Treatment overview:
chemoradiation
addition of chemotherapy (5-FU plus mitomycin) to radiation therapy may reduce local failure and colostomy rates
drugs of choice - fluorouracil (Adrucil, 5-FU) plus mitomycin (Mutamycin)
addition of mitomycin to chemoradiation with 5-FU may improve colostomy-free survival
cisplatin may be associated with less hematologic toxicity than mitomycin as part of chemoradiation but increased risk for colostomy
assessment of response to chemoradiation recommended at 6-8 weeks
radiotherapy
three-dimensional conformal radiotherapy (3D-CRT) may improve survival and freedom from relapse compared to conventional radiotherapy
external beam radiation without chemotherapy reported to be effective for T1 and T2 lesions in case series
pelvic irradiation associated with increased risk of pelvic fracture in older women
abdominoperineal resection (APR) considered salvage therapy for persistent or recurrent disease after chemoradiation
Medications:
drugs of choice according to The Medical Letter
drugs of choice - fluorouracil (Adrucil, 5-FU) plus mitomycin (Mutamycin)
alternative - cisplatin (Platinol) plus fluorouracil (Adrucil, 5-FU)
addition of chemotherapy (5-FU plus mitomycin) to radiation therapy may reduce local failure and colostomy rates
based on 2 randomized trials without blinding
UKCCCR trial
585 patients aged 26-88 years with epidermoid anal cancer were randomized to chemoradiation (radiation plus mitomycin plus 5-FU) vs. radiotherapy alone and followed for median 42 months
external beam radiation with 45 Gy as central axis dose given for 4-5 weeks
chemotherapy given with first course of radiotherapy
initial chemotherapy was 5-FU (1,000 mg/m
2
IV for 4 days or 750 mg/m
2
for 5 days) plus mitomycin (12 mg/m
2
IV given on day 1 of first course of radiotherapy)
subsequent chemotherapy was 5-FU (same dose) without mitomycin during final week of first radiotherapy course
562 (96%) patients who had ≥ 6 weeks of treatment were analyzed
comparing chemoradiation vs. radiation alone at 3 years
39% vs. 61% local failure (p < 0.0001, NNT 5)
65% vs. 58% overall survival (not significant)
EORTC trial
110 patients with locally advanced anal cancer were randomized to chemoradiation (5-FU plus mitomycin plus radiation) vs. radiation alone and followed for median 42 months
radiotherapy consisted of 45 Gy given in 5 weeks (daily dose 1.8 Gy), additional treatment given at 6 weeks if partial (20 Gy) or complete (15 Gy) response
chemotherapy (given with first course of radiotherapy) consisted of fluorouracil 750 mg/m
2
IV continuously on days 1-5 and 29-33 plus mitomycin 15 mg/m
2
as single dose on day 1
comparing chemoradiation vs. radiation alone
80% vs. 54% had complete remission
68% vs. 50% estimated locoregional control at 5 years (p = 0.02, NNT 6)
72% vs. 40% estimated colostomy-free rate (p = 0.002, NNT 3)
58% vs. 54% overall survival (not significant)
no significant differences in severe side effects but anal ulcers more frequent with combination therapy
addition of mitomycin to chemoradiation with 5-FU may improve colostomy-free survival
based on randomized trial with allocation concealment and blinding not stated
310 patients with anal canal cancer were given chemoradiation with 5-FU (1,000 mg/m
2
on days 1 and 29) plus radiotherapy (45-50 Gy over 5 weeks) and then randomized to mitomycin (10 mg/m
2
on days 1 and 29) vs. no additional treatment and followed for median 3 years
patients with residual tumor had salvage treatment with radiation 9 Gy, 5-FU, and cisplatin 100 mg/m
2
291 patients (94%) were analyzed
comparing chemoradiation with vs. without mitomycin at 4 years
9% vs. 22% colostomy rate (p = 0.002, NNT 8)
71% vs. 59% colostomy-free survival (p = 0.014, NNT 9)
73% vs. 51% disease-free survival (p = 0.0003, NNT 5)
no significant differences in overall survival
grade 4-5 toxicity occurred in 23% of patients with mitomycin vs. 7% without (p < 0.001, NNH 7)
cisplatin may be associated with less hematologic toxicity than mitomycin as part of chemoradiation but increased risk for colostomy
based on randomized trial without blinding
682 patients with anal cancer were given radiation and were randomized to 5-FU plus cisplatin vs. 5-FU plus mitomycin
5-FU plus cisplatin group treated with
5-FU 1,000 mg/m
2
daily (days 1-4, 29-32, 57-60, 85-88)
cisplatin 75 mg/m
2
(days 1, 29, 57, 85)
radiation 45-59 Gy starting on day 57
5-FU plus mitomycin group treated with
5-FU 1,000 mg/m
2
daily (days 1-4, 29-32)
mitomycin 10 mg/m
2
bolus (days 1, 29)
radiation 45-59 Gy
median follow-up 2.51 years
644 (94.4%) patients analyzed
comparing chemoradiation with cisplatin vs. chemoradiation with mitomycin
42% vs. 61% had grade 3-4 hematologic toxicity (p = 0.001, NNT 6 favoring cisplatin)
16% vs. 10% had colostomy at 3 years (p = 0.02, NNH 17)
19% vs. 10% had colostomy at 5 years (p = 0.02, NNH 11)
61% vs. 67% disease-free survival at 3 years (not significant)
54% vs. 60% disease-free survival at 5 years (not significant)
76% vs. 84% overall survival at 3 years (not significant)
70% vs. 75% overall survival at 5 years (not significant)
Surgery:
abdominoperineal resection (APR)
results in permanent end colostomy
current recommended role is salvage therapy for persistent or recurrent disease following chemoradiation in patients who are not candidates for salvage chemoradiation
Other management:
three-dimensional conformal radiotherapy (3D-CRT) may improve survival and freedom from relapse compared to conventional radiotherapy
based on prospective cohort study
62 consecutive patients with anal cancer had 3D-CRT 54 Gy in 30 fractions continuously and were compared to 60 historical controls having conventional radiotherapy with median 54 Gy in split course
all patients had concurrent chemotherapy with 5-fluorouracil plus either mitomycin-C or cis-platinum
comparing 3D-CRT vs. conventional radiation at 5 years
80.7% vs. 53.9% overall survival (p = 0.017, NNT 4)
70.2% vs. 46.1% freedom from relapse (p = 0.016, NNT 4)
85.1% vs. 61.1% actuarial local control (p = 0.005, NNT 5)
external radiation therapy without chemotherapy reported to be effective for T1 and T2 lesions
based on 3 case series
case series of 305 patients with cancer of anal canal
305 patients with anal cancer had curative-intent radiotherapy (median dose 45 Gy) and were followed for mean 103 months
279 patients had EBRT 20 Gy boost after rest period of 4-6 weeks
17 had interstitial (192)Ir brachytherapy boost after rest period of 4-6 weeks
7 patients had only 1 course of EBRT
2 patients had interstitial (192)Ir brachytherapy only
19 patients had concomitant chemotherapy with 5-FU plus either cisplatin or mitomycin-C
local tumor clinical response rates at end of radiotherapy
96% for T1 tumors
87% for T2 tumors
79% for T3 tumors
44% for T4 tumors
74% disease-free survival at 10 years
factors associated with disease-free survival were
interval between 2 courses of radiotherapy
pretreatment anal function score
clinical compete response after radiotherapy
case series of 72 patients with cancer of anal canal
all patients treated with external beam radiation (commonly 5,000 centigray over 4 weeks)
5-year outcomes
66% actuarial survival
78% disease-specific survival (71% T1, 88% T2, 41% T3, 42% T4)
17 patients (24%) had local recurrence
53 patients (74%) retained anal function
6 patients (8%) had severe late complications
case series of 18 patients with cancer of anal canal
all had radiation 45-50 Gy in 25-28 fractions, 16 had additional radiation increasing total dose to 55-67 Gy
follow-up ranged from 2.5-11.2 years
94% projected survival at 5 years
100% projected freedom from local recurrence at 5 years
no patient required permanent colostomy or had permanent sphincter function loss
chemotherapy plus external beam radiation followed by interstitial implant reported to have 84% loco-regional control in patients with T3 and T4 anal cancer
based on case series
31 patients with T3 or T4 anal cancer had external beam radiation 30 Gy plus 5-FU plus mitomycin-C followed by interstitial (192)Ir implant boost (median implant dose 31.3 Gy at 0.5 cm delivered at mean 0.52 Gy/hour)
6 patients had local persistence
4 developed local recurrence
8 patients had abdominoperineal resection (APR)
84% local regional control after initial treatment and APR
pelvic irradiation associated with increased risk of pelvic fracture in older women
based on retrospective cohort study
6,428 women > 65 years old with pelvic malignancies included 556 women with anal cancer, 1,605 with cervical cancer and 4,267 with rectal cancer
rates of pelvic fracture in women who had pelvic irradiation vs. women who did not have pelvic irradiation
14% vs. 5% in women with anal cancer
7% vs. 5% in women with cervical cancer
9% vs. 9% in women with rectal cancer
cumulative 5-year fracture rate (after adjusting for length of follow-up) in women who had pelvic irradiation vs. women who did not have pelvic irradiation
14% vs. 7.5% in women with anal cancer
8.2% vs. 5.9% in women with cervical cancer
11.2% vs. 8.7% in women with rectal cancer