Systematic review of the value of chemoradiotherapy in the management of locally advanced pancreatic adenocarcinoma

Introduction. - At the request of the National Thesaurus of Gastrointestinal Cancer (TNCD), the SOR program, led by the French National Cancer Institute (INCa), completed a systematic review to evaluate the value of chemoradiotherapy (CRT) in the management of locally advanced pancreatic adenocarcinoma in collaboration with clinician experts. Methods. - Results of a systematic literature search using Medline (R) (from 1980 to 2008) were completed by a consult of evidence-based medicine websites. All phase III randomized trials and systematic reviews concerning non-resectable locally advanced pancreatic adenocarcinoma and non-metastatic (stage 111) were included in the study. Some phase 11 trials were also included if no phase III trials were retrieved. The following interventions were compared: CRT versus best supportive care, CRT versus radiotherapy, and CRT versus chemotherapy. The modalities of CRT regimens and the sequences of chemotherapy-CRT versus CRT were also studied. The quality and clinical relevance of the trials were evaluated using validated checklists, allowing associating each result with a level of evidence. Data synthesis was performed considering both efficacy and toxicity outcomes for each intervention. Results. - Nineteen references were included in this systematic review: two meta-analyses, 11 randomized trials, five non-randomized trials and one randomized trial only published in abstract form. After a clinical and methodological critical appraisal, compared to the alternative best supportive care, concomitant CRT increases overall survival (C). Concomitant CRT compared to the radiotherapy alone increases the overall survival (B 1) but is more toxic (B 1). Concomitant CRT compared to chemotherapy alone is not superior in terms of survival (B 1) and increases toxicity (A). Concerning administration modalities of radiotherapy, recent data are in favour to a limited irradiation to the tumoral volume (C) and to a total dose of 50 to 60Gy in association with 5-fluorouracile (5-FU). The study of radiotherapy associated drugs shows that 5-FU is the reference (131) and the value of gemcitabine must be proved in randomized trials. Finally, the study of sequences chemotherapy-CRT has recently showed that induction chemotherapy before CRT improves survival (C). Validation of this strategy in a randomized trial is warranted. Conclusion. - The use of CRT for locally advanced pancreatic adenocarcinoma is based on a few randomized trials even if this treatment appears superior in terms of survival compared to best supportive care and radiotherapy alone. This review shows the need to conduct other specific randomized trials in order to validate the value of CRT, especially compared to chemotherapy alone.