This article critically reviews and ranks 107 prospective, randomized controlled trials (RCT) for pancreatic adenocarcinoma published between 2000 and 2008 identified through a standard MEDLINE literature search strategy, according to a standardized, previously published 3-tiered system (Ia, Ib, and Ic). All trials included in this article are Ia or Ib. Types of treatment reviewed include surgery, chemotherapy, molecular therapy, radiation therapy, immunotherapy, and palliative therapy.
The authors of this article have identified 107 prospective, randomized controlled trials (RCT) for pancreatic adenocarcinoma through a standard MEDLINE literature search strategy that were published between 2000 and 2008. The articles are critically reviewed and ranked according to a standardized, previously published 3-tiered system (Ia, Ib, and Ic). All trials included in this article are Ia or Ib.
Overall, there was a near 2-fold increase in RCT published per year on pancreas cancer compared with the previous study period (1977–2000). This surge was due mostly to an increase for advanced disease trials, the increased reporting of endoscopic stent trials, and advances in targeted molecular therapies.
Randomized controlled trials in pancreas cancer between 1977 and 2000
The authors previously reported surgical trials conducted within this time period with the largest impact on clinical practice. These trials included studies of the role of extended retroperitoneal lymphadenectomy for periampullary cancers, the type of pancreaticoenteric reconstruction after pancreaticoduodenectomy, and the use of prophylactic gastrojejunostomy for unresectable pancreatic cancer. There was no evidence that a distal gastrectomy with perigastric and extensive retroperitoneal lymphadenectomy improved outcome, and there was no advantage for pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy. Although the randomized trial on prophylactic gastrojejunostomy for unresectable periampullary cancer indicated a decrease in the incidence of late gastric outlet obstruction and related complications in the prophylactic bypass group, the authors alluded to the emerging role of duodenal stents that would diminish the role of this procedure in the palliation of unresectable pancreas cancer in the near future.
There were 2 landmark chemotherapy/chemoradiation trials during this period, including a small randomized trial of gemcitabine use in advanced pancreas cancer. Quality of life was improved in the gemcitabine arm compared with the 5-fluorouracil (5-FU) arm (24% vs 5%; P = .002), and there were also improvements in median survival (5.7 vs 4.4 months; P = .003), time to disease progression (9 vs 4 weeks; P = .002), and 12-month survival (18% vs 2% for the gemcitabine arm; P = .0025). Although the results were limited because of the single-blinded design of the study, they represent the first implications of superior clinical efficacy of gemcitabine-based systemic chemotherapy. The EORTC GTCCG trial was a small study that observed a trend toward improved survival ( P = .09) in patients who were randomized to adjuvant radiation therapy and 5-FU after surgery. Randomized trials investigating nutritional interventions and the prophylactic use of octreotide to prevent pancreatic fistulas did not demonstrate any advantage in outcome in the intervention groups.
Surgery
There were 14 surgical trials reported, of which three compared pylorus preserving pancreaticoduodenectomy (PPPD) to a standard Whipple procedure ( Table 1 ). Both procedures were shown to be equally effective for the treatment of pancreatic and periampullary cancers, with similar overall long-term and disease-free survival rates. Both procedures were associated with comparable operating time, blood loss, hospital stay, mortality (5.3%), morbidity, positive resection margins, and quality of life (QOL). The two largest trials reported similar rates of delayed gastric emptying between groups, and only a minor postoperative increase in capacity to work at 6 months in the PPPD group (56 vs 77%; P = .019). Previous findings of reduced blood loss and operating time in the PPPD group were not confirmed by these larger trials. These studies demonstrate the long-term oncologic equivalency of the two procedures and suggest only minor short-term advantages associated with PPPD.
| Trial | Randomization | N | Significance Demonstrated | Classification |
|---|---|---|---|---|
| Tran | PPPD vs standard PD | 170 | No difference in operation time, blood loss, hospital stay, delayed gastric emptying, morbidity, mortality, or oncologic outcome | Ia |
| Seiler | PPPD vs standard | 214 | Both procedures are equally effective, PPPD offers minor advantages in early postop period | Ia |
| Lin | PPPD vs standard | 36 | No significant difference in terms of operation time and blood loss. Delayed gastric emptying more common in PPPD group | Ib |
| Yeo | standard PD (PPPD) vs extended PD | 294 | Similar mortality, increased morbidity; no difference in survival | Ib |
| Farnell | standard PD vs PD with ELND | 132 | No difference in survival or complications but decrement in QOL at 4 months with ELND | Ib |
| Tran | Duct occlusion vs pancreaticojejunostomy | 169 | Duct occlusion does not reduce postop complications but increases endocrine insufficiency | Ib |
| Suc | PD vs PD with temporary duct occlusion | 182 | Ductal occlusion by intracanal injection of fibrin glue has no impact on severity of intra-abdominal complications | Ib |
| Bassi | PD with PJ vs PD with PG | 151 | PG did not show any significant advantage in overall postop complications but had lower rate of collections and DGE | Ib |
| Peng | conventional PJ after PD vs binding PJ | 217 | Binding pancreaticojejunostomy after PD significantly decreases postop complications and leak rates | Ib |
| Conlon | Surgery + intraperitoneal drain vs Surgery + no drain | 179 | No reduction in deaths or complications (need for interventional radiology or surgical intervention) | Ia |
| Imamura | Resection vs no resection + chemoradiation | 42 | Locally invasive, but resectable pancreas cancer is best treated with resection | Ib |
| Lygidakis | Radical pancreatectomy vs palliative gastro-biliary bypass | 56 | Radical pancreatectomy, splenectomy, and vascular reconstruction is superior to bypass in patients with pancreas cancer and vascular invasion | Ib |
| Yilmaz | Isoperistaltic gastrojejunostomy vs antiperistaltic gastrojejunostomy | 44 | Both operations suitable for patients Ib with unresectable PC | Ib |
| Navarra | Open palliative gastrojejunostomy vs laparoscopic gastrojejunostomy | 24 | Laparoscopic gastrojejunostomy is a safe and feasible alternative to open gastrojejunostomy | Ib |
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