Presentation by Yossef Nasseri, M.D. Yosef Nasseri, M.D., is a founding member of The Surgery Group of Los Angeles, a Los Angeles based physician group providing a comprehensive approach to surgical care through advanced technology, long-term patient follow-up, and direct physician access. Dr. Nasseri is double board-certified in general and colorectal surgery and specializes in cutting-edge robotic and minimally invasive techniques for the treatment of colon and rectal cancers, inflammatory bowel disease, benign anorectal diseases, a variety of hernias, and general surgery.

1. Anal Cancer
What’s the Bottom Line on Vaccination,
Screening, and Treatment
Yosef Nasseri M.D.
The Surgery Group of Los Angeles

2. No Relevant
Disclosures

3. Overview
• Anal Cancer
– Incidence
– Risk Factors
• Prevention
– Risk stratification
– Vaccination
– Screening
• Treatment
– HPV
– Anal Cancer

4. Anatomy

5. Anatomy

6. Anal Cancer

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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!

13. Anal Cancer
Prevention

14. 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

15. 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;60:1705-1708
Pediatrics 2012:129:602-605

16. 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;12:862-870
PATRICIA trial. Lancet Oncology 2011;13:69-99

17. 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;60:1705-1708
Pediatrics 2012:129:602-605
Female: 9 … 11 – 26
Male: 9 … 11 – 21 … 26

18. 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

19. 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?

20. Prevention & Screening
Who? What? When? Where?
Screening Methods
• Physical Examination
– Anal Exam
– DRE
– Anoscopy
• Anal pap smears
• High resolution anoscopy
– 5% acetic acid

21. Prevention & Screening
Who? 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

22. Prevention & Screening
Who? 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

23. Prevention & Screening
Who? 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

24. Prevention & Screening
Who? 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

25. Treatment
HPV Dysplasia
LSIL = low grade = condyloma
HSIS = high grade = carcinoma in situ

26. 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

27. Treatment: HPV LSIL, HSIL
Goal: 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%

28. Treatment
Anal Cancer

29. 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%

30. 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

31. 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

32. Anal Cancer
Location, 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 buttocksSkin Cancer

33. 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

34. 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

35. 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

36. 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

37. Anal Cancer:
Prevention and Screening
“Working Where the Sun
Don’t Shine”