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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.
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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”