There is conflicting evidence for the role of chemoradiation therapy in unresectable locally advanced pancreatic cancer. Chemoradiation therapy increases overall survival when compared with best supportive care or compared with radiation therapy alone. Chemoradiation therapy is not superior to chemotherapy in terms of survival.rr
The concept of sequential chemotherapy followed by chemo-radiation is founded on the hypothesis that a period of initial disease control with chemotherapy alone might allow the selection of patients without occult micro-metastatic disease, who might benefit from radiation therapy in terms of local control and survival.
A search of the literature did not find strong evidence to support the use of capecitabine as the chemotherapy backbone with radiation therapy, however, it is commonly used in other cancers. The expert reference panel supported publication of the protocol on the basis of the information summarised below.
The evidence for chemoradiation therapy after initial chemotherapy is largely based on retrospective datarr and the small exploratory randomised phase II SCALOP study.r The combination of radiation therapy with capecitabine was less toxic than the combination with gemcitabine, despite gemcitabine being given at a fairly low dose. This benefit was achieved with no compromise in progression-free survival and local control, and an apparent improvement in overall survival. The good efficacy and toxicity profile seems to favour capecitabine for combination with radiation therapy in this setting, which suggests that capecitabine could be favoured as a template regimen in trials to assess new radiosensitisers or radiation therapy dose escalation.
The use of CRT in LAPC has decreased given the uncertain benefit in the LAP-07 trial.r In this study, at a median follow-up of 36 months, there was no statistically significant difference in overall survival between chemotherapy alone versus chemotherapy followed by chemo-radiation therapy (OS 16.5 vs 13.3 months, p=0.83), however, CRT did show an improvement in local control.r This study has been criticised for having several radiation therapy deviations and that a subset of patients randomly assigned to receive chemoradiation therapy did not receive treatment. The formal publication of this trial is awaited.
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase III studies |
Hammel et al.r
(LAP-07) abstract 2013 |
No |
No |
CRT vs CT following induction CT.
Capecitabine 800 mg/m2 twice a day during RT (54 Gy) |
Phase II studies |
Mukherjee et al.r
(SCALOP), 2013 |
Yes |
Yes |
Cape CRT vs Gem CRT following induction CT.
Capecitabine 830 mg/m2 twice a day during RT (50.4 Gy) |
Observational studies |
Krishnan et al. 2007r |
Yes |
No |
CRT vs CRT following induction CT.
Capecitabine 800-900 mg/m2 twice a day during RT (30 Gy) |
|
Kim et al 2013r |
Yes |
No |
Cape CRT vs bolus 5FU CRT.
Capecitabine 800 mg/m2 twice a day during RT (55.8 Gy) |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.2 2015 |
Yes |
- |
- |
BCCA |
Feb 2014 |
Yes |
No |
Capecitabine 825 mg/m2 twice a day during RT |
CCO |
- |
N/A |
- |
- |
Efficacy
Outcomer |
Capecitabine
(n=35) |
Gemcitabine
(n=36) |
Hazard ratio |
Median progression-free survival |
12.0 months |
10.4 months |
0.60
(95% CI 0.32-1.12;p=0.11) |
Median local progression-free survival |
14.6 months |
12.0 months |
- |
Distant progression-free survival |
14.3 months |
11.9 months |
- |
Median overall survival |
15.2 months |
13.4 months |
0.39
(95% CI 0.18-0.81;p=0.012) |
Objective disease response at 26 weeks from registration |
Complete response |
6% |
0 |
- |
Partial response |
17% |
19% |
- |
Stable disease |
63% |
67% |
- |
Toxicity
In the SCALOP trial, compared to pre-CRT baseline (week 17), at the end of CRT (week 23), patients on Cape-CRT arm experienced significantly better HRQL outcomes in terms of cognitive functioning (p=0.04), fatigue (p=0.05), bloating (p=0.04) and dry mouth (p=0.03). The differences were no longer significant at week 26 or 39 apart from cognitive function scores (p=0.01) and dry mouth (p<0.01), which remained significant at week 39.r
The better HRQL in the Cape-CRT arm further supports the use of Capecitabine rather than Gemcitabine as concomitant chemotherapy with radiation in locally advanced pancreatic cancer.
Grade 3-4 toxic effectsr |
Induction chemotherapy (all randomised patients, n=74) % |
Chemoradiation therapy |
Capecitabine
(n=34) % |
Gemcitabine
(n=38) % |
Any |
55 |
12 |
37 |
Haematological |
38 |
0 |
18 |
Haemoglobin |
3 |
0 |
0 |
Leucocytes |
14 |
0 |
13 |
Absolute neutrophil count |
38 |
0 |
11 |
Non-haematological |
32 |
12 |
26 |
Constitutional symptoms |
3 |
6 |
13 |
Fatigue |
3 |
6 |
11 |
Hand-foot syndrome |
5 |
0 |
0 |
Gastrointestinal symptoms |
9 |
0 |
16 |
Diarrhoea |
4 |
0 |
8 |
Nausea/vomiting |
1 |
0 |
8 |
Anorexia |
0 |
0 |
8 |
Infection |
11 |
0 |
5 |
Febrile neutropenia |
3 |
0 |
3 |