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.
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!
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?
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
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%
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
Progression of persistent human papillovmavirus (HPV) infection in the cells of the cervix. From left to right, there is a progression from initially normal cells. The nucleus-to-cytoplasm ratio increases as cells progress through the stages of dysplasia and into cancer. Abbreviations: CIN, cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion. Reprinted with permission from Lowy and Schiller. 27