Anal CancerWhat’s the Bottom Line on Vaccination,

Screening, and Treatment

Yosef Nasseri M.D.

The Surgery Group of Los Angeles

No Relevant Disclosures

Overview• Anal Cancer

– Incidence– Risk Factors

• Prevention– Risk stratification– Vaccination– Screening

• Treatment– HPV– Anal Cancer

Anatomy

Anatomy

Anal Cancer

Anal Cancer• Incidence

– 2012 NCCN Anal Cancer Data• 6230 new cases of anal cancer per year

– Women 3,980– Men 2,250

• 780 Deaths

– 2.2% of GI Cancers• Increased incidence 1979 - 2000

– 1.5 increase in women– 1.9 increase in men

http://www.nccn.org

Anal Cancer: Risk Factors• 95% associated with HPV

– Human Papiloma Virus, a papovavirus, 8 kb genome– Most common viral sexually transmitted disease

• HPV: Necessary, but not sufficient– Cell-Mediated Immunity Dysfunction– Immunosuppression

• Solid OrganTransplantation• Anti-TNF therapy• HIV• Hematologic Malignancies

– Smoking– Autoimmune Disorders

NCCN, CDC, NCI, ACA, ASCRS Databases

Anal Cancer: Risk Factors• High Risk HPV Serotypes

– HPV-16, HPV-18 – detected in > 80% of anal cancer specimens– CDC: estimates 86-97% of cancers of the anus are

attributed to HPV infection– Other Oncogenic HPV strains: 31, 33, 35, 39, 45, 51,

52, 56, 58, 59, and 66

• Immunosuppression facilitates persistence of HPV infection– HIV+, MSM incidence 131 / 100,000 persons– Solid Organ Transplant– Anti-TNF Therapy

Anal Cancer: Terminology• Condyloma

– AIN I– LSIL

• Dysplasia– Bowen’s Disease– Anal SCC in situ– AIN II– AIN III– HSIL

• Anal Cancer– Invasive Squamous

Cell Carcinoma of the Anus

– SCC Anus

Anal Cancer: Similar HPV Pathway as Cervical Cancer

Progression of persistent HPV infection in the cervix

Ortoski R A , and Kell C S J Am Osteopath Assoc 2011;111:S35-S43

Anal Cancer: Terminology• Condyloma

– AIN I– LSIL

• Dysplasia– Bowen’s Disease– Anal SCC in situ– AIN II– AIN III– HSIL

• Anal Cancer– Invasive Squamous

Cell Carcinoma of the Anus

– SCC Anus

Whew!

Anal CancerPrevention

Prevention• Vaccination

– Recombinant HPV Quadrivalent Vaccine, HPV4 (Gardasil®) • FDA Approved 12/23/2010 for anal cancer prevention• HPV types 6, 11, 16, 18• Ages 9 – 26• 3 shots over 6 months

– Efficacy 78%• RCT: 602 healthy MSM, age 16 – 26 years

– 3 year observational study– No anal cancer– Placebo: HSIL 24 cases– Vaccine: HSIL 5 cases

Palefsky JM et al HPV Vaccine against Anal HPV and AIN NEJM 2011;365:1576-1585

Prevention• Vaccination

– Recombinant HPV Quadrivalent Vaccine, HPV4 (Gardasil®) • FDA Approved 12/23/2010 for anal cancer prevention• HPV types 6, 11, 16, 18• Ages 9 – 26

– Practice Guidelines• Advisory Committee on Immunization Practices (ACIP)

– Routine use of vaccine • Female age 11 – 26• Male age 11-21

• American Academy of Pediatrics (AAP)– Agree with Above, plus MSM up to age 26

ACIP MMWR Morb Mortal Wkly Rep 2010;59:626-629 & 2011;60:1705-1708Pediatrics 2012:129:602-605

Prevention• Vaccination

– Bivalent HPV Vaccine against HPV-16 and 18, HPV2 (Cervarix®)

– Efficacy in anal lesions pending

– Data only currently for cervical HPV and Dysplasia:• Efficacy in preventing initial HPV infection 84%• Reduced high-grade CIN in young women

Efficacy of a bivalent HPV 16/18 vaccine Lancet Oncol 2011;12:862-870PATRICIA trial. Lancet Oncology 2011;13:69-99

Prevention• Vaccination

– Recombinant HPV Quadrivalent Vaccine, HPV4 (Gardasil®)

• FDA Approved 12/23/2010 for anal cancer prevention– HPV types 6, 11, 16, 18– Ages 9 – 26

• Practice Guidelines– ACIP

• Female age 11 – 26• Male age 11 – 21

– AAP• plus MSM up to age 26

ACIP MMWR Morb Mortal Wkly Rep 2010;59:626-629 & 2011;60:1705-1708Pediatrics 2012:129:602-605

Female: 9 … 11 – 26

Male: 9 … 11 – 21 … 26

Prevention• There is No Effective Barrier Protection

– HPV pools at the base of the penis, scrotum, and vaginal introitus

– Only preventative method is abstinence

– Anal HPV can be present without ARI

Prevention• Routine Screening for High Risk Patient

Populations

– HIV +, Male, CD4 counts < 500 x 106 cells / L– HIV +, MSM– HSIL – high grade anal intraepithelial neoplasm– Immunosuppression

• Solid organ transplantation• Multi-modal immunosuppressive therapy

• Screening Methods?• What time interval is routine?

Prevention & ScreeningWho? What? When? Where?

Screening Methods

• Physical Examination– Anal Exam– DRE– Anoscopy

• Anal pap smears

• High resolution anoscopy– 5% acetic acid

Prevention & ScreeningWho? What? When? Where?

• ANAL Lesions– Lesions that are not visible or

are incompletely visible with gentle traction to spread the buttocks

• Peri-Anal Lesions– Lesions that are completely

visible with gentle traction to spread butocks

• SCC Skin Cancer

Prevention & ScreeningWho? What? When? Where?

• High Resolution Anoscopy– H&P, HRA every 6

months– Surgical ablation of

persistent lesions

• Expectant Management– H&P, DRE, Anoscopy

every 6 months– Surgical ablation of a

new or ulcerative lesions

Welton et al Hi Res Anoscopy DCR 2008;51:829-35Cosman B. , UCSD,

Unpublished data

Prevention & ScreeningWho? What? When? Where?

• High Resolution Anoscopy– Rate of progression to

cancer 1.2%– Complications 4%– 57% recurrence rate,

average 19 months

• Expectant Management– Rate of progression of

HSIL to invasive cancer: 1% per year 

– The cancers that arise are curable

– Patients who progress to cancer often do so more than once 

Welton et al Hi Res Anoscopy DCR 2008;51:829-35

Cosman B. , UCSD, Unpublished data

Prevention & ScreeningWho? What? When? Where?

• Who? – high risk individuals– HIV +, Male, CD4 counts < 500 x 106 cells / L– HIV +, MSM– HSIL – high grade anal intraepithelial neoplasm– Immunosuppression

• What? – at minimum, H&P, DRE, Anoscopy– Refer to specialty clinic if available– Ongoing HIV testing

• When?– HSIL: Every 3 months x 1 year if, then every 6

months– Evaluate any new or ulcerative lesion when it arises

TreatmentHPV Dysplasia

LSIL = low grade = condylomaHSIS = high grade = carcinoma in situ

Treatment: HPV LSIL, HSIL

• Surgical Methods:– Excision– Cryotherapy– Fulguration– Electrodesication

• Topical Treatments:(not approved for use in anal canal)

– Podofilox 0.5% gel• Purified product of antimitotic

plant resin podophyllin• BID x 3 days, off 4 days

repeat x 1 month

– Imiquimod (Aldera)• 3x per week, apply at bedtime (6-8 hr)

x 16 weeks

– Trichloracetic acid

– Less common: topical 5-FU, Cidofovir

Goal: destruction or removal of all obvious disease while minimizing morbidity

Treatment: HPV LSIL, HSILGoal: destruction or removal of all obvious disease while minimizing morbidity

Method of Action

Clearance Rate

Recurrence Rate

Podofilox 0.5% gel, soln

Anti-mitotic 35-80% 10 – 20%

Imiquimod(Aldera)

Immune response modifier ( IFN-α)

50% 11%

Surgery Excision, Destruction

60 – 90% 20 – 30%

TreatmentAnal Cancer

Anal Cancer Treatment Prognosis

• Independent Poor Prognostic Indicators for Survival and Local Control– Positive lymph nodes, tumor size > 5 cm, male sex,

skin ulceration

• Staging– T1 < 2 cm; T2 2 – 5 cm– T3 > 5 cm– T4 invades adj organs– N 1 peri rectal LN– N2 unilateral ilac or inguinal LN– N3 = N1+ N2

http://www.nccn.org

Stage 5-year Survival Rate

I (T1N0) 71%

II (T2-T3, N0) 64%

III B (T1-3, N1, T4N0) 48%

III B (T4N1, T1-4N2-3) 43%

IV (Metastasis) 21%

Treatment: Anal Cancer

• Anal Cancer Staging

– H&P, DRE, Anoscopy, colonoscopy, Inguinal LN exam

– X-sectional imaging Chest/Abd/Pelvis (PET CT)

– HIV testing, CD4 levels when positive

– Cervical cancer screening in women

http://www.nccn.org

Treatment: Anal Cancer• Traditional Protocol - APR

• APR 5 year survival 40-70%• High local recurrence rates• Permanent colostomy

• Nigro Protocol– 1974 complete tumor regression in patients treated

with combined radiation and chemotherapy (CMT)– Changed management from APR to CMT

• 70% Survival• Low local recurrence rates• Sphincter preservation

http://www.nccn.org

Anal CancerLocation, Location, Location

• ANAL Lesions– “Anal Canal”– Lesions that are not visible or

are incompletely visible with gentle traction to spread the buttocks

• Peri-Anal Lesions– “Anal Margin”– Lesions that are completely

visible with gentle traction to spread buttocks

Skin Cancer

Treatment: Anal Canal Cancer

• Combined Modality Therapy (CMT)– Primary treatment for non-metastatic anal canal

cancer

– Chemotherapy 1st and 5th week• Mitomycin day 1 or 2 of 1st & 5th week• 5-FU 96 – 120 hour infusion during 1st & 5th weeks

– Radiation Therapy for 5 weeks• Minimum of 45 Gy to primary cancer

http://www.nccn.org

Treatment: Anal Margin Cancer

• Either local excision or CMT depending on the clinical stage– Local Excision: T1 & T2 tumors with 1 cm margin– CMT +/- APR: T3 &T4 tumors

• Combined Modality Therapy (CMT)– Chemotherapy 1st and 5th week

• Mitomycin C, 5-FU

– Radiation Therapy for 5 weeks• 45 Gy to primary cancer

http://www.nccn.org

Treatment: Anal Cancer• Post-treatment Surveillance

• H&P, DRE, Anoscopy 8 – 12 weeks after CMT– 29% of patients without complete response at 11 weeks

achieved complete response by 26 weeks

• Complete Remission– Follow up every 3 – 6 months for 5 years– DRE, anoscopy, inguinal LN evaluation– Annual Chest/Abd/Pelvis Imaging x 3 years

• Recurrence, Incomplete Response– APR

ASCO Meeting Abstracts 2012;30:4004; NCCN Quidelines

Review• Anal Cancer

– Incidence:– Risk Factors:

• HPV Prevention– Risk stratification– Vaccination

– Screening

• Treatment– HPV Dysplasia

– Anal Cancer

Rare, but incidence on the rise

HPV, HIV, MSM, Immunosuppression (IS)

HIV+, CD4 < 500 , MSM, HSIL, IS

HPV 6, 11, 16, 18 Vaccine (Gardasil®)

– M / F: Ages 9…11 – 21 / 26 (…26 MSM)

H&P, DRE, Anoscopy– Biopsy all new or ulcerative lesions– Get Path on all high risk patients

Topical (Podofilox, Aldera), Surgery

Refer to a specialist

Anal Cancer: Prevention and Screening

“Working Where the Sun Don’t Shine”