Anal cancer

Anal Carcinoma
• Ranjita Pallavi, Fellow 1

Overview
• 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
smoking.
• The association between anal cancer and persistent infection with a
high risk form of HPV like HPV-16,18 is strong.

Risk Reduction
• 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.

Anatomy
• 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
verge.

Anatomy
• 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
anorectal ring.
• 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.

Anatomy
• The anal margin starts at
the anal verge and
includes the perianal skin
over a 5-6 cm radius from
the squamous
mucocutaneous junction.
• It is covered by epidermis,
not mucosa.
• Tumors can involve both
the anal canal and anal
margin.

Sentinel nodes of the anus are inguinal nodes.

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.

Methods
• 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
Gy.
• 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.

Results
• 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
resections.
• 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.

Results
• 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.

Locoregional control/Colostomy free interval

Methods
• 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.

Results
• 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.

• Journal of Clinical Oncology 1996

Purpose
• 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).

Results
• 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
years.
• Toxicity was greater in the MMC arm (23% v 7% grade 4 and 5
toxicity; P < or = .001).

Conclusions
• Despite greater toxicity, the use of MMC in a definitive CR regimen for
anal cancer is justified, particularly in patients with large primary
tumors.
• Salvage CR should be attempted in patients with residual disease
following definitive CR before resorting to radical surgery.

Purpose
• 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.

Methods
• 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
German institutions.
• 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.

Methods
• 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.

Results
• 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.

Conclusion
• Thus, Capecitabine could replace fluorouracil in adjuvant or
neoadjuvant chemoradiotherapy regimens for patients with locally
advanced rectal cancer.

Purpose
• 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.

Methods
• 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
maintenance).

Findings
• 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;
p=0·64).
• Overall, toxic effects were similar in each group.
• The most common grade 3–4 toxic effects were skin, pain, haematological,
and gastrointestinal.
• 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
0·75–1·21; p=0·70).

Methods
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
end point.
Other endpoints included progression free survival (PFS) and overall survival
(OS).
The results below include complete toxicity and preliminary efficacy data
(including only the first 28 patients from E3205).

Results
• CX plus CDDP/5-FU/RT is feasible in patients with SCAC, including
patients with HIV infection.

Methods
• 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.

Results
• 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
infusion.
• 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
chemotherapy.
• 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
effective.

Anal cancer

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