Pocket Oncology (Pocket Notebook Series), 1st Ed.

ANAL CANCER

David B. Page and Neil H. Segal

Epidemiology

• 6230 new cases & ∼780 death in 2012

• Increasing incidence (1.9 fold for men, 1.5 for women) from 1970s to 2000s

• A/w HPV infxn, receptive anal intercourse, MSM, STD, cervical/vulvovaginal CA, immunosuppression (transplant or HIV), hematologic malignancy, autoimmune disorders, smoking

• HPV (dsDNA nonenveloped virus) is #1 causative agent; HPV DNA detected in 84% of specimens (commonly HPV-16, HPV-18)

• HPV prevalence is ↑ in MSM population (detectable in 1/3 of HIV+ men & 1/8 of HIV- men)

• HAART Rx ↑ HIV-associated survival but does not impact progression of anal CA precursors. This contributes to recent ↑ in anal CA incidence from 19 → 78/100 k among HIV-positive

• HPV vaccination likely to be effective but is not yet routinely administered for all (N Engl J Med 2011;365:1576); high-resolution anoscopy & HPV testing are still unproven screening measures

Clinical Manifestations

• Sx: 45% rectal bleeding, 30% sx mass

• ¹/² of CAs are localized at Dx (80% 5-y OS); 29% regional LN involvement (60% 5-y OS); 12% distant mets (31% 5-y OS)

• Stepwise model of premalignant low-grade AIN I → high-grade (AIN II–III) → CA is less validated compared to cervical neoplasia model; progression rates are lower, & the role of ablative Rx of AIN is uncertain (Lancet Oncol2012;13:487)

• Anatomic zones separated by anorectal ring & anal verge: Anal canal → between anorectal ring & anal verge; anal margin→ includes anal verge & 6 cm radius of surrounding skin

Figure 15-4 Copyright Devita: Principles & Practice of Oncology 2011

• LN Drainage: Proximal to dentate line → anorectal, perirectal, & paravertebral LN, possibly internal iliac, inferior mesenteric if more proximal; distal to dentate line → superficial inguinal nodes; proximal to dentate → anorectal, perirectal, & paravertebral nodes & possibly internal iliac, inferior mesenteric if more proximal

• Met sites: Liver, lung, extrapelvic LN

Pathology and Molecular Biology

• HPV E2 peptide: Attaches HPV DNA to chromatin, allowing steady viral production

• HPV E6 peptide: Mediates degradation of p53, impeding cellular arrest & apoptosis; also mediates degradation of NFX1-91 telomerase repressor

• HPV E7 peptide: Inactivates pRb, promoting cell cycle progression

• Most anal CAs are of SCC histotype. Histologic variants (keratinizing, nonkeratinizing, basaloid) do not alter tx/prognosis

• Anal adenoca & anal melanoma are treated according to rectal adenoca & melanoma guidelines, respectively

Workup and Staging

• Initial w/u w/DRE, anoscopy, endorectal U/S, inguinal node exam, CT or MRI of abdomen/pelvis, chest XR/CT, HIV test/CD4 count, GYN exam. Consider PET/CT

• Stage 0: CA in situ (Bowens, HSIL, AIN II–III); Stage I: Tumor ≤2 cm (T1); Stage II: Tumor 2–5 cm (T2) or >5 cm w/no invasion of vagina, urethra, or bladder (T3); Stage IIIA: T1–T3 & involved perirectal LN (N1), or tumor invading vagina, urethra, or bladder (T4) + N0; Stage IIIB: T4N1, or unilateral internal iliac or inguinal LN (N2), or N3 (perirectal & inguinal LN, or bilateral internal iliac/inguinal LN); Stage IV: Distant mets (M1)

• Consider bx by FNA for clinically suspicious LN

Management: Nonmetastatic Disease

• 1st-line tx: Nigro Protocol in 1970s established chemoradiotherapy as standard compared to up-front APR; chemoradiotherapy is superior to RT alone (J Clin Oncol 1997;15:2040)

• Chemotherapy: Infusional 5-FU w/bolus MMC as illustrated above (J Clin Oncol 1996;14:2527); 70% 6-mo local control

• Radiation: Dosing of ≤ 59 Gy is sufficient, w/no additional benefit to high-dose RT or induction chemo (ACCORD-03, J Clin Oncol 2009;27:4033); tx breaks should be minimized, but may be necessary 2° to acute anoproctitis, perineal dermatitis, or cytopenia. Chronic adverse effects may include anal ulcers, stenosis, & necrosis

• RTOG 98-11 protocol commonly used: 45–59 Gy to 1° tumor & 30.6–45 Gy to pelvis, anus, perineum, & inguinal nodes. IMRT: ↓ Tox & equal efficacy in preliminary trial (J Clin Oncol 2007;25:4581); IMRT is acceptable only at experienced centers (must avoid “marginal-miss” ↓ in local control)

• 3-fold ↑ pelvic fracture risk in women s/p XRT

• Females should be considered for vaginal dilator to reduce vaginal stenosis

• Post-tx follow-up: Repeat DRE at 8–12 wks, repeat in 4 wks if regression w/o CR. If CR, repeat DRE, anoscopy, inguinal exam q3–6mos for 5 y, annual imaging CT CAP for 3 y if T3/T4, node-positive, or slow regression

• Clinical trials underway are evaluating role of cetuximab or Cap/OX

• HIV pts (especially w/CD4 count ≥200/mm3) should be treated w/same protocols. Data suggests similar ORR & OS but ↑ skin tox & local relapse

Management: Anal Margin Cancer

• Low stage (T1N0), well differentiated: Surgical excision & re-excision if necessary for negative margins

• Higher-stage/positive margins: Treat w/chemoRT (as above)

Management: Refractory/Recurrent and Metastatic Disease

• Confirm progression w/bx & restaging CT and/or PET

• If locally progressive, proceed to salvage APR (removal of anus, rectum, partial sigmoid, regional nodes) w/colostomy (Ann Surg Oncol 2007;14:478); subsequent 5-y OS 39–64%

• For unresectable/met, 1st-line standard is CIS-based regimen, w/5-FU infusion 1000 mg/mo2/d d 1–5 & CIS 100 mg/mo2 d 2 q4wks (Bull Cancer 1999;86:861). Modification to dose & schedule may be necessary

• No evidence exists to support metastasectomy in anal CA

• Clinical trial preferred for subsequent Rx

*This section is an overview of appendiceal CAs w/main focus on adenoca (other tumor types including appendiceal carcinoids & lymphomas discussed elsewhere)

*This section will focus on small bowel adenoca (malignant small bowel NETs, carcinoids, lymphomas, & sarcomas discussed elsewhere)