Additional data regarding the potential benefit of postoperative adjuvant therapy will come from the European Organization for Research and Treatment of Cancer (EORTC) and the European Study Group for Pancreatic Cancer (ESPCA). The EORTC initiated a study in 1987 comparing adjuvant 5-FU-based chemoradiation following pancreatectomy with surgery alone. More than 150 patients have been entered; results are not yet available. In 1994, a study was initiated by the ESPCA randomizing patients following pancreatectomy to one of four treatment groups: (1) no adjuvant therapy; (2) 5-FU-based chemoradiation; (3) 5-FU-based chemoradiation followed by systemic 5-FU and leucovorin; and (4) 5-FU and leucovorin without EBRT.

The risk of delaying adjuvant therapy, combined with small published experiences of successful pancreatic resection following EBRT, prompted many institutions to initiate studies in which chemoradiation was given before pancreaticoduodenectomy for patients with potentially resectable (or locally advanced) adenocarcinoma of the pancreas. The preoperative use of chemoradiation is supported by the following considerations:

Radiation therapy is more effective on well-oxygenated cells that have not been devascularized by surgery.
Peritoneal tumor cell implantation due to the manipulation of surgery may be prevented by preoperative chemoradiation.
The high frequency of positive-margin resections recently reported supports the concern that the retroperitoneal margin of excision, even when negative, may be only a few millimeters; surgery alone may therefore be an inadequate strategy for local tumor control.
Patients with disseminated disease evident on restaging studies after chemoradiation will not be subjected to laparotomy.
Because radiation therapy and chemotherapy will be given first, delayed postoperative recovery will have no effect on the delivery of multimodality therapy, a frequent problem in adjuvant therapy studies.

In patients who receive chemoradiation before surgery, a repeat staging CT scan after chemoradiation reveals liver metastases in 25%. If these patients had undergone pancreaticoduodenectomy at the time of diagnosis, it is probable that the liver metastases would have been subclinical; these patients would therefore have undergone a major surgical procedure only to have liver metastases found soon after surgery. In the MDACC trial, patients who were found to have disease progression at the time of restaging had a median survival of only 6.7 months. The avoidance of a lengthy recovery period and the potential morbidity of pancreaticoduodenectomy in patients with such a short expected survival duration represent distinct advantages of preoperative over postoperative chemoradiation. When delivering multimodality therapy for any disease, it is beneficial, when possible, to deliver the most toxic therapy last, thereby avoiding morbidity in patients who experience rapid disease progression not amenable to currently available therapies.
The survival advantage for the combination of chemoradiation and surgery compared with surgery alone likely results from improved local-regional tumor control. Because of the poor rates of response to 5-FU-based systemic therapy in patients with measurable metastatic disease, it is unlikely that current chemoradiation regimens significantly impact the development of distant metastatic disease. Recent data from Staley and colleagues at MDACC support this belief. Thirty-nine patients received preoperative 5-FU-based chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for adenocarcinoma of the pancreatic head. Thirty-eight of them were evaluable for patterns of treatment failure; there was one perioperative death. Overall, there were 38 recurrences in 29 patients: 8 (21%) were local-regional (pancreatic bed or peritoneal cavity or both), and 30 (79%) were distant (lung, liver, or bone). The liver was the most frequent site of tumor recurrence, and liver metastases were a component of treatment failure in 53% of patients (69% of all patients who had recurrences). Fourteen patients (37% of all patients; 48% of patients who had recurrences) had liver metastases as their only site of recurrence. Isolated local or peritoneal recurrences were documented in only four patients (11%). This improvement in local-regional control was seen despite the fact that 14 of 38 evaluable patients had undergone laparotomy with tumor manipulation and biopsy before referral for chemoradiation and reoperation. If these 14 patients were excluded, only two patients (8%) would have experienced local or peritoneal recurrence as any component of treatment failure. However, because of the large percentage of patients who developed distant metastatic disease, predominantly in the liver, improved local-regional tumor control translated into only a small improvement in median survival compared with that in other recently published studies. Therefore, in the absence of effective systemic therapy, the goal of chemoradiation (preoperative or postoperative) and pancreatectomy should be to maximize local-regional tumor control while minimizing treatment-related toxicity and cost.