By

Osama Elzaafarany, MDAssistant lecturer of clinical oncology

Medical Research Institute, Alexandria University

Jan 2015

Estimated new cases and deaths from anal, anal canal, and ano-rectal cancer in the United States in 2014:

• New cases: 7,210.

• Deaths: 950.

Anal cancer is an uncommon malignancy and accounts for only a small percentage (2%) of all GIT cancers.

Peak incidence in 70th decade, but highly variable

Human papilloma virus (HPV-16, 18 & 31)

Female gender (many series of data)

HIV positive patients.

Sexual promiscuity- particularly receptive anal

intercourse

Cigarette smoking

Anal canal extends from the

anorectal ring (dentate line) to the

anal verge(3-4 cm).

Regions:-

Intraanal lesions:Cannot be visualized or only slightly

visualized with gentle traction on the

buttocks

Perianal lesions:Completely visible; within a 5-cm radius of

anal opening with gentle traction

Skin lesions:

Outside of the 5-cm radius

Distal anal canal drains to inguinal nodes,

femoral and hence ext iliac

Proximal tumours drain to mesorectal, then

inf mesenteric, to para-aortic

Lymph node involvement at diagnosis is

observed in 30%–40% of cases while systemic

spread is uncommon with distant extra-pelvic

metastases recorded in 5%–8% at onset.

Anal cancer may arise from a precursor dysplastic lesion(AIN) or

“anal squamous intra-epithelial lesions”.

progression from AIN 3 to invasive malignancy in immuno-

competent patients is rare, but appears to be more likely in immuno-

suppressed patients, and is influenced by HIV seropositivity, low

CD4 count and serotype of HPV infection.

HPV-associated tumours usually retain wild-type P53, and this

explains why patients with HPV-associated tumours respond well to

concurrent chemoradiotherapy.

Data on the interaction with wild-type P53 in cigarette smokers, as in

head and neck cancer, are lacking.

HPV-related vaginal and cervical intra-epithelial and malignant

squamous lesions should be screened for in younger women.

Squamous cell carcinoma: Cloacogenic carcinoma.

Transitional cell carcinoma,

Basaloid carcinoma.

Keratinizing carcinoma.

Adenocarcinoma.

Small cell carcinoma.

Undifferentiated ca.

The World Health Organization (3rd & 4th edition)

classification of malignant epithelial tumors of the anal

canal includes :-

Tumours of the anal margin are generally well differentiated

and often occur in men, in contrast to canal tumours which are

normally poorly differentiated and more common in women.

Some authors report that a basaloid histological subtype has

a higher risk of developing metastatic disease.

The biology and prognosis of keratinising and non-

keratinising tumours of the anal canal also appear to be

similar.

Verrucous carcinomas: are a variant and are sometimes

described as giant condylomas or Buschke–Lowenstein

tumours, which may have a better prognosis than SCC, for

whom some consider surgery the best option.

• Abdomino-perineal resection was previously thought to be

required for all but small anal cancers occurring below the dentate

line with about 70% of patients surviving 5 or more years, but

such surgery is no longer the treatment of choice.

• However, smaller lesions (<2 cm in diameter), involving the anal

margin and not poorly differentiated may be treated by primary

surgery in the form of a local excision provided adequate margins

(>5 mm) can be obtained without compromising sphincter

function.

• Radiation therapy alone may lead to a 5 year survival rate in

excess of 70%, but high doses (≥60 Gy) may yield necrosis or

fibrosis.

Chemotherapy with fluorouracil (5FU) and cisplatin concurrent

with lower dose radiation therapy as utilized in the RTOG8314

trial has a 5 ys survival rate in excess of 70% with low levels

of acute and chronic morbidity, and few patients require

surgery for dermal or sphincter toxic effects.

The optimal dose of radiation with concurrent chemotherapy to

optimize local control and minimize sphincter toxic effects

has been studied in the RTOG9208 trial, for example, and

appears to be in the 45 - 60 Gy range

The Anal Cancer Trial (ACT1) from the United Kingdom

Coordinating Committee on Cancer Research:

Demonstrated the superiority of chemoradiation with 5-FU and

mitomycin C (MMC) over radiation alone with regard to local

failure and deaths from anal cancer.

Longterm follow up of this study has revealed 25.3 fewer

patients with locoregional relapse and 12.5 fewer anal cancer

deaths per 100 patients treated with chemoradiation compared

with 100 patients treated with radiation alone.

9.1% increase in non-anal cancer deaths was seen in the first 5

years following chemoradiation, which was not seen after 10

years.

ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــNorthover J, GlynneJones R, SebagMontefiore D, et al.: Chemoradiation for the treatment

of epidermoid anal cancer: 13year followup of the first randomised UKCCCR Anal Cancer

Trial (ACT I). Br J Cancer 102 (7): 11238,, 2010

The choice of chemotherapy during concurrent

chemo-radiation has been the subject of several

trials.

Analysis of an intergroup trial (Flam M, et al. J

Clin Oncol 1996) that compared radiation therapy plus 5FU

and MMC with radiation therapy plus 5FU alone in

patients with anal cancer demonstrated lower

colostomy rates as well as higher colostomy free and

disease free survival (DFS) with the addition of

MMC.

The intergroup, randomized, phase III trial (RTOG 9811) examined whether MMC could be replaced by cisplatin in combination with 5FU during concurrent chemoradiation:

In the cisplatin arm of this study, two cycles of induction 5FU

and cisplatin were given before concurrent chemoradiation with 5FU and cisplatin.

The MMC arm had improved local control and colostomy freesurvival, but no improvement was found in DFS or overall survival (OS).

Longterm follow up of the RTOG9811 trial has been published and demonstrated superior 5-year DFS and OS. One potentialexplanation for the inferiority of the cisplatin arm is delay in time to radiation, given the induction strategy employed in this study.

A strategy of maintenance chemotherapy with 5FUand cisplatin after chemoradiation with 5FU and MMC or 5FU and cisplatin was evaluated in the ACTII trial, and 3-year PFS was not improved (74% with maintenance chemotherapy vs. 73% without maintenance Chemotherapy.

Induction chemotherapy and dose intensification were examined in the UNICANCER ACCORD03 trial, which did not demonstrate an advantage in colostomy freesurvival with induction chemotherapy with 5FU and cisplatinor with radiation dose intensification.

LOWER BORDER

UPPER BORDER

MINI. 2.5 CM MARGIN AROUND ANUS &

TUMOR

Field arrangement:

Capecitabine is an accepted alternative to 5-FU in

CCRT based in retrospectve studies.

Cetuximab (Anti-EGFR ) is effective with accepted

toxicity profile when combined with Cisplatin-5FU and RTx,

based in phase II studies.

Brachytherapy: There are currently limited data on the

use of HDR brachytherapy in anal cancer and lack of

consensus on the optimal fractionation schedule. Curative

brachytherapy as a single modality is not recommended,

but may be applicable as a boost following response to

CCRT.

Standard salvage therapy for those patients with either

gross or microscopic residual disease following

chemoradiation therapy has been abdomino-perineal

resection.

Alternately, patients may be treated with additional

salvage chemoradiation therapy in the form of 5FU,

cisplatin, and a radiation boost to potentially avoid

permanent colostomy.

Because of the small number of cases, information that

can only come from patient participation in Well designed

clinical trials is needed to improve the management of anal

cancer. Patients with stages II, III, and IV disease should be

considered candidates for clinical trials.

• Approximately 10%–20% of patients suffer distant relapse.

• The most common sites of metastatic spread are to the para-

aortic nodes, liver, lungs and skin, which usually appear

relatively late and in the context of local persistence or

recurrence of disease following treatment.

• The prognosis in this group is poor with only 10% of patients

with distant metastases surviving 2 years or more, but long-

term survivors are described.

• Patients with small volume or isolated metastatic disease

should be further discussed by an appropriate Multi-

disceplinary team, in case there are surgical or CRT options.

• There is no consensus on the standard chemotherapy treatment.

The choice of chemotherapy is often influenced by previously used

agents in the initial CRT regimen, but regimens with good

documented activity are limited and generally have produced

unsatisfactory results.

• Otherwise fit patients with symptomatic metastatic or recurrent

disease not amenable to surgery should be considered for

chemotherapy; combination of cisplatin+5-FU.

• Activity is also reported for carboplatin, doxorubicin, taxanes and

irinotecan ± cetuximab, or combinations of these agents.

• Responses are rarely complete and usually of short duration.

Combinations of 5-FU based CCRT and other cytotoxic agents e.g

Mitomycin C = (MMC), have been established as the standard of care,

leading to complete tumour regression in 80%–90% of patients, with

locoregional failures of 15%.

Adenocarcinoma arises from the columnar epithelium of the anal canal and its incidence is low accounting for less than 5 % of all anal malignancies.

Extension of rectal cancer into the anal canal is the more common presentation. Occasionally, adenocarcinomamay occur in patients with ulcerative colitis or Crohndisease who have ileal pouch-anal anastomosis.

APR should be offered for early-stage disease.

For locally advanced disease (T3 or any T with N + ), a multimodality approach should be considered. Patients treated with APR had significantly improved 5-year OS than those treated with radiation alone.

Anorectal melanoma is rare and accounts for less than 3 % of all malignant melanomas and less than 1 % of all anal canal tumors.

The 5 -year OS rate is generally less than 20 % . The initial stage at presentation largely determines OS.

Ross et al. from the M. D. Anderson Cancer Center reviewed a series of 32 patients with melanoma treated with either APR or local resection.

Local recurrence was lower in the APR group (29 % for APR; 5 8 % for local excision) . However, there was no difference in OS between the two groups ( 19 . 5 months for APR; 18 .9 months for local resection ) .

Most authors recommend local excision of anorectalmelanoma if adequate margins could be achieved.