anal cancer - what's the bottom line on vaccination, screenings, and treatment

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”