CRT.

This study accrued a total of 13 patients who did not re-

ceive a planned 2-week treatment break, which the larger

number of study patients did receive. Complete response

rates of 78% were noted in patients without a treatment

break, which was higher than in subjects who did receive

a break in therapy. The RTOG 9208 trial

131

included a

2-week treatment break, which was associated with in-

creased locoregional failure rates and lower colostomy-

free survival rates. Treatment breaks and interruptions to

CRT should be avoided if possible, although they occur

as frequently as in 80% of patients with anal cancer,

133

making treatment compliance a major and potentially

modiﬁable factor associated with survival.

Surveillance

Disease surveillance should typically start 8 to 12 weeks

from the completion of CRT. Grade of Recommendation:

Strong recommendation based on moderate-quality

evidence, 1B.

Slow tumor regression after completion of CRT is based

on evidence from trials, such ACT II, in which randomly

assigned patients had clinical complete response docu-

mented at 11 and 26 weeks postcompletion of CRT. Data

from this trial indicate that 29% of patients who did

not demonstrate a complete remission at 11 weeks had

achieved a complete response by 26 weeks, with durable

response.

124

Most patients are reasonably comfortable with anal

examination by the eighth week after completion of CRT,

although earlier evaluation to ensure symptom control

should be tailored to the individual. The National Com-

prehensive Cancer Network guidelines

134

recommend

evaluation at 8 to 12 weeks after completion of CRT. Clini-

cal assessment should include digital rectal examination,

anoscopy, and palpation of the inguinal lymph nodes. Be-

cause of slow tumor regression, biopsies for persistent dis-

ease are typically avoided at 8 to 12 weeks and <6 months

post-CRT.

Posttreatment imaging is most frequently undertaken

3 months from the completion of CRT, when treatment-

related ﬁbrosis and residual tumor could be distin-

guished.

135

Imaging recommendations from the National

Comprehensive Cancer Network guidelines include CT

of the chest, abdomen, and pelvis annually for 3 years (if

T3–T4 or inguinal node positive).

Surveillance involving digital rectal examination, anos-

copy, and imaging should be continued for 5 years after

completion of CRT. Grade of Recommendation: Strong

recommendation based on moderate-quality evidence, 1B.

After the ﬁrst evaluation post-CRT, additional surveil-

lance including digital anorectal examination, anosco-

py, and palpation of inguinal lymph nodes every 3 to 6

months for those in complete remission or every 4 weeks

until remission <6 months is recommended in patients

with evidence of persistent disease.

134

Patients with re-

sidual changes require close follow-up and documenta-

tion of any changes identiﬁed. New tissue thickening,

growth, or ulceration should be evaluated. Examination

under anesthesia and potential targeted biopsy should

be considered in patients with persistent abnormalities

5 to 6 months after CRT, stenosis, pain, or scarring pre-

STEWART ET AL: ANAL CANCER CLINICAL PRACTICE GUIDELINES

768

venting adequate surveillance examinations. The major-

ity of relapses and thus the most efﬁcient time for more

frequent surveillance are within the ﬁrst 3 years of com-

pletion of CRT. The ACT II trial with long-term follow-

up demonstrated <1% of relapses occurring beyond 3

years.

124

Other trials suggest that this may be closer to

5%; thus, there seems to be some rationale to continue

surveillance out to 5 years.

125,136

CT scans of the chest, abdomen, and pelvis annually

for 3 years for patients with T3 to T4 tumors or positive

inguinal lymph nodes are also recommended. There are

no formal recommendations with regard to post-CRT

EAUS, MRI, or PET/CT. One retrospective study evaluat-

ing the impact of PET/CT on assessing for residual tumor

in 52 patients after CRT showed negative predictive and

positive predictive values of 100% and 71%.

137

Vercellino

et al

138

showed a sensitivity for the detection of persistent

or recurrent disease of 93% and speciﬁcity of 81% with

PET/CT, leading to changes in management in 20% of pa-

tients. The role of post-CRT imaging with MRI and PET/

CT to detect locoregional persistent or recurrent tumor

seems to be evolving; however, its true ability to impact

earlier salvage compared with clinical evaluation remains

inconclusive.

Treatment of Recurrent or Persistent Disease

APR is effective salvage therapy for persistent or recur-

rent disease. Grade of Recommendation: Strong recom-

mendation based on moderate-quality evidence, 1B.

Approximately 20% to 30% of patients will have persis-

tent or recurrent disease after primary CRT.

133

Predictors

of recurrent and persistent locoregional disease after de-

ﬁnitive CRT include higher T and N stages at original

presentation, HIV-positive status, and the inability to

complete CRT.

133,139

Although patients with persistent

disease who present within 6 months of completing CRT

have been reported to have worse prognosis,

140–142

recent

data suggest that persistent and recurrent disease does

not show any signiﬁcant difference in survival, and pa-

tients with late recurrence (>24 mo) may have a better

prognosis.

143

APR is recommended for persistent or recurrent dis-

ease for salvage therapy, with reported 5-year locoregional

control in 30% to 77% of patients

144–148

and 5-year overall

survival rates of 24% to 69%.

141,142,145–149

Positive surgi-

cal margins (microscopic or macroscopic), male sex, and

higher Charlson comorbidity index portend a worse prog-

nosis, whereas younger age (<55 y), as well as T1 to T2 and

N0 to N1 disease have been associated with higher overall

survival after APR.

145,150

Major wound complications are common, reported in

36% to 80%.

145

Muscle ﬂap reconstruction has been asso-

ciated with signiﬁcantly lower rates of such complications

without major donor-site morbidity.

148,151,152

Pedicled

muscle ﬂaps have shown a signiﬁcantly lower rate of recip-

ient site complications than V–Y advancement ﬂaps, with

the vertical rectus abdominis myocutaneous ﬂap showing

superior results compared with the gracilis ﬂap in terms of

the overall reduction of complications.

153

Patients with HIV or AIDS who present with anal cancer

as the ﬁrst manifestation of their immunosuppression,

and who are not medically deconditioned, can be safely

treated according to the same regimens as immunocom-

petent patients. Grade of Recommendation: Strong rec-

ommendation based on medium-quality evidence, IC.

As the medical management of HIV has improved

and as the life expectancy of patients with HIV has

increased, older and smaller retrospective studies that

suggested poorer outcomes for HIV-positive patients

treated for anal cancer have been questioned in terms

of their generalizability to the management of current

HIV patients with anal cancer. One of these earlier ret-

rospective studies suggesting that well-compensated

HIV patients could be treated similarly to HIV-negative

patients was published in 1999 by Hoffman et al.

154

this small retrospective analysis of 17 HIV-positive pa-

tients with anal cancer treated with either CRT or ra-

diation alone, patients with CD4 counts ≥200 cells per

cubic millimeter had excellent disease control with an

incidence of treatment toxicities similar to what has

been described in the literature for immunocompetent

patients. Patients with a CD4 count <200 cells per cubic

millimeter (n = 8) had a significantly higher incidence

of treatment toxicities, although with 7 of these 8 pa-

tients achieving disease control. A more recent publi-

cation from 2010

155

evaluated 21 HIV-positive patients

receiving CRT. Completion of treatment was achieved

in all 21 patients, with a complete response of 81% and

6 patients (29%) dying of disease. The authors noted

that the 5-year local control, cancer-specific, and over-

all survival rates were 59%, 75%, and 67%. Because the

majority of the patients were able to complete CRT

without dose reductions in either radiation or che-

motherapy, this study also supported the concept that

HIV-positive patients could be treated according to

standard regimens with the expectation of good toler-

ance to therapy. Another recent retrospective study

156

of 36 HIV-positive patients treated with standard regi-

mens of CRT again demonstrated completion of treat-

ment in all of the patients, with complete response rates

of 86% and with 5-year local control, colostomy-free,

cancer-specific, and overall survival rates of 72%, 87%,

77%, and 74%. This study noted a CRT-related decline

in CD4 counts for <6 years after treatment, although

this decrease in CD4 counts was not associated with

increased HIV-related morbidity, with oncologic out-

comes comparable to descriptions of the HIV-negative

population in the literature.

DISEASES OF THE COLON & RECTUM VOLUME 61: 7 (2018)

769

One of the largest retrospective studies on this

subject to date was a review of patient data from the

Veteran’s Affairs system,

157

analyzing 1184 individuals

treated for squamous cancers of the anus, of whom 175

were documented to be HIV positive. As with previous

studies, this study reported no difference in the receipt

of treatment based on HIV status, with 2-year observed

survival rates of 77% and 75% among HIV-positive and

HIV-negative individuals. Based on multivariate analy-

sis, HIV status was not associated with differences in

survival.

There are insufﬁcient data to comment on whether

highly active antiretroviral therapy is associated with im-

proved outcomes after CRT. Patients with ongoing HIV/

AIDS disease–related complications present before their

diagnosis of anal cancer may not tolerate standard CRT

and may require dose reductions; this subpopulation of

patients with HIV is therefore at risk for higher CRT toxic-

ity rates and worse oncologic outcomes.

Perianal squamous cancers, which are well-differentiat-

ed, node-negative, T1 lesions, can be adequately treated

with wide-local excision with 1-cm margins of resec-

tion. All other anal margin cancers are preferentially

treated with CRT. Grade of Recommendation: Strong

recommendation based on low-quality evidence, IC.

Patients with well-differentiated, node-negative T1 lesions

involving the perianal skin are preferentially treated with

wide-local excision provided that 1-cm margins of resec-

tion can be obtained without compromising the patient’s

sphincter mechanism, which would compromise the

functional outcome of a local excision. The data in sup-

port of wide-local excision are from small retrospective

studies, although the outcomes of these studies are con-

sistently excellent, with 5-year survival rates of 100%.

158

In addition, wide-local excision avoids the toxicity asso-

ciated with radiotherapy. Any perianal squamous cancers

that do not meet the above-mentioned favorable criteria

should be treated with CRT, because there is a well-docu-

mented history of locoregional recurrence and decreased

survival when such cancers are treated with wide-local

excision.

106,159

Treatment of Distant Disease

Systemic chemotherapy should be considered for patients

with distant metastatic disease. Metastasectomy, radiation,

and radiofrequency ablation can be considered in selected

cases. Grade of Recommendation: Weak recommendation

based on low- or very-low–quality evidence, 2C.

Because of high response rates with chemoradiation, re-

ports comparing treatment of patients with metastatic dis-

ease are limited. The most extensive published experience

is a retrospective review of a 14-year experience at a single

center in France.

160

A total of 50 patients, 10 with synchro-

nous disease at the time of diagnosis and 40 with distant

failure after chemoradiation, were treated with multimodal

therapy. Patients received ≥1 chemotherapy regimen, 13

had surgical metastasectomy, 11 had radiotherapy, and 6

had radiofrequency ablation. Median overall survival was

20 months. Overall response rate was 56%. There was no

clear advantage of any chemotherapy regimen, but patients

who could also have resection, radiation, or ablation had

an overall survival of 22 months compared with 13 months

with chemotherapy alone (p = 0.002). A similar-sized cohort

has been published in abstract form, including 53 patients

treated with chemotherapy, with a median overall survival

of 38 months.

161,162

A small single-center study reported in

1999 that included 19 patients with metastatic anal cancer

treated with 5-FU and cisplatin described a response rate of

66%, with 1 patient achieving a complete response.

163

A sin-

gle-center report described the combination of carboplatin

and paclitaxel in 13 patients with a response rate of 62%,

with 2 patients achieving a complete response.

164

Targeted therapy to the epidermal growth factor re-

ceptor (EGFR) has been considered because of the high ex-

pression of EGFR in anal cancers.

165

The use of cetuximab

in the setting of localized disease has been limited by toxic-

ity when combined with traditional chemoradiation.

166,167

However, response rate was high, and it is possible that, in

the metastatic setting, without concurrent radiation, there

is a role for the addition of an EGFR inhibitor to cytotoxic

chemotherapy regimens. Because of the lack of uniform

treatment, there are also active clinical trials in this area

available at clinicaltrials.gov, examining novel approaches

including pembrolizumab and nivolumab.

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