LAPC has a poor prognosis, and treatment advances have evolved slowly. Until now, the optimal therapy for patients with LAPC remains elusive. Since a series of seminal studies from the GITSG in 1981,6 chemoradiotherapy for inoperable adenocarcinoma of the pancreas has been a standard treatment in the US. According to the National Comprehensive Cancer Network (NCCN) guidelines version 2, 2014,36 both 5-fluorouracil and GEM-based CRT are recommended for patients with non-metastatic LAPC, although several small RCTs9,10,37 and one meta-analysis11 suggested that GEM-based CRT seemed better than 5-fluorouracil-based CRT. Recently, two novel oral FU drugs, capecitabine and S-1, have shown favorable antitumor activity when used in combination with RT for treating LAPC in the concurrent setting; thus, both of these drugs are regarded as promising agents for the management of LAPC. However, to the best of our knowledge, there is lack of head-to-head comparison data available for oral FU versus GEM-based CRT in the treatment of LAPC, excepting one small RCT conducted by Mukherjee et al.17 In that trial, the authors concluded that capecitabine-based CRT might be preferable to GEM-based CRT for LAPC, but these findings should be interpreted with caution due to a non-significant difference between the two regimens and the relatively small sample size.17 As a result, we conducted the current systematic review and meta-analysis to evaluate the efficacy and toxicities of oral FU-based CRT compared with GEM-based CRT for the treatment of LAPC.
A total of 843 patients from 23 studies met the inclusion criteria and were used in the meta-analysis. Based on pooled results, we found that S-1-based CRT resulted in a statistically increased 1- and 2-year survival, but not for 1-year PFS and ORR, while comparable efficacy was found to be comparable between capecitabine-based CRT and GEM-based CRT in terms of OS, PFS, and ORR. Additionally, our results indicated that oral FU-based CRT is also advantageous in reducing treatment toxicity in LAPC when compared to GEM-based CRT. However, more evidence is still required before oral FU-based CRT can become the standard treatment for LAPC patients. We could not pool the results about quality of life (QoL) due to only one trial17 reporting QoL results, and a detailed QoL analysis is planned by the authors of the current review.
Several limitations exist in the present analysis. First and most importantly, the application of formal meta-analytic methods to observational studies has been controversial.38 One of the most important reasons for this is that the designs and populations of reviewed studies are often diverse, and these differences may influence the pooled estimates. However, when only one small RCT is available, a meta-analysis of observational studies is one of the few methods available for assessing efficacy and toxicities.39 Moreover, meta-analysis reduces the uncertainty surrounding the pooled estimates, and is a valuable method to inform the decision whether more evidence is needed, which is a timely discussion topic with regard to chemoradiotherapy in LAPC. However, potential bias may have occurred in the current review due to selection bias. Finally, the present meta-analysis only considers published literature, and lack of individual patient data prevented us from adjusting the treatment effect according to disease and patient variables.
Currently available clinical evidence for LAPC indicates that oral FU plus RT may be a safe and feasible regimen for patients with LAPC, with similar efficacy and low rate of toxicities compared with GEM plus RT. However, the overall quantity and quality of data regarding oral FU and GEM-based CRT are poor. The reported results do not allow for definite conclusions. As a result, prospective randomized studies, definitively comparing the survival and treatment toxicity between oral FU and GEM-based CRT, are strongly encouraged to clearly set the role of oral FU-based CRT in the treatment of LAPC.
We are indebted to the authors of the primary studies, for without their contributions, this work would have been impossible.
The authors report no conflicts of interest in this work.
Yong-Feng Yang1, Xiao-Hui Cao1, Chao-En Bao1, Xin Wan2
1Department of Radiation Oncology, Third Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
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