Osama Elzaafarany, MD
Assistant lecturer of clinical oncology
Medical Research Institute, Alexandria University
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
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
Anal canal extends from the
anorectal ring (dentate line) to the
anal verge(3-4 cm).
Cannot be visualized or only slightly
visualized with gentle traction on the
Completely visible; within a 5-cm radius of
anal opening with gentle traction
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
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:
Transitional cell carcinoma,
Small cell carcinoma.
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
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
• Radiation therapy alone may lead to a 5 year survival rate in
excess of 70%, but high doses (≥60 Gy) may yield necrosis or
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
Northover 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
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
The intergroup, randomized, phase III trial (RTOG
9811) examined whether MMC could be replaced by
cisplatin in combination with 5FU during concurrent
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 free
survival, but no improvement was found in DFS or overall
Longterm follow up of the RTOG9811 trial has been published
and demonstrated superior 5-year DFS and OS. One potential
explanation for the inferiority of the cisplatin arm is delay in
time to radiation, given the induction strategy employed in this
A strategy of maintenance chemotherapy with 5FU
and 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 free
survival with induction chemotherapy with 5FU and cisplatin
or with radiation dose intensification.
MINI. 2.5 CM MARGIN AROUND ANUS &
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
Standard salvage therapy for those patients with either
gross or microscopic residual disease following
chemoradiation therapy has been abdomino-perineal
Alternately, patients may be treated with additional
salvage chemoradiation therapy in the form of 5FU,
cisplatin, and a radiation boost to potentially avoid
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
• 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, adenocarcinoma
may occur in patients with ulcerative colitis or Crohn
disease 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
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 anorectal
melanoma if adequate margins could be achieved.