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Gastrointestinal Oncology, Pancreatic Cancer
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Surgical Treatment of Pancreatic Cancer

Published Online: June 3rd 2011 European Oncology & Haematology, 2011;7(1):36-42 DOI: https://doi.org/10.17925/EOH.2011.07.01.36
Authors: Magnus Bergenfeldt, Åke Andrén-Sandberg
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Abstract:
Overview

Surgical resection offers the only hope for cure of pancreatic carcinoma. Pancreaticoduodenectomy (Whipple’s operation) is the standard procedure for cancer in the right hemipancreas, while resection of the pancreatic tail is used for left-sided pancreatic cancer. Total pancreatomy is used for diffuse/multifocal disease, but has severe metabolic consequences. This article summarises recent advances in the field. Today, pancreatic resection has a post-operative mortality rate of a few per cent and the long-term outcome after curative resection has improved: a median survival of 12–24 months and a five-year survival of 10–20% can be expected. Various technical modifications of Whipple’s operation have been described, but generally they do not outperform the original procedure. More complex procedures including vascular resection and/or extended lymphadenectomy can also be performed safely today, but generally they do not result in a better outcome. Although surgery is crucial for the treatment of pancreatic cancer, it has become obvious that pancreatic cancer can only rarely be cured by surgery alone; therefore, recent advances in adjuvant oncological therapy are discussed.

Keywords

Pancreatic cancer, surgery, technical modifications, extended pancreaticoduodenectomy, octreotide, adjuvant therapy, neoadjuvant therapy

Article:

Despite many years of continuous effort, pancreatic carcinoma remains a highly lethal disease and a challenge to the medical community. Most patients will be diagnosed in an advanced stage of the disease and will be candidates for oncological palliative therapy or supportive care only. These patient groups have a life expectancy of only a few months. It is documented that less than one of these patients will be alive after five years.1,2 Surgical resection remains the only hope for long-term survival, but this option is available only for patients with a tumour confined to the pancreas. In population studies, 5–12% of patients were candidates for pancreatic resection.3–6 The era of modern pancreatic surgery began with the introduction of pancreaticoduodenectomy (PD) in the US by Whipple in the late 1930s;7 however, the operation had previously been performed in Europe by Codivilla in 1898 and by Kausch in 1912.8 Whipple’s operation was soon recognised as a demanding and complication-prone procedure. In the first few decades, mortality rates exceeding 20% were reported even by large institutions, and some authors suggested that the procedure should be abandoned in favour of safer bypass surgery.9,10 However, further development was inspired by some early surgical series with no case fatalities.11,12 Today, pancreatic surgery is a standard procedure and the mortality rate should not exceed a few per cent (see Table 1).13–24

While PD (Whipple’s operation) is the standard procedure for cancer in the right hemipancreas, resection of the pancreatic tail is used for left-sided pancreatic cancer.25 Total pancreatomy is indicated for diffuse or multifocal disease, but it is used judiciously as it inevitably causes severe metabolic consequences (complete endocrine and exocrine insufficiency). Further pancreatic procedures have been designed, mostly as technical modifications of Whipple’s operation, to alleviate the short- and long-term complications of the procedure. This article provides a summary of current standards in pancreatic surgery, with special reference to technical achievements and post-operative outcome. In the last section, the most recent advances in adjuvant oncological therapy are discussed. Although surgery is crucial in the treatment of pancreatic cancer, it is obvious that surgery alone cannot cure the disease in most cases. The grim reality is that the majority of resected patients will eventually succumb to locoregional and/or distant recurrent disease. Classic Pancreaticoduodenectomy
(Whipple’s Operation)

The original description by Whipple in 193526 was of a two-stage procedure that initially aimed to diminish the consequences of coagulopathy due to malabsorption of vitamin K. Today, the term Whipple’s operation is used for an operation that includes en bloc resection of the pancreatic head and duodenum together with the antrum of the stomach, the gall bladder and the distal bile duct. The operation is reserved for pancreatic cancer confined to the pancreas, and the standard procedure is resection with microscopically cancer-free margins (R0-resection) including the regional lymph nodes. Therefore the pre-operative work-up aims to exclude patients with distant metastases (most commonly peritoneal spread and liver metastases) including those with overgrowth on adjacent anatomical structures. Several authors advocate that a pre-operative exploratory laparoscopy with laparoscopic ultrasound should be performed before laparotomy as it is an accurate method of excluding cancer spread to the peritoneum, regional lymph glands and extrapancreatic tissue.27 If the pre-operative investigation does not show extrapancreatic disease, one may proceed to laparotomy.

Whipple’s operation has become a highly standardised procedure. The technical details are well described by Warshaw28 and Pedrazzoli et al.25 The first phase of the operation includes a thorough inspection of the peritoneal surfaces and dissection of the hepatoduodenal ligament, duodenum, pancreatic head and superior mesenteric vessels, with the dual aim of excluding extrapancreatic spread and preparing for resection. In the second phase, the antrum, the bile duct and the first part of the jejunum are transected. The pancreatic neck is transected over the portal vein and after ligation of multiple vessels between the pancreatic head and mesenteric vessels, the specimen can be removed. The posterior (retroperitoneal) dissection plane is of utmost importance, and the dissection should also proceed very close to the superior mesenteric vessels to remove all perivascular nervous and lymphatic tissue.25 In the third and final phase, gastrointestinal continuity is restored by creating three anastomoses: pancreaticojejunostomy (PJ), hepaticojejunostomy and gastrojejunostomy. Leakage in the PJ, which occurs in 2–30% of patients, is a serious problem after PD as it is a major cause of post-operative morbidity and mortality.18,22,29–37 Consequently, several anastomotic techniques have been described, including the new ‘binding anastomosis ad modum Peng’.38,39 Stenting the anastomosis with a plastic tube represents another approach to reducing leakage; currently, there are two randomised studies suggesting a positive effect of this technique.40,41 Furthermore, several technical modifications of the Whipple procedure have been designed to reduce this risk (see below).

When a post-operative pancreatojejunal leakage occurs, percutaneous drainage rather than re-operation is the initially preferred method today.29,42 Rarely, the pancreatic remnant must be removed due to sepsis or uncontrolled bleeding.43 Improved management of leakage and other complications, which afflict 20–40% of patients, has drastically improved the post-operative mortality rate in the last few decades. In surgical series from more recent years, the reported post-operative mortality rates usually amount to a few per cent only (see Table 1).13–24

There are no randomised controlled studies of pancreatic resection versus no resection looking at the efficacy of the operation. However, there is a randomised Japanese study comparing surgery and chemoradiotherapy for resectable pancreatic cancer, which showed a better survival rate after surgical resection.44 Recent surgical series usually report a median survival of 12–24 months and a corresponding five-year survival rate of 10–20% (see Table 2).13,20,21,23,24,45–49 However, a wide range of outcomes can be noted among different series.

Several studies have performed analyses of factors that may influence the long-term outcome, usually employing multivariance statistics (see Table 3).21,23,24,45,48,50–54 One of the most important factors for achieving a ‘good’ result with surgery is patient selection.50,51 Important patient-related factors are age and intercurrent disease.23,24 Among tumour-specific factors, tumour grade and size have been found to be significant, as has the presence of regional lymph gland metastases (the ‘N factor’).21,23,24,45,48,52–54 While patient-related and tumour-specific factors should influence the pre- and peri-operative assessment, the execution of surgery may have a more direct influence on short- and long-term outcome. As would be expected, a completed R0 resection has repeatedly been found to improve the post-operative prognosis.21,52,53 The presence of post-operative complications such as bile leak and peri-operative blood transfusion has a negative effect on long-term survival, although the causal relationship is not clear.24,48,52 In the last few decades, data have also accumulated that convincingly show an association between the result of surgery and the case load on the surgeon/team as well as the size of the cancer hospital. Several studies indicate that larger hospitals achieve better results after pancreatic resection, in both the long and short term.17,51,55–58 The case load on the individual surgeon seems important, but there may also be other potential but poorly defined factors due to differences in patient selection, referral patterns, waiting lists and so on.57 In the last decade, these data have led to a plea for centralisation of pancreatic surgery in the developed world, although Dutch data indicate that the change may take time.58 However, it is important that, when discussing the organisation of healthcare and technological progress, we keep the surgeon’s and surgery’s roles in perspective. This was eloquently stated by Dr Blake Cady in 1997: “In the field of surgical oncology, tumor biology is king, patient selection is queen, and technical manoeuvres are the prince and princess who try, but usually fail, to usurp the throne”.59 Modifications of Pancreaticoduodenectomy
Several modifications of Whipple’s operation have been described. Pylorus-preserving PD (PPPD) was introduced in 1978 as a more ‘physiological’ procedure.60 Preservation of the hormonal secretion and sphincter function of the antrum–pylorus complex was supposed to give benefits in terms of nutrition and gastrointestinal function. In the last decade, PPPD has been compared with classic PD in several randomised studies and meta-analyses, and the two procedures have been found to be equal in terms of biliary leakage, post-operative bleeding, wound infection and pulmonary complications, as well as the rate of re-operations and mortality.61–72 An early observation was that PPPD seemed to cause an increased rate of delayed gastric emptying, but this was not verified in the randomised studies (it may have been related to a too early evaluation during the learning curve). Also, regarding post-operative quality of life and long-term outcome, no significant differences have been found. In summary, PPPD and classic PD seem to be equally safe and efficient, but it has been suggested that PPPD should be used carefully in cases of tumours close to the proximal duodenum.73

Pancreaticogastrostomy (PG) was tailored as a safer mode of reconstruction. A further suggested benefit is the possibility of inspecting and cannulating the pancreatogastric anastomosis by a simple gastroscopy. To date, there have been four randomised controlled trials comparing PG with pancreaticojejunal anastomosis.74–77 Three of the studies did not reveal significant differences between the two methods, while the fourth randomised controlled trial showed that post-operative abscesses and pancreatic fistulae were less common after PG.76 A meta-analysis from 200678 suggested that PG was the safer mode of pancreatic reconstruction, but was based mainly on observational studies together with only one of the randomised controlled trials.74 Another meta-analysis found PG to be superior or equal to PJ, but signs of bias were also revealed.79 Currently, there is insufficient evidence to favour PG over pancreatojejunostomy, or vice versa.

Ligation or occlusion of the pancreatic duct represent further attempts to reduce pancreatojejunal leakage, but generally these attempts have not been successful. In three randomised controlled trials, duct occlusion did not decrease post-operative complications, but resulted in an increased risk of diabetes.80–82

Adminstration of somatostatin or its analogues aims to reduce the secretion of pancreatic juice and, thereby, the rate or consequences of pancreaticojejunal leakage. Despite a large number of randomised controlled trials and meta-analyses, clear-cut evidence for the use of somatostatin (or its analogues) has not been established.83–100 Specifically, a recent meta-analysis was unable to show a significant reduction of pancreas-specific complications.100 Although it has been suggested that the drugs may be of use in cases of ‘fragile pancreas’ or other technical problems, sufficient data to support this assumption are lacking. Currently, there is not enough evidence for the routine use of somatostatin (or its analogues) in pancreatic resection, even though many surgeons use it when the pancreatic remnant is soft or has a small duct.

Other Pancreatic Resections
Left-sided resection is indicated for malignancies in the pancreatic body and tail.25 There are several case series describing short- and long-term outcome, but no randomised controlled trials.101–106 Pancreatic fistulae occur at a rate at least similar to that of Whipple’s procedure, although the consequences may be less grave. Left-sided pancreatic cancers are less often resectable than right-sided cancers, as they are notoriously symptom-free until they are in an advanced stage.4 Involvement of the splenic vein or artery does not constitute a contraindication, as long as a radical excision is possible. When compared stage to stage, long-term survival seems to be similar to that of pancreatic head cancer.106,107 Thus, although it is an option for a subset of patients only, resection of left-sided pancreatic cancer represents an effective treatment in selected cases.

Total pancreatectomy is an option for diffuse neoplastic disease (such as intraductal papillary mucinous neoplasms), and is also rarely used for cancers growing diffusely or multifocally in the pancreatic body. The long-term nutritional and metabolic sequelae (especially brittle diabetes) of this operation make it a less attractive alternative if a lesser resection is possible.108

Extended Procedures
The poor long-term prognosis after PD, as well as the high rate of lymph node metastases (40–60%) in many series, is the rationale for attempts of more extensive lymph node dissection. Early uncontrolled series were published from Japan, and later three randomised controlled trials compared extensive lymphadenectomy with the standard operation.19,109–113 Extensive lymphadenectomy did not increase post-operative morbidity or mortality, but failed to increase long-term survival.19,109–113 There seems to be a higher rate of late sequelae, but the data are not consistent.19,111–113 Also, a meta-analysis of 16 comparative studies failed to show a significant benefit of the extended procedure.114 To conclude, extensive lymphadenectomy does not increase post-operative morbidity or mortality, but does not improve long-term survival either. However, if better adjuvant treatment becomes available, this conclusion may have to be re-evaluated. Some 40% of pancreatic cancers are locally advanced at the time of diagnosis, often due to adherence to the portal or mestenteric vein. This is often regarded as a criterion of unresectability by many surgeons, who will then proceed with resection of an adherent vein only if the ‘point of no return’ has been passed, while other surgeons consider vascular resection a necessary adjunct to PD. Consequently, some authors report high rates of vessel resection in their surgical series.115–117 There are no randomised controlled trials available comparing pancreatic resection with and without vascular resection; the literature consists of several case series reporting various pancreatic resections with varying rates of venous and/or arterial resection. Recently, a systematic review of the outcome of portal–mesenteric vein resection during pancreatectomy was published.116 In this review, 52 studies describing 6,333 pancreatic resections were analysed. In 1,646 patients (26%), a concomitant venous resection was performed. The analysis revealed that this is a time-consuming procedure with high intraoperative blood loss. The reported post-operative morbidity and mortality rates were 42 and 6%, respectively (in the studies providing such information). A positive resection margin (R+) was present in 40% of patients and lymph node positivity (N+) was 67% (range 42–97%). The calculated median survival was 13 months (from 31 studies including 917 patients). Thus, the review shows that venous involvement is associated with high rates of positive resection margins and lymph node metastases, and that the possibility of cure by surgery is improbable. The same should be true for arterial resection. However, from a palliative point of view, pancreatectomy plus venous resection and reconstruction can be performed as safely as conventional pancreatectomy and is associated with a better survival rate than other palliative measures.117 Taken together, a judicious use of vascular resection seems appropriate. At the same time, one may state that pancreatic resections should be performed only in centres where there is at least competence for the resection and reconstruction of the portal–mesenteric veins.

Adjuvant Oncological Therapy
Although five-year survival rates may have improved, survival at five years does not equal cure. In reality, death continues beyond five years, and the absolute majority of resected patients will die from the disease.2,45,118 It is obvious that pancreatic carcinoma cannot generally be cured by surgery alone. Adjuvant therapy was developed on the basis of studies that indicated – contrary to common knowledge at the time – that 5-fluorouracil (5-FU) and radiation had a demonstrable effect in advanced pancreatic cancer.119–123 In the mid-1980s, the Gastrointestinal Tumor Study Group (GITSG) published a small randomised controlled trial and a supportive non-randomised trial that showed a survival benefit for radiotherapy combined with 5-FU versus surgery alone.124,125 Although criticism was not lacking (few patients, slow patient accrual, selection bias), these studies had great impact on the therapy tradition in the US, and several non-randomised treatment series were subsequently published.30,126–130 Europeans were more hesitant about adjuvant therapy, especially as two European randomised controlled trials failed to show a survival benefit.131,132 A turning point was the European Study Group for Pancreatic Cancer 1 (ESPAC-1) study.53,133,134 In a joint effort between 53 hospitals in 11 countries, 289 patients were randomised into a 2×2 factorial study, a further 68 patients were randomly assigned to chemoradiotherapy or no chemoradiotherapy and a further 188 were randomised to chemotherapy or no chemotherapy. Subgroup analyses (for which the study was underpowered) showed median survivals of 17 months in the observation group, 12 months with chemoradiation, 22 months with chemotherapy alone and 20 months with both chemotherapy and chemoradiation. The corresponding five-year survival estimates were 11, 7, 29 and 13%, respectively. The study group concluded that adjuvant 5-FU had a positive effect on survival, while chemoradiotherapy seemed to have a negative effect.134

The positive results with palliative gemcitabine for advanced pancreatic cancer made this a logical candidate for further studies.135 In 2007, the results of a randomised controlled trial of adjuvant gemcitabine versus surgery alone (the CONKO-1 trial) were published.136 Post-operative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone: the median disease-free survival was 13 months versus seven months in the control group. At the 2008 American Society of Clinical Oncology (ASCO) annual meeting, it was further reported that post-operative gemcitabine prolonged medial overall survival from 20 to 23 months. The corresponding three- and five-year survival rates were, respectively, 36 and 21% with gemcitabine versus 20 and 9% in the observation group.137 In a Japanese study, adjuvant gemcitabine resulted in a significantly longer disease-free survival than surgery alone: 11 versus five months. The corresponding median overall survivals were 22 and 18 months, respectively.138 Further weak support was given by the Radiation Therapy Oncology Group (RTOG)-9704 trial, in which gemcitabine added before and after flurouracil-based chemoradiotherapy resulted in a slightly longer overall survival than the addition of 5-FU (21 versus 17 months, which was statistically non-significant).139 By contrast, the randomised ESPAC-3 study failed to show a significant difference in survival between post-operative adjuvant 5-FU and gemcitabine; median survival was a reasonable 23 months in both groups, which compares well with earlier studies.140 Thus, although the most recent randomised controlled trials support the use of adjuvant chemotherapy, there is currently not enough evidence to favour gemcitabine over 5-FU in terms of long-term outcome. However, there are indications that the side effects are less severe if gemcitabine is used.140

Some researchers propose that multidrug adjuvant treatment may be more efficient, a strategy that has also been tried in the past.52,126,131,141–145 A regimen of 5-FU, cisplatinum and interferon has shown promising results in phase II studies, but at the price of a high rate of toxicity.146,147 Although many US protocols have included fluorouracil-based chemoradiotherapy, its role in the adjuvant situation remains unsettled. European researchers argue that it is of no proven benefit regarding survival,133,134,140 while the RTOG-9707 study group claims that it decreases the risk of locoregional recurrence.139

A problematic feature of post-operative adjuvant therapy is that as many as 20–30% of resected patients never receive treatment because of slow recovery or other reasons.124,125,132,148,149 Neoadjuvant chemoradiotherapy has been proposed as a more logical way to deliver therapy. Although there may be several potential advantages, they are mostly of unproved clinical benefit.150 Available phase II data indicate that pre-operative treatment is safe and does not increase peri-operative morbidity or mortality, and it has even been suggested that local post-radiation fibrosis may decrease the rate of pancreatojejunal leakage.151–153 In clinical series, neoadjuvant therapy and subsequent pancreatic resection have typically resulted in median survivals of 19–25 months and five-year survivals of 19–28%, which compare well with post-operative therapy.115,142,143,149,151,154–158 However, there is a potential bias introduced by the selection process. Randomised controlled trials proving an overall benefit of neoadjuvant therapy are lacking and the risk of missing a resectable tumour due to growth during the treatment period has been proposed. A further question is whether extensive neoadjuvant therapy may actually cause downstaging, as has been claimed in some studies.156,157,159,160 Further comparative studies between neoadjuvant and adjuvant therapy are needed.

Future Aspects
The improvement in post-operative morbidity and mortality due to better surgical technique and improved peri-operative management is expected to continue. One of the major factors is the early treatment of post-operative complications by a dedicated multiprofessional team (surgeon, anaesthesiologist, gastroenterologist, radiologist and specialised nurses). Substantial improvements in long-term survival cannot be expected without better (more effective, less toxic) adjuvant and neoadjuvant therapies. On the other hand, when better adjuvant therapy appears, further refinement of the surgical techniques may become rewarding. Better oncological therapy may make more extensive procedures as well as treatment of patients with advanced disease worthwhile. The possibility of using pre-operative oncological regimens as neoadjuvant or downstaging therapy needs to be further studied, and relevant comparisons with post-operative adjuvant therapy should be performed.

In recent years, the pharmacological and endoscopic palliation of unresectable pancreatic cancer in particular has been an area of much development. However, more research is needed in this field. Specifically, the role of palliative resection of pancreatic cancer could be investigated further.161 A dedicated, multidisciplinary effort around palliative patients is required; it should be remembered that these patients by far outnumber patients who are resectable with curative intention. ■

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Magnus Bergenfeldt, Department of Surgical Gastroenterology, Herlev Hospital, Ringvej 75, 2730 Herlev, Denmark. E: musz185@hotmail.com

Received

2010-08-31T00:00:00

References

  1. Gudjonsson B, Cancer of the pancreas. 50 years of surgery, Cancer, 1987;60:2284–2303.
  2. Carpelan-Holmström M, Nordling S, Pukkala E, et al., Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry, Gut, 2005;54:385–7.
  3. Hedberg M, Borgström A, Genell S, Janzon L, Survival following pancreatic carcinoma: a follow-up study of all cases recorded in Malmö, Sweden, 1977–1991, Br J Surg, 1998;85:1641–4.
  4. Bramhall SR, Allum WH, Jones AG, et al., Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study, Br J Surg, 1995;82:111–5.
  5. Sener SF, Fremgen A, Menck HR, Winchester DP, Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995, using the National Cancer Database, J Am Coll Surg, 1999;189:1–7.
  6. Andrén-Sandberg A, Neoptolemos JP, Resection for pancreatic cancer in the new millennium, Pancreatology, 2002;2:431–9.
  7. Whipple AO, The rationale of radical surgery for cancer of the pancreas and ampullary region, Ann Surg, 1941;114:612–5.
  8. Beger HG, Gansauge F, Master of surgery in Archiv für Klinische Chirurgie, Langenbecks Arch Surg, 2010;395(Suppl. 1): 17–21.
  9. Crile G Jr, The advantages of bypass operations over radical pancreatoduodenectomy in the treatment of pancreatic carcinoma, Surg Gynecol Obstet, 1970;130:1049–53.
  10. Shapiro TM, Adenocarcinoma of the pancreas: a statistical analysis of biliary bypass vs Whipple resection in good risk patients, Ann Surg, 1975;182:715–21.
  11. Howard JM, Pancreatico-duodenectomy: forty-one consecutive Whipple resections without an operative mortality, Ann Surg, 1968;168:629–40.
  12. Trede M, Schwall G, Saeger HD, Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality, Ann Surg, 1990;211:447–58.
  13. Nitecki SS, Sarr MG, Colby TV, van Heerden JA, Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving?, Ann Surg, 1995;221:59–66.
  14. Fernandez-del Castillo C, Rattner DW, Warshaw AL, Standards for pancreatic resection in the 1990s, Arch Surg, 1995;130:295–9, discussion 299–300.
  15. Delcore R, Rodriguez FJ, Forster J, et al., Significance of lymph node metastases in patients with pancreatic cancer undergoing curative resection, Am J Surg, 1996;172:463–8, discussion 468–9.
  16. Conlon KC, Klimstra DS, Brennan MF, Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors, Ann Surg, 1996;223:273–9.
  17. Gouma DJ, van Geenen RC, van Gulik TM, et al., Rates of complications and death after pancreaticoduodenectomy: risk factors and the impact of hospital volume, Ann Surg, 2000;232:786–95.
  18. Balcom JH 4th, Rattner DW, Warshaw AL, et al., Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization, Arch Surg, 2001;136:391–8.
  19. Yeo CJ, Cameron JL, Lillemoe KD, et al., Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality, Ann Surg, 2002;236:355–66.
  20. Richter A, Niedergethmann M, Sturm JW, et al., Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience, World J Surg, 2003;27:324–9.
  21. Wagner M, Redaelli C, Lietz M, et al., Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma, Br J Surg, 2004;91:586–94.
  22. Schmidt CM, Powell ES, Yiannoutsos CT, et al., Pancreaticoduodenectomy: a 20-year experience in 516 patients, Arch Surg, 2004;139:718–25.
  23. Jarufe NP, Coldham C, Mayer AD, et al., Favourable prognostic factors in a large UK experience of adenocarcinoma of the head of the pancreas and periampullary region, Dig Surg, 2004;21:202–9.
  24. Winter JM, Cameron JL, Campbell KA, et al., 1423 pancreaticoduodenectomies for pancreatic cancer: A singleinstitution experience, J Gastrointest Surg, 2006;10:1199–1210.
  25. Pedrazzoli S, Beger HG, Obertop H, et al., A surgical and pathological based classification of resective treatment of pancreatic cancer. Summary of an international workshop on surgical procedures in pancreatic cancer, Dig Surg, 1999;16:337–45.
  26. Whipple AO, Parsons WB, Mullins CR, Treatment of carcinoma of the ampulla of Vater, Ann Surg, 1935;102:763–9.
  27. Hariharan D, Constantinides VA, Froeling FE, et al., The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of pancreatico-biliary cancers – a meta-analysis, Eur J Surg Oncol, 2010;36(10):941–8.
  28. Warshaw AL, Thayer SP, Pancreaticoduodenectomy, J Gastrointest Surg, 2004;8:733–41.
  29. Haddad LB, Scatton O, Randone B, et al., Pancreatic fistula after pancreaticoduodenectomy: the conservative treatment of choice, HPB (Oxford), 2009;11:203–9.
  30. Yeo CJ, Cameron JL, Lillemoe KD, et al., Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients, Ann Surg, 1995;221:721–33.
  31. Bassi C, Falconi M, Salvia R, et al., Management of complications after ancreaticoduodenectomy in a high volume center: results on 150 consecutive patients, Dig Surg, 2001;18:453–7.
  32. Yeo CJ, Cameron JL, Sohn TA, et al., Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes, Ann Surg, 1997;226:248–57.
  33. Lin JW, Cameron JL, Yeo CJ, et al., Risk factors and outcomes in postpancreaticoduodenectomy pancreaticocutaneous fistula, J Gastrointest Surg, 2004;8: 951–9.
  34. Munoz-Bongrand N, Sauvanet A, Denys A, et al., Conservative management of pancreatic fistula after pancreaticoduodenectomy with pancreaticogastrostomy, J Am Coll Surg, 2004;199:198–203.
  35. Sarr MG; Pancreatic Surgery Group, The potent somatostatin analogue vapreotide does not decrease pancreas-specific complications after elective pancreatectomy: a prospective, multicenter, double-blinded, randomized, placebocontrolled trial, J Am Coll Surg, 2003;196:556–65.
  36. Buchler MW, Friess H, Wagner M, et al., Pancreatic fistula after pancreatic head resection, Br J Surg, 2000;87:883–9.
  37. Grobmyer SR, Rivadeneira DE, Goodman CA, et al., Pancreatic anastomotic failure after pancreaticoduodenectomy, Am J Surg, 2000;180:117–20.
  38. Z’graggen K, Uhl W, Friess H, Büchler MW, How to do a safe pancreatic anastomosis, J Hepatobiliary Pancreat Surg, 2002;9:733–7.
  39. Peng SY, Wang JW, Li JT, et al., Binding pancreaticojejunostomy – a safe and reliable anastomosis procedure, HPB (Oxford), 2004;6:154–60.
  40. Poon RT, Fan ST, Lo CM, et al., External drainage of pancreatic duct with a stent to reduce leakage rate of pancreaticojejunostomy after pancreaticoduodenectomy: a prospective randomized trial, Ann Surg, 2007;246:425–33.
  41. Kamoda Y, Fujino Y, Matsumoto I, et al., Usefulness of performing a pancreaticojejunostomy with an internal stent after a pancreatoduodenectomy, Surg Today, 2008;38:524–8.
  42. Büchler MW, Friess H, Wagner M, et al., Pancreatic fistula after pancreatic head resection, Br J Surg, 2000;87:883–9.
  43. Yekebas EF, Wolfram L, Cataldegirmen G, et al., Postpancreatectomy hemorrhage: diagnosis and treatment: an analysis in 1669 consecutive pancreatic resections, Ann Surg, 2007;246:269–80.
  44. Doi R, Imamura M, Hosotani R, et al.; Japan Pancreatic Cancer Study Group, Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: final results of a randomized multi-institutional trial, Surg Today, 2008;38:1021–8.
  45. Geer RJ, Brennan MF, Prognostic indicators for survival after resection of pancreatic adenocarcinoma, Am J Surg, 1993;165:68–72.
  46. Allema JH, Reinders ME, van Gulik TM, et al., Prognostic factors for survival after pancreaticoduodenectomy for patients with carcinoma of the pancreatic head region, Cancer, 1995;75:2069–76.
  47. Kuhlmann KF, de Castro SM, Wesseling JG, et al., Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients, Eur J Cancer, 2004;40:549–58.
  48. Howard TJ, Krug JE, Yu J, et al., A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon’s contribution to long-term survival in pancreatic cancer, J Gastrointest Surg, 2006;10: 1338–45.
  49. Raut CP, Tseng JF, Sun CC, et al., Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma, Ann Surg, 2007;246:52–60.
  50. Finlayson E, Fan Z, Birkmeyer JD, Outcomes in octogenarians undergoing high-risk cancer operation: a national study, J Am Coll Surg, 2007;205:729–34.
  51. Birkmeyer JD, Sun Y, Wong SL, Stukel TA, Hospital volume and late survival after cancer surgery, Ann Surg, 2007;245:777–83.
  52. Sohn TA, Yeo CJ, Cameron JL, et al., Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators, J Gastrointest Surg, 2000;4:567–79.
  53. Neoptolemos JP, Stocken DD, Dunn JA, et al.; European Study Group for Pancreatic Cancer, Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial, Ann Surg, 2001;234: 758–68.
  54. Butturini G, Stocken DD, Wente MN, et al.; Pancreatic Cancer Meta-Analysis Group, Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials, Arch Surg, 2008;143:75–83.
  55. Birkmeyer JD, Warshaw AL, Finlayson SR, et al., Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy, Surgery, 1999;125:250–6.
  56. Birkmeyer JD, Warshaw AL, Finlayson SR, et al., Relationship between hospital volume and late survival after pancreaticoduodenectomy, Surgery, 1999;126:178–83.
  57. Birkmeyer JD, Stukel TA, Siewers AE, et al., Surgeon volume and operative mortality in the United States, N Engl J Med, 2003;349:2117–27.
  58. van Heek NT, Kuhlmann KF, Scholten RJ, et al., Hospital volume and mortality after pancreatic resection: a systematic review and an evaluation of intervention in the Netherlands, Ann Surg, 2005;242:781–8, discussion 788–90.
  59. Cady B, Basic principles in surgical oncology, Arch Surg, 1997;132:338–46.
  60. Traverso LW, The Longmire I, II, and III operations, Am J Surg, 2003;185:399–406.
  61. Lin PW, Lin YJ, Prospective randomized comparison between pylorus-preserving and standard pancreaticoduodenectomy, Br J Surg, 1999;86:603–7.
  62. Seiler CA, Wagner M, Schaller B, et al., Pylorus preserving or classical Whipple operation in tumors. Initial clinical results of a prospective randomized study, Swiss Surg, 2000;6:275– 82.
  63. Seiler CA, Wagner M, Sadowski C, et al., Randomized prospective trial of pylorus-preserving vs. Classic duodenopancreatectomy (Whipple procedure): initial clinical results, J Gastrointest Surg, 2000;4:443–52.
  64. Nguyen TC, Sohn TA, Cameron JL, et al., Standard vs. radical pancreaticoduodenectomy for periampullary adenocarcinoma: a prospective, randomized trial evaluating quality of life in pancreaticoduodenectomy survivors, J Gastrointest Surg, 2003;7:1–9.
  65. Tran KT, Smeenk HG, van Eijck CH, et al., Pylorus preserving pancreaticoduodenectomy versus standard Whipple procedure: a prospective, randomized, multicenter analysis of 170 patients with pancreatic and periampullary tumors, Ann Surg, 2004;240:738–45.
  66. Lin PW, Shan YS, Lin YJ, Hung CJ, Pancreaticoduodenectomy for pancreatic head cancer: PPPD versus Whipple procedure, Hepatogastroenterology, 2005;52:1601–4.
  67. Seiler CA, Wagner M, Bachmann T, et al., Randomized clinical trial of pylorus-preserving duodenopancreatectomy versus classical Whipple resection-long term results, Br J Surg, 2005;92:547–56.
  68. Karanicolas PJ, Davies E, Kunz R, et al., The pylorus: take it or leave it? Systematic review and meta-analysis of pyloruspreserving versus standard whipple pancreaticoduodenectomy for pancreatic or periampullary cancer, Ann Surg Oncol, 2007;14:1825–34.
  69. Diener MK, Knaebel HP, Heukaufer C, et al., A systematic review and meta-analysis of pylorus-preserving versus classical pancreaticoduodenectomy for surgical treatment of periampullary and pancreatic carcinoma, Ann Surg, 2007;245:187–200.
  70. Srinarmwong C, Luechakiettisak P, Prasitvilai W, Standard Whipple’s operation versus pylorus preserving pancreaticoduodenectomy: a randomized controlled trial study, J Med Assoc Thai, 2008;91:693–8.
  71. Diener MK, Heukaufer C, Schwarzer G, et al., Pancreaticoduodenectomy (classic Whipple) versus pyloruspreserving pancreaticoduodenectomy (pp Whipple) for surgical treatment of periampullary and pancreatic carcinoma, Cochrane Database Syst Rev, 2008;(2):CD006053.
  72. Iqbal N, Lovegrove RE, Tilney HS, et al., A comparison of pancreaticoduodenectomy with pylorus preserving pancreaticoduodenectomy: a meta-analysis of 2822 patients, Eur J Surg Oncol, 2008;34:1237–45.
  73. Patel AG, Toyama MT, Kusske AM, et al., Pylorus-preserving Whipple resection for pancreatic cancer. Is it any better?, Arch Surg, 1995;130:838–42.
  74. Yeo CJ, Cameron JL, Maher MM, et al., A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy, Ann Surg, 1995;222:580–88.
  75. Bassi C, Falconi M, Molinari E, et al., Reconstruction by pancreaticojejunostomy versus pancreaticogastrostomy following pancreatectomy: results of a comparative study, Ann Surg, 2005;242:767–71.
  76. Takano S, Ito Y, Watanabe Y, et al., Pancreaticojejunostomy versus pancreaticogastrostomy in reconstruction following pancreaticoduodenectomy, Br J Surg, 2000;87:423–7.
  77. Duffas JP, Suc B, Msika S, et al.; French Associations for Research in Surgery, A controlled randomized multicenter trial of pancreatogastrostomy or pancreatojejunostomy after pancreatoduodenectomy, Am J Surg, 2005;189:720–9.
  78. McKay A, Mackenzie S, Sutherland FR, et al., Meta-analysis of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy, Br J Surg, 2006;93:929–36.
  79. Wente MN, Shrikhande SV, Müller MW, et al., Pancreaticojejunostomy versus pancreaticogastrostomy: systematic review and meta-analysis, Am J Surg, 2007;193:171–83.
  80. D’Andrea AA, Costantino V, Sperti C, Pedrazzoli S, Human fibrin sealant in pancreatic surgery: it is useful in preventing fistulas? A prospective randomized study, Ital J Gastroenterol, 1994;26:283–6.
  81. Tran K, Van Eijck C, Di Carlo V, et al., Occlusion of the pancreatic duct versus pancreaticojejunostomy: a prospective randomized trial, Ann Surg, 2002;236:422–8.
  82. Suc B, Msika S, Fingerhut A, et al.; and the French Associations for Surgical Research, Temporary fibrin glue occlusion of the main pancreatic duct in the prevention of intra-abdominal complications after pancreatic resection: prospective randomized trial, Ann Surg, 2003;237:57–65.
  83. Klempa I, Baca I, Menzel J, Schuszdiarra V, Effect of somatostatin on basal and stimulated exocrine pancreatic secretion after partial duodenopancreatectomy. A clinical experimental study, Chirurg, 1991;62:293–9.
  84. Büchler M, Friess H, Klempa I, et al., Role of octreotide in the prevention of postoperative complications following pancreatic resection, Am J Surg, 1992;163:125–30, discussion 130–1.
  85. Bassi C, Falconi M, Lombardi D, et al., Prophylaxis of complications after pancreatic surgery: results of a multicenter trial in Italy. Italian Study Group, Digestion, 1994;55(Suppl. 1):41–7.
  86. Pederzoli P, Bassi C, Falconi M, Camboni MG, Efficacy of octreotide in the prevention of complications of elective pancreatic surgery. Italian Study Group, Br J Surg, 1994;81:265–9.
  87. Montorsi M, Zago M, Mosca F, et al., Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections: a prospective, controlled, randomized clinical trial, Surgery, 1995;117:26–31.
  88. Friess H, Klempa I, Hermanek P, et al., Prophylaxis of complications after pancreatic surgery: results of a multicenter trial in Germany, Digestion, 1994;55(Suppl. 1): 35–40.
  89. Friess H, Beger HG, Sulkowski U, et al., Randomized controlled multicentre study of the prevention of complications by octreotide in patients undergoing surgery for chronic pancreatitis, Br J Surg, 1995;82:1270–3. Erratum: Br J Surg, 1996;83:126.
  90. Lowy AM, Lee JE, Pisters PW, et al., Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease, Ann Surg, 1997;226:632–41.
  91. Yeo CJ, Cameron JL, Lillemoe KD, et al., Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial, Ann Surg, 2000;232:419–29.
  92. Gouillat C, Chipponi J, Baulieux J, et al., Randomized controlled multicentre trial of somatostatin infusion after pancreaticoduodenectomy, Br J Surg, 2001;88:1456–62.
  93. Shan YS, Sy ED, Lin PW, Role of somatostatin in the prevention of pancreatic stump-related morbidity following elective pancreaticoduodenectomy in high-risk patients and elimination of surgeon-related factors: prospective, randomized, controlled trial, World J Surg, 2003;27:709–14.
  94. Sarr MG; Pancreatic Surgery Group, The potent somatostatin analogue vapreotide does not decrease pancreas-specific complications after elective pancreatectomy: a prospective, multicenter, double-blinded, randomized, placebocontrolled trial, J Am Coll Surg, 2003;196:556–64.
  95. Suc B, Msika S, Piccinini M, et al.; French Associations for Surgical Research, Octreotide in the prevention of intraabdominal complications following elective pancreatic resection: a prospective, multicenter randomized controlled trial, Arch Surg, 2004;139:288–94.
  96. Hesse UJ, De Decker C, Houtmeyers P, et al., Prospectively randomized trial using perioperative low dose octreotide to prevent organ related and general complications following pancreatic surgery and pancreatico-jejunostomy, Acta Chir Belg, 2005;105:383–7.
  97. Li-Ling J, Irving M, Somatostatin and octreotide in the prevention of postoperative pancreatic complications and the treatment of enterocutaneous pancreatic fistulas: a systematic review of randomized controlled trials, Br J Surg, 2001;88:190–9.
  98. Connor S, Alexakis N, Garden OJ, et al., Meta-analysis of the value of somatostatin and its analogues in reducing complications associated with pancreatic surgery, Br J Surg, 2005;29:1059–67.
  99. Alghamdi AA, Jawas AM, Hart RS, Use of octreotide for the prevention of pancreatic fistula after elective pancreatic surgery: a systematic review and meta-analysis, Am J Surg, 2007;50:459–66.
  100. Zeng Q, Zhang Q, Han S, et al., Efficacy of somatostatin and its analogues in prevention of postoperative complications after pancreaticoduodenectomy: a meta-analysis of randomized controlled trials, Pancreas, 2008;36:18–25.
  101. Nordback IH, Hruban RH, Boitnott JK, et al., Carcinoma of the body and tail of the pancreas, Am J Surg, 1992;164:26–31.
  102. Sperti C, Pasquali C, Pedrazzoli S, Ductal adenocarcinoma of the body and tail of the pancreas, J Am Coll Surg, 1997;185:255–9.
  103. Lillemoe KD, Kaushal S, Cameron JL, et al., Distal pancreatectomy: indications and outcomes in 235 patients, Ann Surg, 1999;229:693–8, discussion 698–700.
  104. Falconi M, Mantovani W, Bettini R, et al., Carcinoma of pancreatic body and tail: are there improvements in diagnosis and treatment modalities over the past decade?, Dig Liver Dis, 2003;35:421–7.
  105. Shoup M, Conlon KC, Klimstra D, Brennan MF, Is extended resection for adenocarcinoma of the body or tail of the pancreas justified?, J Gastrointest Surg, 2003;7:946–52.
  106. Bergenfeldt M, Moesgaard F, Burcharth F, Curative resection for left-sided pancreatic malignancy, HPB (Oxford), 2006;8:211–5.
  107. Miyata M, Dousei T, Tanaka Y, et al., Surgical aspect of cancer of the distal pancreas. Comparison of operative findings, mortality, morbidity, physicalperformance status and survival in cancer of the proximal and distal pancreas, Dig Surg, 1991;8:225–30.
  108. Fujimori N, Nakamura T, Oono T, et al., Adenocarcinoma involving the whole pancreas with multiple pancreatic masses, Intern Med, 2010;49:1527–32.
  109. Pedrazzoli S, DiCarlo V, Dionigi R, et al., Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group, Ann Surg, 1998;228:508–17.
  110. Yeo CJ, Cameron JL, Sohn TA, et al., Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: comparison of morbidity and mortality and short-term outcome, Ann Surg, 1999;229:613–22.
  111. Riall TS, Cameron JL, Lillemoe KD, et al., Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma – part 3: update on 5-year survival, J Gastrointest Surg, 2005;9:1191–1204.
  112. Nguyen TC, Sohn TA, Cameron JL, et al., Standard vs. radical pancreaticoduodenectomy for periampullary adenocarcinoma: a prospective, randomized trial evaluating quality of life in pancreaticoduodenectomy survivors, J Gastrointest Surg, 2003;7:1–9.
  113. Farnell MB, Pearson RK, Sarr MG, et al.; Pancreas Cancer Working Group, A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma, Surgery, 2005;138:618–28.
  114. Iqbal N, Lovegrove RE, Tilney HS, et al., A comparison of pancreaticoduodenectomy with extended pancreaticoduodenectomy: a meta-analysis of 1909 patients, Eur J Surg Oncol, 2009;35:79–86.
  115. Breslin TM, Hess KR, Harbison DB, et al., Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas : treatment variables and survival duration, Ann Surg Oncol, 2001;8:123–32.
  116. Siriwardana HP, Siriwardena AK, Systematic review of outcome of synchronous portal-superior mesenteric vein resection during pancreatectomy for cancer, Br J Surg, 2006;93:662–73.
  117. Boggi U, Del Chiaro M, Croce C, et al., Prognostic implications of tumor invasion or adhesion to peripancreatic vessels in resected pancreatic cancer, Surgery, 2009;146:869–81.
  118. Allison DC, Piantadosi S, Hruban RH, et al., DNA content and other factors associated with ten-year survival after resection of pancreatic carcinoma, J Surg Oncol, 1998;67:151–9.
  119. Moertel CG, Childs DS Jr, Reitemeier RJ, et al., Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer, Lancet, 1969;2:865–7.
  120. Tepper J, Nardi G, Suit H, Carcinoma of the pancreas : Review of MGH experience from 1963 to 1973: Analysis of surgical failure and implication for radiation therapy, Cancer, 1976;37:1519–24.
  121. Pilepich MV, Miller HH, Preoperative irradiation in carcinoma of the pancreas, Cancer, 1980;46:1945–9.
  122. Moertel CG, Frytak S, Hahn RG, et al., Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group, Cancer, 1981;48:1705–10.
  123. Kopelson G, Curative surgery for adenocarcinoma of the pancreas/ampulla of Vater: the role of adjuvant pre- or postoperative radiation therapy, Int J Radiat Oncol Biol Phys, 1983;9:911–5.
  124. Kalser MH, Ellenberg SS, Pancreatic Cancer. Adjuvant combined radiation and chemotherapy following curative radiation, Arch Surg, 1985;120:899–903.
  125. The Gastrointestinal Tumor Study Group (GITSG), Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer, Cancer, 1987;59:2006–10.
  126. Whittington R, Bryer MP, Haller DG, et al., Adjuvant therapy of resected adenocarcinoma of the pancreas, Int J Radiat Oncol Biol Phys, 1991;21:1137–43.
  127. Foo ML, Gunderson LL, Nagorney DM, et al., Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation ± 5 fluorouracil, Int J Radiat Oncol Biol Phys, 1993;26:483–9.
  128. Abrams RA, Grochow LB, Chakravarthy A, et al., Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma : survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels, Int J Radiat Oncol Biol Phys, 1999;44:1039–46.
  129. Paulino AC, Resected pancreatic cancer treated with adjuvant radiotherapy with or without 5-fluorouracil: treatment results and patterns of failure, Am J Clin Oncol, 1999;22:489–94.
  130. Mehta VK, Fisher GA, Ford JM, et al., Adjuvant radiotherapy and concomitant 5-Fluorouracil by protracted venous infusion for resected pancreatic cancer, Int J Radiat Oncol Biol Phys, 2000;48:1483–7.
  131. Bakkevold KE, Arnesjo B, Dahl O, Kambestad B, Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater – results of a controlled, prospective, randomized multicentre study, Eur J Cancer, 1993;29A:698–703.
  132. Klinkenbijl JH, Jeekel J, Sahmoud T, et al., Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group, Ann Surg, 1999;230:776–82, discussion 782–4.
  133. Neoptolemos JP, Dunn JA, Stocken DD, et al.; European Study Group for Pancreatic Cancer, Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial, Lancet, 2001;358:1576–85.
  134. Neoptolemos JP, Stokken DD, Friess H, et al.; European Study Group for Pancreatic Cancer, A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer, N Engl J Med, 2004;350:1200–10.
  135. Burris HA 3rd, Moore MJ, Andersen J, et al., Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial, J Clin Oncol, 1997;15:2403–13.
  136. Oettle H, Post S, Neuhaus P, et al., Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial, JAMA, 2007;297:267–77.
  137. Neuhaus P, Riess H, Post S, et al., CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation with resected pancreatic cancer, J Clin Oncol, 2008;26(Suppl. 20):abstract LBA4504.
  138. Ueno H, Kosuge T, Matsuyama Y, et al., A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer, Br J Cancer, 2009;101:908–15.
  139. Regine WF, Winter KA, Abrams RA, et al., Fluorouracil vs gemcitabine chemotherapy before and after fluorouracilbased chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial, JAMA, 2008;299:1019–26.
  140. Neoptolemos J, Büchler M, Stocken DD, et al., A multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemctabine (GEM) in patients with resected pancreatic ductal adenocarcinoma, J Clin Oncol, 2009;27(Suppl. 18): abstract LBA4505.
  141. Beger HG, Link KH, Gansauge F, Intraarterial adjuvant chemotherapy after pancreticoduodenectomy : significant reduction in occurrence of liver metastasis, World J Surg, 1999;23:946–9.
  142. Pendurthi TK, Hoffman JP, Ross E, et al., Preoperative versus postoperative chemoradiation for patients with resected pancreatic adenocarcinoma, Am Surg, 1998;64:686–92.
  143. Hoffman JP, Lipsitz S, Pisansky T, et al., Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas : an Eastern Cooperative Oncology Group Study, J Clin Oncol, 1998;16:317–23.
  144. Breslin TM, Hess KR, Harbison DB, et al., Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration, Ann Surg Oncol, 2001;8:123–32.
  145. White R, Lee C, Anscher M, et al., Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas, Ann Surg Oncol, 1999;6:38–45.
  146. Nukui Y, Picozzi VJ, Traverso LW, Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma, Am J Surg, 2000;179:367–71.
  147. Picozzi VJ, Abrams RA, Decker PA, et al.; for the American College of Surgeons Oncology Group, Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2bbased chemoradiation: ACOSOG Trial Z05031, Ann Oncol, 2011;22:348–54.
  148. Yeo CJ, Abrams RA, Grochow LB, et al., Pancreaticoduodenectomy for pancreatic adenocarcinoma :postoperative adjuvant chemoradiation improves survival. A prospective single-institution expeerience, Ann Surg, 1997;225:621–33.
  149. Spitz FR, Abbruzzese JL, Lee JE, et al., Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas, J Clin Oncol, 1997;15:928–37.
  150. Bergenfeldt M, Albertsson M, Current state of adjuvant therapy in resected pancreatic adenocarcinoma, Acta Oncol, 2006;45:124–35.
  151. Staley CA, Lee JE, Cleary KR, et al., Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head, Am J Surg, 1996;171:118–24.
  152. Ishikawa O, Ohigashi H, Imaoka S, et al., Concomitant benefit of preoperative irradiation in preventing pancreas fistula formation after pancreatoduodenectomy, Arch Surg, 1991;126:885–9.
  153. Lowy AM, Lee JE, Pisters PW, et al., Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease, Ann Surg, 1997;226:632–41.
  154. Pisters PW, Abbruzzese JL, Janjan NA, et al., Rapidfractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma, J Clin Oncol, 1998;16:3843–50.
  155. Snady H, Bruckner H, Cooperman A, et al., Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial, Cancer, 2000;89:314–27.
  156. White R, Lee C, Anscher M, et al., Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas, Ann Surg Oncol, 1999;6:38–45.
  157. White RR, Hurwitz HI, Morse MA, et al., Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas, Ann Surg Oncol, 2001;8:758–65.
  158. Pisters PW, Wolff RA, Janjan NA, et al., Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome, J Clin Oncol, 2002;20:2537–44.
  159. White RR, Paulson EK, Freed KS, et al., Staging of pancreatic cancer before and after neoadjuvant chemoradiation, J Gastrointest Surg, 2001;5:626–33.
  160. Bjerregaard JK, Mortensen MB, Jensen HA, et al., Long-term results of concurrent radiotherapy and UFT in patients with locally advanced pancreatic cancer, Radiother Oncol, 2009;92:226–30.
  161. Köninger J, Wente MN, Müller-Stich BP, et al., R2 resection in pancreatic cancer – does it make sense?, Langenbecks Arch Surg, 2008;393:929–34.

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