Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer Results of the first prospective randomized phase II trial.

Survival rates of patients with pancreatic cancer have improved only marginally during the last 30 years with a 5-year survival rate of only 6 % [1]. In contrast, the prognosis of patients with rectal carcinoma has improved substantially during the same timeframe [2]. This progress was due to standardizing surgical therapy [3] worldwide and by the implementation of multimodal therapy [4–6]. Moreover, in rectal cancer it was found early that a clear circumferential margin is important and that even margins below 1 mm cause a significant increase in the rate of local recurrence [7]. All these measures caused a decline in local recurrence from 50 % to about 10 % and an increase of 5-year survival rates up to more than 50 % worldwide. This progress led to the hypothesis that the much poorer prognosis of ductal adenocarcinoma of the pancreas might be improved in an analogous manner. Adjuvant therapy has been tested in a series of RCT phase III trials, the most important of these are ESPAC-1, CONKO-001, RTOG 97–04, and ESPAC-3 [8–11]. But these trials were still running or results were not yet available when the present trial was planned and conducted. The results of these trials led to a change in standard treatment recommending adjuvant treatment with chemotherapy since 2007 in Germany [12]. The concept of neoadjuvant rather than adjuvant treatment in pancreatic cancer appears attractive for several reasons. First, up to 30 % of the tumors staged as resectable cannot be resected due to undetected metastatic disease or underestimated tumor contact to peripancreatic vessels [13]. Second, up to 30 % of the patients cannot receive adjuvant therapy because of poor post-operative performance status [14]. Both groups of patients are not included into adjuvant trials, though improving overall survival in both arms (adjuvant therapy vs. no adjuvant therapy) by simple patient selection. Neoadjuvant treatment is thought to be better tolerated than adjuvant treatment and avoids postsurgical morbidity in patients with rapidly metastasizing tumors. Nonrandomized trials using the neoadjuvant approach support this rationale: median OS beyond 30 months for patients after neoadjuvant treatment and tumor resection were described in several retrospective data analyses [15–18]. Therefore, in 1999 we started to plan this multicenter randomized phase II study in patients with locally resectable cancer or probably locally resectable cancer of the pancreatic head with strict imaging eligibility criteria defining vascular involvement. To our knowledge, this is the first RCT for patients with primary and borderline (meanwhile evolved technical term for “probably”) resectable cancer of the pancreatic head comparing primary surgery with neoadjuvant treatment followed by surgery, starting with randomization in 2003. Here, we report the full results of this trial, which was not picked up by the majority of the research community at the time the trial was conducted. As a consequence, the trial could not be completed and therefore shows a lack of statistical significance due to the poor recruiting rate. On the other hand, the reporting of negative trials (i.e., a trial with no clear interpretable results) is important to improve future trials. An extended version of this manuscript including a detailed description of all methods employed in this study is provided as supplementary material.