Anal Cancer
BACKGROUND
What is the incidence of anal cancer in the U.S.?
~7,000 cases/yr in the U.S.
Is there a sex predilection for anal cancer?
Yes. Anal cancer is more common in females than males (2:1).
What are some risk factors for anal cancer?
Hx of STDs/anal warts; multiple sexual partners (>10); anal-receptive intercourse; immunodeficiency (HIV, solid organ transplantation); smoking; Hx of cervical, vulvar, or vaginal cancer (HPV)
Is anal cancer an AIDS-defining illness?
No. However, the demographically adjusted rate ratio for HIV infected men and women relative to uninfected cohorts is 80 and 30, respectively. Cervical cancer is an AIDS-defining illness.
What is the predominant histology of anal cancer?
Squamous cell carcinoma (75%–80%) is the predominant histology.
What virus strains are strongly associated with anal cancer?
HPV strains 16, 18, 31, 33, and 35 are strongly associated with anal cancer. Anal cancers are associated with HPV infection in 75%–90% of cases, with HPV16 the most common subtype.
How long is the anal canal, and where does it extend?
The anal canal is 4-cm long, extending distally from the anal verge (palpable junction between the internal sphincter and subcutaneous part of the external sphincter, aka the intersphincteric groove) to the anorectal ring (where the rectum enters the puborectalis sling) proximally.
What is the histopathologic significance of the dentate line (aka pectinate line)?
The dentate line is the anatomic site where mucosa changes from nonkeratinized squamous epithelium distally to colorectal-type columnar mucosa proximally (dividing the upper from the lower anal canal).
Describe the anatomic location of the anal verge.
The anal verge is located at the junction of nonkeratinized squamous epithelium of the anal canal and keratinized squamous epithelium (true epidermis) of perianal skin.
Which site carries a better prognosis: the anal margin or anal canal?
The anal margin carries a better prognosis.
Which pathology carries a higher risk for local and distant recurrence?
Adenocarcinoma carries a higher risk.
What is the significance of the dentate line in terms of LN drainage?
Above dentate line: drains to pudendal/hypogastric/obturator/hemorrhoidal → internal iliac nodes
Below dentate line: drains to inguinal/femoral nodes → external iliacs
What % of anal cancer pts present with +LNs?
25%–35% of these pts present with +LNs.
What are the 2 most common sites of DM?
Liver and lung
What is the occult positivity rate for inguinal nodes (i.e., if clinically–) in anal cancer?
For inguinal nodes, the occult positivity rate is 10%–15%.
What is the rate of extrapelvic visceral mets at presentation for anal cancer?
Extrapelvic visceral mets are present in 5%–10% of pts.
In anal cancer, what % of clinically palpable LNs are actually involved by cancer?
50% of clinically palpable LNs involve cancer, while the other 50% are usually reactive hyperplasia.
In anal cancers, what are the most important prognostic factors for LC and survival?
Tumor size and DOI predict for LC. The extent of inguinal or pelvic LN involvement predicts for survival.
WORKUP/STAGING
What are 4 common presenting Sx in anal cancer?
Bleeding, pain/sensation of mass, rectal urgency, and pruritus
What does the workup for anal cancer pts include?
Anal cancer workup: H&P (including gyn exam for women with cervical cancer screening), labs (HIV if risk factors), imaging, Bx of lesion, and FNA of suspicious LN
What imaging studies are typically done for anal cancer pts?
Transanal US (to assess for perirectal nodes/assess invasion), CXR or CT chest with IV contrast, CT abdomen/pelvis with IV and oral contrast, and PET/CT
Is PET/CT more or less sensitive than diagnostic CT alone for detecting locoregional and met Dz?
Mistrangelo M et al. (IJROBP 2012) found PET/CT to be superior to CT in detecting the primary tumor (89% vs. 75%); Bhuva NJ et al. also found PET/CT diagnosed occult metastatic Dz following CT imaging in 5% of pts and changed staging in 42% of pts, with the majority being upstaged. (Ann Oncol 2012)
What features of anal lesions need to be appreciated on physical exam? Why?
The degree of circumferential involvement and anal sphincter tone should be appreciated, b/c these may dictate Tx.
What is the approach to suspicious inguinal LNs in anal cancer pts?
FNA Bx should be performed for suspicious inguinal LNs.
On what is the T staging for anal cancer based? Define T1-T4.
T staging as per AJCC 7th edition for anal cancer is based on the size of the lesion.
T1: ≤2 cm
T2: >2–5 cm
T3: >5 cm
T4: invasion of adjacent organs (vagina, urethra, bladder)
Does tumor invasion of sphincter muscle by anal cancer constitute a T4 lesion?
No. Direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or sphincter muscle are not classified as T4.
Most pts with anal cancer present with what T stage?
Most anal cancer pts present at stage T2 or T3.
What is the N staging of isolated perirectal nodal involvement in anal cancer?
Isolated perirectal nodal involvement is staged as N1.
What is the N staging of unilat inguinal or internal iliac LNs in anal cancer?
Unilat inguinal or internal iliac LNs are staged as N2.
What N stage is an anal cancer pt with both perirectal and inguinal LNs?
Perirectal and inguinal LNs reflect stage N3.
What N stage is an anal cancer pt with bilat inguinal or internal iliac LNs?
Bilat inguinal or internal iliac LNs reflect stage N3.
What anal cancer pts have AJCC stage III Dz?
Node+ or T4 pts have AJCC stage III Dz.
What is the AJCC 7th edition (2011) stage grouping for anal cancer?
Stage I: T1N0
Stage II: T2N0 or T3N0
Stage IIIA: T1-3N1 or T4N0
Stage IIIB: T4N1 or TXN2 or N3
Stage IV: TXNXM1
What are the 5-yr OS and LR rates after surgical resection alone for anal cancer?
The 5-yr OS rate after complete surgical resection is ~70%, and the LR rate is ~40%. (Mayo review of 118 pts: Boman BM et al., Cancer 1984)
What % of pts who relapse develop local recurrent Dz as part of the total failure pattern?
∼80% develop local recurrent Dz. (Boman BM et al., Cancer 1984. Note: This was also a surgical series.)
What are the OS and sphincter preservation rates for all-comers with anal cancer at 5 yrs after definitive CRT?
OS is ~70% (RTOG 9811) and sphincter preservation rate is 65%–75% after CRT alone.
TREATMENT/PROGNOSIS
What are the criteria for local excision alone in anal cancer? What are the LC rates in such carefully selected pts?
Small T1 lesion (<2 cm), well differentiated, –margins, <40% circumferential involvement, no sphincter involvement, compliant pts. For these well-selected pts, there is >90% LC. (Boman BM et al., Cancer 1984)
Can radiotherapy alone be employed for early-stage anal cancer?
Yes. However, it can be employed only for T1N0 lesions. There were excellent LC rates of 100% and CR rates of 96% in 1 series. (Deniaud-Alexandre E et al., IJROBP 2003)
What was the standard surgical procedure for anal cancer before the advent of CRT? What was the disadvantage of this approach?
Abdominoperineal resection (APR) is the standard surgical procedure, but the disadvantage is that it requires permanent colostomy.
Currently, when should surgery alone be considered sufficient for management of anal cancer?
Surgery is sufficient with anal margin cancers in which the sphincter can be spared.
Historically, what has been the sphincter preservation approach for the Tx of anal cancers?
Radiotherapy alone was employed in Europe since the early 1900s, whereas surgical resection was standard in the U.S. Radiotherapy alone produced similar survival and control rates as surgery but allowed sphincter preservation. These results were better for less advanced tumors. Papillon and Montbarbon (Dis Colon Rectum 1987) reported (in the largest series of 159 pts with the use of EBRT and interstitial brachytherapy [30–42 Gy EBRT → implant 15–20 Gy]) a 5-yr OS of 65% and a sphincter preservation rate of 70%–82% (>4-cm tumor vs. <4-cm tumor).
What 2 seminal studies from the 1970s and 1980s in the U.S. demonstrated that surgical resection may not be needed after CRT, even after a short course of Tx?
The Wayne State experience (Nigro ND et al., Dis Colon Rectum 1974, 1983): preop regimen of 30 Gy/15 fx with continuous infusion 5-FU (1000 mg/m2 × 4 days) and mitomycin-C (MMC; 15 mg/m2 bolus), with APR scheduled 6 wks after the regimen. 31 pts had completion surgery vs. 73 had definitive CRT alone. 71% pts had pCR in the surgical specimen. In the surgery arm, the follow-up NED rate was 79%. In the definitive CRT arm, the follow-up NED rate was 82%.
Princess Margaret Hospital (Cummings BM et al., IJROBP 1991): prospective nonrandomized studies comparing RT alone, 5-FU + RT, or 5-FU/MMC + RT. OS was 70% in all groups, with LC best in the 5-FU/MMC arm of 93% compared with 60% in the RT-alone arm.
What was the chemo regimen and RT dose delivered in the original anal cancer studies by Nigro ND et al.?
In Nigro ND et al., the regimen was 5-FU (1,000 mg/m2 × 4 days)/MMC (15 mg/m2 bolus) with an RT dose of 30 Gy (2 Gy per fx). (Dis Colon Rectum 1974, 1983)
Anal margin tumors are treated like what other cancer?
Anal margin tumors are treated in the same manner as skin cancer.
What is the current Tx paradigm for anal canal cancer?
Anal cancer Tx paradigm: definitive CRT
What chemo doses are used in anal cancer, and what is the scheduling?
Anal cancer doses/scheduling: 5-FU 1000 mg/m2/day intravenously on days 1–4 and 29–32; MMC 10 mg/m2 intravenous bolus on days 1 and 29
What is the main radiobiologic advantage of MMC?
MMC is a hypoxic cell radiosensitizer.
For which pts is APR currently reserved?
APR is reserved as salvage for pts who fail RT or those who have had prior pelvic RT.
Are there data directly comparing surgery with CRT in anal cancer?
No. There is no randomized evidence. However, 1 retrospective analysis from Sweden showed better 5-yr OS in pts who rcvd RT ± chemo, supporting CRT as a better initial Tx option. (Goldman S et al., Int J Colorectal Dis 1989)
What 2 major European randomized studies in anal cancer demonstrated the inferiority of definitive RT compared to combined CRT?
UK Coordinating Committee on Cancer Research (UKCCCR) (ACT I) (Lancet 1996): 585 pts, any stage, randomized to RT vs. RT + 5-FU/MMC. RT was 45 Gy to the pelvis → 15–25 Gy with >50% response. If there was <50% response, then surgery was performed. Response was measured 6 wks after completion of induction therapy. The CR rate trended better in CRT (39% vs. 30%, p = 0.08), with 3-yr LC of 64% vs. 41% (p <0.0001). The risk of death from anal cancer was also reduced in the CRT arm (HR 0.71, p = 0.02), but there was a nonsignificant benefit of 3-yr OS of 65% vs. 58% (p = 0.25).
13-yr update (Northover J et al., Br J Cancer 2010): The absolute risk of LRR was reduced by 25% and remained stable after 5 yrs. The risk of death was reduced by 12%, and absolute reduction in the colostomy rates remained at 10%, favoring CRT (all SS).
EORTC (Bartelink H et al., JCO 1997): 577 pts, T3-4 or node+, RT vs. RT + 5-FU/MMC. Boost was given based on the response assessed at 6 wks: 20 Gy to CR and 15 Gy to PR. The CR rate was measured after completion of the entire course of therapy. The CR rate was superior in the CRT arm (80% vs. 54%, p = 0.02), as well as 3-yr LC (69% vs. 55%, p = 0.02), but not 3-yr OS (69% vs. 64%).
What is 1 explanation why the UKCCCR study had substantially inferior rates of CR and LC compared with the EORTC study in anal cancer?
1. The CR rate was measured 6 wks after induction therapy in the UKCCCR, whereas it was measured 6 wks after completion of all therapy in the EORTC study (which had a longer course of Tx b/c boost was not delivered until after 6 wks of initial therapy).
2. The definition of LC is different between the 2 studies. In the UKCCCR study, the definition was more strict, with failure defined as <50% tumor reduction after just 6 wks of 45 Gy to the pelvis.
Can MMC be removed from the standard regimen of 5-FU/MMC for the Tx of anal cancer? What major study addressed this question?
No. MMC cannot be deleted from the standard regimen.
RTOG 87-04 (Flam M et al., JCO 1996): 291 pts, MMC/5-FU + RT vs. 5-FU + RT. RT was 45–50.4 Gy. There was no difference in OS (76% vs. 67%, p = 0.31), but MMC improved the CR rate (92% vs. 22%) and colostomy rate (9% vs. 22%) at 4 yrs. Grade 4 or 5 heme toxicity was worse (26% vs. 7%).
Can cisplatin be substituted for MMC in the Tx of anal cancer? What 2 major studies addressed this question?
2 RCTs suggest that substituting cisplatin for MMC does not improve and possibly worsens outcomes:
RTOG 98-11 (Gunderson LL et al., JCO 2012): 649 pts, all stages except T1 or M1; excluded AIDS or prior cancers; randomized to standard MMC-based therapy vs. 2 cycles of cisplatin/5-FU → cisplatin/5-FU × 2 with RT. RT was 45 Gy to the pelvis, with boost for T2 residual to 10–14 Gy. DFS and OS were significantly superior in MMC-arm. 5-yr DFS: 67.8% vs. 57.8%, p = 0.006; 5-yr OS: 78.3% vs. 70.7%, p = 0.026. There was a trend toward statistical superiority of MMC arm for colostomy-free survival, locoregional failure, and colostomy failure. Acute grade 3–4 severe heme toxicity was significantly worse in the MMC arm (61.8% vs. 42.0%, p <0.001) but not in long-term toxicities (13.1% vs. 10.7%). Major criticism: Neoadj chemo on the experimental arm may have confounded the results.
ACTII (James R et al., Lancet Oncol 2013): 2 × 2 design, 940 pts (T1-2 [50%], T3-4 (43%), 30% N+, 85% anal canal, 15% anal margin) treated with 5-FU (1000 mg/m2/day, days 1–4, days 29–32) and RT (50.4 Gy) and randomized to concurrent MMC (12 mg/m2, day 1) or CDDP (cis-diamminedichloroplatinum) (60 mg/m2, days 1 and 29). 2nd randomization involved adding maintenance therapy (4 wks after CRT) to 2 cycles 5-FU/CDDP or no maintenance. Median follow-up was 5.1 yrs. Results: No difference in CR rate at 26 wks (90.5% MMC vs. 89.6% cis). Hematologic grade three-quarters side effects occurred in 26% cis vs. 16% MMC. 3-yr PFS, OS, and colostomy-free survival did not differ significantly between groups. The authors concluded that 5-FU/MMC/RT without maintenance chemo remain the standard of care.
What is the role of brachytherapy in anal cancer?
Brachytherapy is generally not done in the U.S. due to poor LC (<30% for large lesions) and higher complication rates. An older French experience showed favorable results with combined interstitial (Ir-192) and EBRT. (Papillon J & Montbarbon JF, Dis Colon Rectum 1987)
What is the recurrence rate after definitive CRT for anal cancer, and what are the salvage rates at 5 yrs?
The recurrence rate is 30%, and the salvage rate at 5 yrs is 40%–60%.
Describe the RTOG AP/PA technique for anal cancer and the corresponding doses.
The initial AP/PA from L5-S1 is 30.6 Gy (at 1.8 Gy/fx), then reduced AP/PA from the bottom of the sacroiliac joints (and off inguinals after 36 Gy if node–) to 45 Gy, then conformal CD to tumor + 2–2.5-cm margin (and electron boost if node+) to 55–59.4 Gy. The dose to the inguinals is supplemented by bilat electron fields that make up for lack of dose contribution from the PA field to the appropriate doses (to 36 Gy or to the final boost volume for node+ Dz).
How is the anal cancer pt simulated for the AP/PA RTOG technique?
Pt is simulated supine with full bladder and oral contrast and with hips in frog-leg position immobilized with vac-lock cradle, with placement of rectal tube, anal BB, and bolus over inguinal nodes.
How is the AP field different from the PA field for the AP/PA RTOG technique in anal cancer?
The AP field is wider (to the edge of the greater trochanter) than the PA field. As well, the PA field is typically of lower energy (6 MV) than the AP field (18 MV). This technique spares the dose to the femoral head and neck.
Per RTOG 98-11, which anal cancer pts need to receive a boost beyond 45 Gy?
Pts with T3, T4, or node+ lesions or T2 lesions with residual Dz after 45 Gy need a boost >45 Gy.
What is the dose per fx for anal cancer per RTOG 98-11?
Per RTOG 98-11, the dose per fx for anal cancer is 1.8 Gy/fx to 45 Gy initially, then 2 Gy/fx to 55–59 Gy total for the CD portion.
What is the min Rx depth for adequate inguinal node coverage in anal cancer?
The min Rx depth is 3 cm.
How far caudally should inguinal nodes be covered in anal cancer?
Inguinal nodes should be covered to the inf border of the lesser trochanter.
What is the MDACC technique for the Tx of anal cancer?
Field setup is similar as in the RTOG technique for the 1st 30.6 Gy. After this dose, the pt is placed prone on a belly board and a 3-field technique is employed, with portal weighted 2 (PA): 1 (right lat): 1 (left lat), energy is 15–18 MV, prescribed to 95% IDL, with the sup border reduced to bottom of the sacroiliac joint. This 3-field plan treats the mini-pelvis to 50.4 Gy. A boost is given to the primary and involved nodes to 55 Gy. The contribution to the inguinals from the 3-field approach is 5–7 Gy. Daily electron boost supplements the needed dose for the involved inguinal area.
What is the standard CRT regimen for anal cancer pts who are HIV+?
HIV+ pts can typically be treated with the same RT + 5-FU/MMC regimen as HIV– pts. HIV+ pts with CD4 counts <200/mm3 or other complications of HIV may require chemo and/or RT dose adjustments.
What is the role/evidence for IMRT in anal cancer?
RTOG 0529, a phase II single arm study, assessed the utility of 5-FU/MMC and dose-painted IMRT in reducing grade 2+ GI/GU toxicities compared with the conventional arm from RTOG 9811. Of 52 evaluable pts, a significant reduction was noted in acute grade 2+ hematologic (73% vs. 85%, p = 0.03), grade 3+ GI (21% vs. 36%, p = 0.008) and grade 3+ dermatologic adverse events (23% vs. 49%, p <0.0001). Of note, 81% required dose-painted IMRT replanning on central review. (Kachnic LA et al., IJROBP 2013) Preliminary cancer control outcomes appear similar to those in RTOG 9811. In addition, numerous retrospective studies suggest decreased toxicity and comparable efficacy. (Milano MT et al., IJROBP 2000; Menkarios C et al., Radiat Oncol 2007)
What RT dose should the bowel be kept under in anal cancer pts?
The bowel should be kept to a dose <45–50.4 Gy.
What is the main toxicity of MMC?
MMC has acute hematologic toxicities but does not contribute to late toxicities.
Most anal cancer recurrences are within what timeframe?
Most anal cancers recur within 2 yrs.
According to the NCCN guidelines (2014), what is the post-Tx follow-up for anal cancer?
Post-Tx anal cancer follow-up: Evaluate in 8–12 wks after Tx with DRE. Bx only if there is suspicious persistent Dz, progressive Dz, or new Sx (e.g., pain, bleeding). If there is complete remission, perform exam q3–6mos for 5 yrs with inguinal nodal evaluation, DRE, and anoscopy. Perform pelvic CT annually × 3 yrs (optional if T3-4 or node+ Dz).
What is the mean time to tumor regression after CRT?
The mean time to tumor regression after CRT is 3 mos (but can be up to 12 mos); therefore, there is no benefit to routine post-Tx Bx. (Cummings BJ et al., IJROBP 1991)
If a pt has Bx-proven persistent Dz 3 mos after completing Tx, should the pt be referred immediately for salvage surgery?
No. Pts may be re-evaluated again after 4 wks. If there is still no regression, or if there is progression, consider Bx again and restage if necessary. If there is evidence of regression, continue observation and evaluation in 3 mos.
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