Radiation Oncology: A Question-Based Review

Anal Cancer

Boris Hristov and Salma Jabbour

image Background

What is the incidence of anal cancer in the U.S.?

5,290 cases/yr in 2009 in the U.S. (ACS 2009)

Is there a gender 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

Is anal cancer an AIDS-defining illness?

No. However, 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.

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) 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?

1.     Above dentate line: drains to pudendal/hypogastric/obturator/hemorroidal → internal iliac nodes

2.     Below dentate line: drains to inguinal/femoral nodes → external iliacs

What % of anal cancer pt 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.

image 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 suspicous LN

What imaging studies are typically done for anal cancer pts?

Transanal US (to assess for perirectal nodes/assess invasion), CXR or CT chest, CT abdomen/pelvis, and PET/CT

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, as 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 for anal cancer is based on the size of the lesion.

1.     T1: ≤2 cm

2.     T2: >2–5 cm

3.     T3: >5 cm

4.     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?

Nodeor T4 pts have AJCC stage III Dz.

What is the AJCC 7th edition (2009) stage grouping for anal cancer?

1.     Stage I: T1N0

2.     Stage II: T2N0 or T3N0

3.     Stage IIIA: T1-3N1 or T4N0

4.     Stage IIIB: T4N1 or TXN2 or N3

5.     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 1984Note: 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.

image 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 (1,000 mg/m2 × 4 days) and mytomycin-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 et al?

In Nigro 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 (200 cGy in 15 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 1,000 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 had prior pelvic RT.

Is there data directly comparing surgery to CRT in anal cancer?

No. There is no randomized evidence. However, 1 retrospective analysis from Sweden showed better 5-yr OS in pts who rcv 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?

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-T4 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 to 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 because 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?

This is controversial. 2 randomized studies are conflicting on the possibility of cisplatin substituting for MMC.

RTOG 98-11 (Ajani JA et al., JAMA 2008): 644 pts, all stages except T1 or M1; excluded AIDS or prior cancers; randomized to standard 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. Only the 5-yr colostomyfree survival rate was better in the standard arm compared to the cisplatin/5-FU arm, but not in DFS, LR/DM, or OS. 5-yr colostomyfree rate: 10% vs. 19%, p = 0.02; 5-yr DFS: 60% vs. 54%, p = 0.17; LRF (HR 1.32 with cisplatin, p = 0.07), DM (HR 1.38 with cisplatin, p = 0.14), 5-yr OS: 75% vs. 70%, p = 0.1. Acute grade 3 or 4 severe heme toxicity was worse in the MMC arm (61% vs. 42%, p <0.001) but not in long-term toxicities (11% vs. 10%). Major criticism: Neoadj chemo on the experimental arm may have confounded the results.

ACTII (James R et al., ASCO 2009): 2 × 2 design, 940 pts (T1-T2 [50%], T3-T4 (43%), 30% N+, 85% anal canal, 15% anal margin) treated with 5-FU (1,000 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 (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 at 3 yrs. Results: No difference in CR rate (94% vs. 95%) and # of colostomies (18 vs. 14), and no difference in RFS or OS with maintenance therapy. MMC had more acute grade 3–4 heme toxicities (25% vs. 13%, p <0.001) but no worse sepsis or non-heme toxicities.

When is neoadj chemo an option for anal cancer?

For advanced T3-T4 lesions and/or bulky N2 or N3, especially if an abscess or fistula. Induction cisplatin or cisplatin/5-FU × 2 per CALGB 9281 → definitive CRT (Meropol NJ et al., JCO 2008) can be used. This phase II study demonstrated an 82% CR rate, with a 4-yr OS of 68% and 50% colostomyfree survival in these poor-risk pts.

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 EB RT (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 rates at 5 yrs are 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 nodelesions 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 are some of the challenges in HIV+ pts?

Challenges for HIV+ pts include lower LC (by one half) and more side effects (2 times) when compared to HIV– pts. OS is similar, though (Oehler-Janne C et al., JCO 2005). Consider substituting MMC for cisplatin/5-FU–based CRT.

What is the role/evidence for IMRT in anal cancer?

Few retrospective studies have shown decreased toxicity and comparable efficacy (French experience: Menkarios C et al., Radiat Oncol 2007; University of Chicago experience: Milano MT et al., IJROBP 2000). This is being prospectively tested in a phase II evaluation through RTOG 0529 using dose-painting techniques. Early results in 51 pts demonstrate significantly better grade 2–3 GI/GU, and skin toxicities compared to RTOG 98-11, with promising clinical response rates (Kachnic LA et al., ASCO-GI 2010)

image Toxicity

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 time frame?

Most anal cancers recur within 2 yrs.

According to the NCCN, 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 nodal evaluation, DRE, and anoscopy. Perform pelvic CT annually × 3 yrs (optional if T3-T4 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. According to the NCCN (2010), the pt can be re-evaluated again in 4 wks. If there is still no regression, or if there is progression, Bx again and restage if necessary. However, if there is evidence of regression, then continue observation and evaluation in 3 mos.