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.
The evidence for chemoradiation therapy after initial chemotherapy is largely based on retrospective datarr and the Phase II SCALOP study.r The role of CRT in LAPC continues to evolve 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 chemoradiation therapy (OS 16.5 vs 13.3 months, p=0.83). 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.
A search of the literature did not find strong evidence to support the use of continuous fluorouracil as the chemotherapy backbone with radiation therapy. However, fluorouracil remains a reference chemotherapy in association with radiation therapy in many studies. The optimal mode and delivery of fluorouracil chemotherapy is unclear.
The expert reference panel supported publication of the protocol on the basis of the information summarised below.
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase III studies |
Hammel et al.
(LAP-07) abstract 2013r |
No |
No |
See comments above |
Phase II studies |
Mukherjee et al.
(SCALOP), 2013r |
Yes |
No |
See comments above |
Observational studies |
Huguet et al. 2007r |
Yes |
No |
See comments above |
|
Krishnan et al. 2007r |
Yes |
No |
See comments above |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.1 2015 |
Yes |
Yes |
- |
BCCA |
Feb 2014 |
N/A |
- |
Supports use with capecitabine |
CCO |
Oct 2013 |
Yes |
Yes |
- |
Efficacy
A summary of the evidence supporting the effect of this protocol is below:
References |
Radiation
(Gy) |
Chemotherapy regimen |
No. of patients randomised (Evaluable) |
Median survival (Months-unless specified) |
p-value |
CRT vs RT alone |
Moertel et al. 1969r |
35-40 |
5FU (bolus 45 mg/kg) |
NR (32) |
10.4 |
NA |
35-40 |
- |
NR (32) |
6.3 |
Moertel et al.
GITSG 9273), 1981r |
60 |
5FU (500 mg/m2 bolus D1-3) then weekly bolus 500 mg/m2 |
111 (86) |
9.3 |
NS |
40 |
5FU (500 mg/m2 bolus D1-3) then weekly bolus 500 mg/m2 |
117 (83) |
9.7 |
60 |
- |
25 (25) |
5.3 |
Cohen et al. 2005r |
59.4 |
5FU 1000 mg/m2/day CI D2-5 and D28-31 of RT + MMC 10 mg/m2 on D2 |
59 |
8.4 |
NS |
59.4 |
- |
49 |
7.1 |
CRT vs CT alone |
Klasassen et al. (ECOG-8232), 1985r |
40 |
5FU (600 mg/m2 D1-3 only)
Post CRT: 5FU weekly bolus (600 mg/m2/wk) |
NR (47) |
8.3 |
N/A |
- |
5FU weekly bolus (600 mg/m2/wk) |
NR (44) |
8.2 |
GITSG, 1988r |
54 |
5FU (350 mg/m2 per day, 1st 3 and last 3 days of RT)
Post CRT: 5FU + streptozocin + MMC (doses as per other arm) |
NR (22) |
9.7 |
N/A |
- |
5FU (600 mg/m2 bolus D1, 8, 29, 36 + streptozocin 1 g/m2/8wk + MMC 10 mg/m2/8wk) |
NR (21) |
7.4 |
Chauffert et al. 2006r |
60 |
5FU CI (300 mg/m2/d CI 5d/wk + cisplatin 20 mg/m2/d on D1-5 and 29-33).
Post CRT: Gemcitabine (1000 mg/m2 wk) |
59 |
8.6 |
0.03 |
- |
Gemcitabine (1000 mg/m2 wk) |
60 |
13 |
Loehrer et al. ECOG-4201 2011r |
50.4 |
Gemcitabine (600 mg/m2/wk + maintenance gemcitabine 1000 mg/m2/wk on D1, 8, 15; 5 cycles) |
34 |
11.1 |
0.017 |
- |
Gemcitabine (1000 mg/m2 wk D1, 8, 15; 7 cycles) |
37 |
9.2 |
Hammel et al. (LAP-07), 2014 (abstract)r |
54 |
Gemcitabine +/- erlotinib -> Capecitabine CRT (1600 mg/m2/day) |
136 |
15.3 |
NS |
- |
Gemcitabine +/- erlotinib -> same CT |
133 |
16.5 |
CRT vs observation alone |
Shinchi et al. 2002r |
50.4 |
5FU CI (200 mg/m2/day) + maintenance 5FU bolus (500 mg/m2) weekly until PD or toxicity |
16 |
13.2 |
<0.01 |
- |
- |
15 |
6.4 |
CRT vs CRT |
Li et al. 2003r |
50.4-61.2 |
Gemcitabine 600 mg/m2wk + maintenance gemcitabine 1000 mg/m2/wk |
18 |
14.5 |
0.027 |
50.4-61.2 |
5FU (500 mg/m2 bolus on D1-3, 15-17, 29-31) + maintenance gemcitabine (1000 mg/m2/wk) |
16 |
6.7 |
Mukherjee et al. (SCALOP), 2013r |
50.4 |
Gemcitabine 1000 mg/m2 D1, 8, 15 q28 d/ capecitabine 830 mg/m2 D1-21 q28d x 3 cycles -> gemcitabine (300 mg/m2/wk) with RT |
38 |
10.4 |
NS |
50.4 |
Gemcitabine 1000 mg/m2 D1, 8, 15 q28 d/ capecitabine 830 mg/m2 BC D1-21 q28d x 3 cycles -> capecitabine 830 mg/m2 BD, Monday to Friday with RT |
36 |
12 |
Abbreviations: CRT, chemoradiation therapy; RT, radiation therapy; 5FU, fluorouracil; CI, continuous infusion; CT, chemotherapy, NA, not available; MMC, mitomycin C; NS, not significant; q, every; d, day; wk, week; PD, progressive disease
Toxicity
In the study by Shinchi et al, chemoradiation-related complications occurred in 4 (25%) of the 16 patients. There was one case of Grade 3 anorexia and nausea, with two cases of Grade 2 nausea. One patient had Grade 2 leukopenia. The study reported that none of the remaining patients suffered any other serious complications due to radiation therapy or fluorouracil chemotherapy.r