• Anal cancer accounts for 2.5% of all digestive system cancers.
• Risk factors include HPV (anal-genital warts), a h/o of receptive anal
intercourse or STD, a h/o cervical, vulvar or vaginal cancer,
immunosuppression after solid organ transplantation or HIV,
hematologic malignancies, certain autoimmune disorders and
• The association between anal cancer and persistent infection with a
high risk form of HPV like HPV-16,18 is strong.
• High grade anal intraepithelial neoplasia (AIN) can be a precursor to
anal cancer. Its treatment may prevent anal cancer development.
• AIN can be identified by cytology, HPV testing, DRE, high resolution
anoscopy and biopsy.
• The anal region is comprised of anal
canal and anal margin.
• Anal canal is the more proximal portion
of the anal region.
• By histologic definition, the most
superior aspect of the anal canal is a 1-2
cm zone between the anal and rectal
epithelium, which has rectal, urothelial,
and squamous histologic characteristics.
• The most inferior aspect of the anal
canal, approx. at the anal verge
corresponds to the area where the
mucosa, lined with modified squamous
epithelium transitions to an epidermis-
lined anal margin.
• The anatomic anal canal begins at the
anorectal ring and extends to the anal
• Functionally, the anal canal is
defined by the sphincter muscles.
• The superior border of the
functional anal canal, separating
it from the rectum, has been
defined as the palpable upper
border of the anal sphincter and
puborectalis muscles of the
• It is approx. 3-5 cm in length and
its inferior border starts at the
anal verge, the lowermost edge
of the sphincter muscles,
corresponding to the introitus of
the anal orifice.
• The functional definition is used
in the radical surgical treatment.
• The anal margin starts at
the anal verge and
includes the perianal skin
over a 5-6 cm radius from
• It is covered by epidermis,
• Tumors can involve both
the anal canal and anal
Primary treatment of non-metastatic anal
cancer: Role of Chemotherapy
• Journal of Clinical Oncology 1997
Purpose of the study
• To investigate the potential gain of the concomitant use of
radiotherapy and chemotherapy in improving local control and
reducing the need for colostomy, a randomized phase III trial was
performed in patients with locally advanced anal cancer.
• From 1987 to 1994, 110 patients were randomized between radiotherapy
alone and a combination of radiotherapy and chemotherapy.
• The patients had T3-4NO-3 or T1-2N1-3 anal cancer.
• Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8
• After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of
partial or complete response, respectively.
• Surgical resection as part of the primary treatment was performed if
possible in patients who had not responded 6 weeks after 45 Gy or with
residual palpable disease after the completion of treatment.
• Chemotherapy was given during radiotherapy: 750 mg/m2 daily
fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a
single dose of mitomycin 15 mg/m2 administered on day 1.
• The addition of chemotherapy to radiotherapy resulted in a
significant increase in the complete remission rate from 54% for
radiotherapy alone to 80% for radiotherapy and chemotherapy, and
from 85% to 96%, respectively, if results are considered after surgical
• This led to a significant improvement of locoregional control and
colostomy-free interval (P = .02 and P = .002, respectively), both in
favor of the combined modality treatment.
• The locoregional control rate improved by 18% at 5 years, while the
colostomy-free rate at that time increased by 32% by the addition of
chemotherapy to radiotherapy.
• The survival rate remained similar in both treatment arms.
• Skin ulceration, nodal involvement, and sex were the most important
prognostic factors for both local control and survival.
• Event-free survival, defined as free of locoregional progression, no
colostomy, and no severe side effects or death, showed significant
improvement (P = .03) in favor of the combined-treatment modality.
• 585 patients were randomized to receive initially either 45 Gy radiotherapy
in twenty or twenty-five fractions over 4-5 weeks (290 patients) or the
same regimen of radiotherapy combined with 5-fluorouracil (1000 mg/m2
for 4 days or 750 mg/m2 for 5 days) by continuous infusion during the first
and the final weeks of radiotherapy and mitomycin (12 mg/m2) on day 1 of
the first course (295 patients).
• Clinical response was assessed 6 weeks after initial treatment: good
responders were recommended for boost radiotherapy and poor
responders for salvage surgery.
• The main endpoint was local-failure rate (> or = 6 weeks after initial
treatment); secondary endpoints were overall and cause-specific survival.
• After a median follow-up of 42 months, 164 of 279 (59%)
radiotherapy patients had a local failure compared with 101 of 283
(36%) CMT patients.
• This gave a 46% reduction in the risk of local failure in the patients
receiving CMT (relative risk 0.54, 95% CI 0.42-0.69, p < 0.0001).
• The risk of death from anal cancer was also reduced in the CMT arm
(0.71, 0.53-0.95, p = 0.02).
• There was no overall survival advantage (0.86, 0.67-1.11, p = 0.25).
• Early morbidity was significantly more frequent in the CMT arm (p =
0.03), but late morbidity occurred at similar rates.
• Definitive chemoradiation (CR) has replaced radical surgery as the
preferred treatment of epidermoid carcinoma of the anal canal.
• To determine the importance of mitomycin (MMC) in the standard CR
regimen and to assess the role of salvage CR in patients who have
residual tumor following CR, a phase III randomized trial was
undertaken by the Radiation Therapy Oncology Group (RTOG)/Eastern
Cooperative Oncology Group (ECOG).
Patients and Methods
• Between August 1988 and December 1991, 310 patients were
randomized to receive either radiotherapy (RT) and fluorouracil (5-FU)
or radiotherapy, 5-FU, and MMC.
• Of 291 assessable patients, 145 received 45 to 50.4 Gy of pelvic RT
plus 5-FU at 1,000 mg/m2/d for 4 days, and 146 received RT, 5-FU,
and MMC (10 mg/m2 per dose for two doses).
• Patients with residual tumor on posttreatment biopsy were treated
with a salvage regimen that consisted of additional pelvic RT (9 Gy), 5-
FU, and cisplatin (100 mg/m2).
• Posttreatment biopsies were positive in 15% of patients in the 5-FU
arm versus 7.7% in the MMC arm (P = .135).
• At 4 years, colostomy rates were lower (9% v 22%; P = .002),
colostomy-free survival higher (71% v 59%; P = .014), and disease-free
survival higher (73% v 51%; P = .0003) in the MMC arm.
• A significant difference in overall survival had not been observed at 4
• Toxicity was greater in the MMC arm (23% v 7% grade 4 and 5
toxicity; P < or = .001).
• Despite greater toxicity, the use of MMC in a definitive CR regimen for
anal cancer is justified, particularly in patients with large primary
• Salvage CR should be attempted in patients with residual disease
following definitive CR before resorting to radical surgery.
• Fluorouracil-based chemoradiotherapy is regarded as a standard
perioperative treatment in locally advanced rectal cancer.
• This study evaluated the efficacy and safety of substituting
fluorouracil with the oral prodrug capecitabine.
• This was a randomised, open-label, multicentre, non-inferiority, phase
3 trial that began in March, 2002, as an adjuvant trial comparing
capecitabine-based chemoradiotherapy with fluorouracil-based
chemoradiotherapy, in patients aged 18 years or older with
pathological stage II–III locally advanced rectal cancer from 35
• Patients in the capecitabine group were scheduled to receive two
cycles of capecitabine (2500 mg/m2 days 1–14, repeated day 22),
followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650
mg/m2 days 1–38), then three cycles of capecitabine.
• Patients in the fluorouracil group received two cycles of bolus
fluorouracil (500 mg/m2 days 1–5, repeated day 29), followed by
chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225
mg/m2 daily), then two cycles of bolus fluorouracil.
• The protocol was amended in March, 2005, to allow a neoadjuvant
cohort in which patients in the capecitabine group received
chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 daily)
followed by radical surgery and five cycles of capecitabine (2500
mg/m2 per day for 14 days) and patients in the fluorouracil group
received chemoradiotherapy (50·4 Gy plus infusional fluorouracil
1000 mg/m2days 1–5 and 29–33) followed by radical surgery and four
cycles of bolus fluorouracil (500 mg/m2 for 5 days).
• The primary endpoint was overall survival. Non-inferiority of
Capecitabine was tested.
• 5-year overall survival in the capecitabine group was non-inferior to that in
the fluorouracil group (76% [95% CI 67–82] vs 67% [58–74]; p=0·0004.
• Similar numbers of patients had local recurrences in each group (12 [6%] in
the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but
fewer patients developed distant metastases in the capecitabine group (37
[19%] vs 54 [28%]; p=0·04).
• Diarrhoea was the most common adverse event in both groups.
• Patients in the capecitabine group had more hand-foot skin reactions,
fatigue and proctitis than did those in the fluorouracil group, whereas
leucopenia was more frequent with fluorouracil than with capecitabine.
• Thus, Capecitabine could replace fluorouracil in adjuvant or
neoadjuvant chemoradiotherapy regimens for patients with locally
advanced rectal cancer.
• Chemoradiation became the standard of care for anal cancer after the
ACT I trial.
• However, only two-thirds of patients achieved local control, with 5-
year survival of 50%; therefore, better treatments are needed.
• The investigators studied whether replacing mitomycin with cisplatin
in chemoradiation improves response, and whether maintenance
chemotherapy after chemoradiation improves survival.
• Patients were randomly assigned to one of four groups, to receive
either mitomycin (12 mg/m2 on day 1) or cisplatin (60 mg/m2 on days
1 and 29), with fluorouracil (1000 mg/m2 per day on days 1–4 and
29–32) and radiotherapy (50·4 Gy in 28 daily fractions); with or
without two courses of maintenance chemotherapy (fluorouracil and
cisplatin at weeks 11 and 14).
• Primary endpoints were complete response at 26 weeks and acute
toxic effects (for chemoradiation), and progression-free survival (for
• 472 patients were assigned to mitomycin, of whom 246 were assigned to
no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of
whom 246 were assigned to no maintenance, 222 to maintenance.
• Median follow-up was 5·1 years.
• 90·5% patients in the mitomycin group versus 89·6% in the cisplatin group
had a complete response at 26 weeks (difference −0·9%, 95% CI −4·9 to 3·1;
• Overall, toxic effects were similar in each group.
• The most common grade 3–4 toxic effects were skin, pain, haematological,
• 3-year progression-free survival was 74% (95% CI 69–77; maintenance)
versus 73% (95% CI 68–77; no maintenance; hazard ratio 0·95, 95% CI
All patients received CX (400 mg/m2 loading, then 250 mg/m2/wk IV x 6-8
wks) plus CDDP (75 mg/m2 IV q28 days x 2) and 5-FU (1000 mg/m2/day IV
infusion days 1-4 q 28 days x 2) concurrently with RT (45-54 Gy) beginning
with CX dose 2. Patients in E3205 also received 2 cycles of CDDP/5-FU alone
prior to CX/CDDP/5-FU/RT; this was discontinued on recommendation of the
NCI Anorectal Task Force after 28 patients.
Both trials were powered to detect a reduction in 3-year local-regional
failure (LRF) rate from 35% to 17.5% (alpha=0.10, beta=0.10), the primary
Other endpoints included progression free survival (PFS) and overall survival
The results below include complete toxicity and preliminary efficacy data
(including only the first 28 patients from E3205).
• CX plus CDDP/5-FU/RT is feasible in patients with SCAC, including
patients with HIV infection.
• Immunocompetent patients with histologically confirmed LAACC
received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil
and cisplatin during weeks 1 and 5), in combination with weekly dose
of cetuximab (250 mg/m2 with a loading dose of 400 mg/m21 week
before irradiation), and a standard dose boost (20 Gy).
• The trial was originally designed to include 81 patients to detect a
15% of objective response increase with the new combination in
comparison with CRT.
• The trial was prematurely stopped after the declaration of 15 serious adverse
events (SAEs) in 14 out of 16 patients.
• Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects,
observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%),
dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%),
and others (n = 9); and three patients suffered from six G3/4 late toxic effects.
• No treatment-related death was reported.
• All 11 assessable patients had an objective response consisting of six complete
(55%) and five partial (45%) response 2 months after the end of the treatment.
• Thirteen patients were followed up with a median of 22 months [95% confidence
interval (CI ): 18–27] and had a 1-year colostomy-free survival, progression-free
and overall survival rate of 67% (95% CI: 40%–86%), 62% (95% CI: 36%–82%), and
92% (95% CI: 67%–99%), respectively.
NCCN Recommendations for Primary
treatment of anal canal cancer: Summary
• Currently, concurrent chemoRT is the recommended primary
treatment for patients with nonmetastatic anal canal cancer.
• Mitomycin and 5-FU or mitomycin and capecitabine are administered
concurrently with radiation.
• Most studies have delivered 5-FU as a protracted 96-120 hour
infusion during the first and fifth weeks of RT, and bolus injection of
mitomycin is typically given on the first or second day of 5-FU
• Capecitabine is given orally, Mon through Fri for 4-6 weeks, with
bolus injecvtion of mitomycin and concurrent radiation.
Treatment of metastatic anal cancer
• Most common sites of anal cancer metastasis outside of the pelvis
include liver, lung and extrapelvic lymph nodes.
• Metastatic disease is usually treated with cisplatin based
• No evidence supporting resection of metastatic disease.
• Palliative RT can be given in case of a symptomatic bulky primary.
• If cisplatin based therapy fails, no other regimens have shown to be