Chemoradiation is the standard of care for the treatment of anal cancer.r The addition of mitomycin (MMC) to continuous-infusional fluorouracil (5-FU) and radiation was shown to confer significant benefit over 5-FU alone, and has been the treatment of choice in anal cancer.rr Capecitabine (an oral fluoropyrimidine), is used as an alternative to intravenous 5-FU in other malignancies with non-inferior efficacy.r There are however no phase III studies of capecitabine in anal cancer.
A search of the literature did not find strong evidence to support the use of capecitabine and mitomycin in the treatment of anal cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II studies by Oliveira et al and Glynne-Jones et al.
The study by Oliveira et al was a small non-randomised single arm phase II study evaluating capecitabine as a substitute for 5-FU with mitomycin and radiation in patients with localised squamous cell carcinoma of the anal canal.r HIV positive patients were considered eligible for the study if they had CD4 > 200 cells/mm3 within 1 month from treatment start. Patients with SCC of the anal canal (clinical T2-4N0M0 or any T with locoregional-positive nodes and M0) were treated with a single dose of IV mitomycin 15 mg/m2 on day 1 and oral capecitabine 825 mg/m2 twice a day from Monday to Friday during radiation therapy (over 5 to 6 weeks). r
The study by Glynne-Jones et al was a small non-randomised single arm phase II study which evaluated the efficacy and toxicity of capecitabine as a substitute for 5-FU with mitomycin and radiation in patients with primary epidermoid anal cancer.r Patients were treated with a single dose IV mitomycin 12 mg/m2 on day 1 and oral capecitabine 825 mg/m2 twice a day on days of radiation therapy (days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-40). r
A number of retrospective studies have also been performed.rrr
The mitomycin and capecitabine doses for this protocol are based on the study by Glynne-Jones et al.r
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Oliveira et al, 2016 |
Yes |
No |
Capecitabine 825mg/m2 twice daily with radiation therapy with a single dose of mitomycin 15mg/m2 on Day 1
|
|
Glynne-Jones et al, 2007 |
Yes |
Yes |
|
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.2 2016 |
Yes |
Yes |
|
BCCA |
- |
N/A |
|
|
CCO |
- |
N/A |
|
|
Efficacy
The study by Oliveira et al had a median follow up of 23.1 months. The rate of complete response at 6 weeks was 69.8% (n=30). Partial response at 6 weeks occurred in 12 patients (27.9%) and 1 patient had disease progression. The locoregional control rate at 6 months was 86% (CI 95%, 0.72– 0.94). The median progression free survival was 21.8 months and overall survival rate was 97.7% at 23.1 months of follow-up.r During the study, 8 patients (18.6%) required colostomy, with two of them being performed before treatment initiation and 7 patients (16.3%) underwent abdominoperineal resection.r
The study by Glynne-Jones et al had a median follow up 14 months. The rate of complete response at 4 weeks was 77% (24 patients).r Partial response at 4 weeks occurred in 5 patients (16%) and 1 patient (3%) was reported to have stable disease. The locoregional control rate at 6 months was 90%.r
|
Oliveirar
n = 43
Phase II
|
Glynne-Jonesr
n = 31
Phase II |
Response assessment clinical (C)/ radiological (R) |
6 weeks C/R |
6 months C/R |
4 weeks C/R |
6 months C/R |
Complete response |
70% |
86% |
77% |
90% |
Partial response |
28% |
7% |
16% |
3% |
Stable disease |
0 |
0 |
3% |
0 |
Progressive disease |
2% |
7% |
0 |
6% |
Progression free survival |
21.8 months |
- |
Colostomy rate |
18% |
- |
Toxicity
In the Oliveira et al study the main grade 3 - 4 toxicities were radiodermatitis, lymphopenia, and neutropenia.r Notably 24 patients (55.8 %) required dose interruption of capecitabine for a mean duration of 11.2 ± 11.03 days and one patient (HIV positive) discontinued due to grade 4 toxicities (including septic shock, pneumonia, herpes encephalitis and macrophage activation syndrome).r
In the Glynne-Jones et al study the main grade 3 - 4 toxicities were radiodermatitis and neutropenia.r 68% of patients received the full dose of chemotherapy with capecitabine and mitomycin without interruption. Five patients discontinued treatment before completion, one due to cardiac chest pain and four due to capecitabine toxicities.
Toxicity Grade 3 / 4 |
Oliveirar
n = 43
Phase II |
Glynne-Jonesr
n = 31
Phase II |
Radiation dermatitis |
10 (23%) |
12 (39%) |
Leukopenia |
3 (7%) |
- |
Lymphopenia |
5 (12%) |
- |
Neutropenia |
1 (2%) |
3 (10%) |
Thrombocytopenia |
3 (7%) |
1 (3%) |
Vomiting |
1 (2%) |
- |
Diarrhoea |
2 (5%) |
1 (3%) |