Topic Highlight Open Access
Copyright ©2010 Baishideng. All rights reserved.
World J Gastrointest Surg. Feb 27, 2010; 2(2): 39-46
Published online Feb 27, 2010. doi: 10.4240/wjgs.v2.i2.39
Extended pancreatic resections and lymphadenectomy: An appraisal of the current evidence
Shailesh V Shrikhande, Department of Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Hospital, Mumbai 400 012, India
Savio G Barreto, Department of General and Digestive Surgery, Flinders Medical Centre and Flinders University, Adelaide, SA 5042, Australia
Author contributions: Shrikhande SV designed the study, analysed and interpreted the data, revised it critically for important intellectual content and approved the final version; Barreto SG acquired and analysed the data, drafted the article and approved the final version.
Correspondence to: Shailesh V Shrikhande, MBBS, MS, MD, Department of Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel-Mumbai 400 012, India. shailushrikhande@hotmail.com
Telephone: + 91-22-24177173 Fax: +91-22-24148114
Received: November 13, 2009
Revised: December 11, 2009
Accepted: December 18, 2009
Published online: February 27, 2010

Abstract

Surgery remains the mainstay of treatment for pancreatic ductal adenocarcinoma and complete removal of the cancer confers a definite survival advantage, especially in early disease. However, the majority of patients do not present with early disease, thus precluding the chance of a cure by standard pancreatoduodenectomy (PD), distal pancreatectomy or total pancreatectomy. For this reason, pancreatic surgeons have attempted to push the limits of resection over the last three decades. The aim of these resections has been to determine whether obtaining a complete resection by extending the limits of conventional resection in patients with advanced disease will yield the results seen with PD alone in early disease. This article revisits the data from such studies in an attempt to determine if the available literature supports the performance of extended resections for pancreatic cancer in terms of improvement of survival.

Key Words: Pancreas, Cancer, Vein, Lymphadenectomy, Artery, Reconstruction



INTRODUCTION

The prognosis for pancreatic cancer has largely remained the same for the last two decades[1]. Pancreatic cancer surgery, which may include pancreatoduodenectomy (PD), distal pancreatectomy (DP) and/or total pancreatectomy (TP), remains the mainstay of treatment for pancreatic cancer and the complete removal of the cancer confers a definite survival advantage in early disease[2]. However, not all patients present with early disease[3] precluding the chance of a cure by standard pancreatic resections in a vast majority of patients. Over the last 3 decades, pancreatic surgeons have attempted to push the limits of resection in patients with advanced disease with an aim to completely remove the tumour[4-8] by performing extended resections. This includes extended lymphadenectomies (removal of lymph nodes in addition to those removed during a standard lymphadenectomy such as the celiac axis nodes, nodes around the common and proper hepatic arteries, and the aorta and inferior vena cava in continuity with the Gerota’s fascia), vascular resections, multiorgan resections and even metastatectomies. However, while the feasibility of such major and often morbid procedures has been demonstrated in high-volume centers, the main outcome that needs to be addressed in such resections is the benefit in terms of overall survival and their impact on the quality of life[9].

The rationale behind the attempts at extended resections stem from a clear understanding that only a complete resection (no residual disease/R0) is associated with the best possible chance of survival for pancreatic cancer[10].

VASCULAR RESECTIONS AND RECONSTRUCTIONS

The proximity of the pancreatic head tumour to the portal vein as a cause for inoperability has been recognised for the last 6 decades. This prompted early experiments of PD with portal vein resections in dogs[11] aimed at determining the feasibility of such an operation. The results of the experiment were not very encouraging. This did not deter further attempts and surgeons continued experimental work attempting the procedure in two stages-initial ligation and then resection of the portal vein in monkeys and cadavers[12,13]. Central to all this work though, was the findings of von Eck and the "Eck fistula"[14]. Von Eck had shown that as a result of porta caval shunting in dogs the liver underwent a certain amount of atrophy. Nonetheless, the dogs lived a normal life for many years and demonstrated no gross clinical disturbances. Around the same year, Mc Dermott[15] attempted, for the first time, a single staged PD with portal vein resection and mesentero-caval anastomosis. The patient was discharged on the 19th postoperative day and was still alive for the 4 mo of follow-up. After that, another surgeon attempted resecting the portal vein and performing a portacaval anastomosis in 2 patients. One patient died after 3 mo and the other after 6 mo as a result of gastrointestinal bleeding and ammonia intoxication. Monge et al[16] in their audit of pancreatic cancer over a period of 22 years recognised the low resectability rate for pancreatic head cancer at the time, due to the proximity to the portal vein. This prompted Fortner et al[4,17,18] to suggest three types of en bloc resections based on the vascular resection (venous or arterial) and reconstruction. They believed that such procedures would not only increase the number of complete resections but also increase the lymph nodal yields. They demonstrated a reduction in post-operative morbidity and mortality with increasing experience with the procedure[18].

Since the description of the vascular resections as part of radical pancreatic cancer surgery, there has been considerable debate over the justification of the performance of such potentially morbid procedures in terms of survival.

Reports of arterial resections and reconstruction have been reported for pancreatic tumours[19-32]. While venous resection and reconstruction has been performed in many series, the resistance to arterial resections (hepatic artery or celiac trunk) is strong.

The basis behind the believed benefit of performing a venous resection over an arterial resection in cancer is that the portal venous system, unlike the arterial system, is not surrounded by perivascular neural plexus and lymphatic tissue[33]. Hence, portal vein involvement potentially remains the only barrier to radical tumour removal[33]. Besides, ‘venous involvement’ described preoperatively usually reflects an abutment of the vessel by the tumour without actual invasion. In the case of arteries, the fact that it is closely related to the neural and lymphatic plexuses implies that the disease is usually metastatic by the time the arteries are involved.

The argument against venous resection and reconstruction is that by the time the tumour infiltrates the portal vein, the incidence of lymph nodal involvement is 67.4%[34], negating the possibility of a cure by surgery. This pessimistic view has, however, been challenged by a number of surgeons who have reported that it is not the venous resection that is the determinant of poor long-term outcomes but rather the disease biology[33-49].

However, there has been considerable debate since then on the actual benefit of such resections in terms of overall survival. In 2006, Siriwardana et al[34] reviewed the available literature up to that time to determine the benefit of portal and superior mesenteric vein resections and reconstructions. Their study, which included data on 1646 patients, indicated that while the procedure could be performed with reasonable morbidity (42%) and mortality (6%), the benefit in terms of overall survival was lacking. Moreover, histopathological analysis of resected lymph nodes was also high, indicating that the disease was beyond cure by the time venous involvement had taken place. However, a closer look at their analysis revealed that in 40% of patients the resection margin was positive-a known indicator of poor outcomes. This precludes an accurate analysis of the benefit of the venous resection in terms of overall survival. This has been shown by other studies[44,45] published after the Siriwardena review[34] that demonstrated no difference in outcomes when venous involvement was documented on histology as compared to absence of venous involvement so long as an R0 resection could be achieved.

Similarly, other studies have confirmed that in cases of venous involvement by the tumour, there are other factors that determine outcome that include: (1) Depth of venous invasion[41]-no difference in survival was noted between patients without portal vein invasion as opposed to involvement of the tunica adventitia. However, outcome following a complete resection of the vein with involvement of tunica media and intima was no different from an incomplete resection; (2) Length of invasion[45]-while no difference was observed in terms of survival between no portal vein invasion and invasion that was unilateral or circumferential, the length of the involved segment did affect outcome. Length of involvement more than 3 cm was associated with poor outcomes.

The addition of neo-adjuvant chemo-radiation protocols may lead to an increased number of patients being offered a complete resection after being termed ‘borderline resectable’ due to likely vessel involvement on the initial staging[50]. The group from MD Anderson Cancer Centre[50] have defined ‘borderline resectable tumours’ as those tumours that exhibit the following: (1) Encasement of a short segment of the hepatic artery, without evidence of tumour extension to the celiac axis, that is amenable to resection and reconstruction; (2) Tumour abutment of the superior mesenteric artery involving < 180° of the circumference of the artery or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumour involvement.

These neoadjuvant chemo-radiation protocols may help separate those who would not benefit from major vascular resection versus those who would indeed benefit from vascular resections and that too with higher probability of R0 resections.

MULTIVISCERAL RESECTIONS

In an attempt to obtain complete removal of pancreatic cancer, surgeons have resorted to en bloc resections that entailed removal of adjacent viscera/vessels that are grossly infiltrated by tumour at the time of PD, DP, or TP[51-55].

There has been considerable confusion in the literature as to the definition of extended resections: some authors have included a splenectomy as an extended resection for a pancreatic body and tail tumour[56]. Similarly, others have performed extended resections including gastrectomies even in the absence of gross invasion[57]. Such articles were not included in our analysis. Classic PD (Whipple’s operation) is essentially a multi-visceral resection which includes the resection of the pancreas with a portion of the stomach. Similarly, DP, as has been performed over the years, involves removal of the spleen. As such, multivisceral resections should strictly be defined as those resections that include removal of adjacent viscera that are not normally removed during the course of the operation but in whom gross involvement by the tumour entails their resection en bloc to achieve an R0 resection.

Table 1 shows some of the larger studies in which such resections were undertaken. Morbidity following such procedures has been shown to vary between 35%-68% while mortality ranged from 0%-3%[20,51,52]. 5-year survival rates have been shown to be between 16%-22%[20,55] with one study even reporting an actuarial 10-year disease specific survival rate of 18%[55]. These recent results indicate an improvement in outcomes following multivisceral resections compared to a previous study published in 1996 by Klempnauer et al[54]. Based on their mortality rate of 17.7% with a 5-year survival rate of 12%, Klempnauer et al[54] had earlier concluded that such resections resulted in increased risk of mortality with an impaired long-term prognosis.

Table 1 Multi-visceral resections for pancreatic cancer (where studies have included vascular resections in the analysis this has been specified).
Author (Ref)YearNumber of patientsNeoadjuvant therapyOrgans resectedMorbidity/MortalitySurvivalConclusions
Klempnauer et al[54]199645Not specifiedColon, stomach, liver, kidney, adrenal31%/17.7%5-YSR = 11.9% Median survival = 7.3 mo (n = 34)Increased mortality and impaired long-term prognosis
Sasson et al[20]20023776% (5-FU or Gemcitabine)Colon & mesocolic vessels, celiac axis, portal vein, liver, adrenal, stomach35%/2.7%5-YSR = 16% (P < 0.08 in favour of en bloc resections)Safe; beneficial in selected patients who receive neoadjuvant therapy
Hartwig et al[51]200910120.8%Colon, stomach, adrenal gland, liver, hepatic or celiac artery, kidney, or small intestine37.6%/3%3-YSR = 37.2%Increased morbidity; Comparable mortality and long-term outcomes
1Nikfarjam et al[52]20097 (19)Not specifiedColon, kidney, liver68%/0%Not specifically addressedComparable morbidity to routine PD
Shoup et al[55]200322Not specifiedColon, stomach, adrenal, portal veinNot specified5-YSR = 22% 10-YSR = 18%Markedly improved survival as compared to those not resected

From the limited data available, what can be concluded at this time is that such resections are technically feasible and when performed in high volume centres with the necessary expertise they have shown to be associated with improved survival as compared to no resection and comparable survival to standard resections for lesions that do not involve adjacent organs. However, given the high morbidity and even mortality associated with these procedures, it should be advised that such resections should be performed only when the possibility of achieving R0 seems distinctly feasible.

EXTENDED LYMPHADENECTOMY

The knowledge of lymph node involvement in pancreatic cancer and the recognition that lymphadenectomy may be linked to survival has been known for the last 5 decades[58,59]. In fact, Fortner et al[4,17,18] proposed the en bloc resection as a means to increasing lymph nodal yield.

In 1999, recognising that positive lymph nodes on histology are a poor risk factor for outcomes following pancreatic resections for pancreatic cancer, leading pancreatic surgeons from around the world issued consensus definitions of the different surgeries for pancreatic cancer[60]. They defined radical surgery as en bloc pancreaticoduodenectomy with extended resection margins, resection of defined lymph nodes and an additional retroperitoneal lymphadenectomy. The definitions of lymphadenectomy as per the consensus definition[60] are in Table 2. The prime issue in terms of lymphadenectomy is whether the performance of an extended lymphadenectomy (EL) offers any survival advantage over standard lymphadenectomy (SL).

Table 2 Definitions of lymphadenectomy for pancreatic cancer according to the consensus definitions published in 1999[60].
Lymph node groupLymph node stations
Pancreatic head cancers
Standard Lymphadenectomy
Lymph nodes of the right side of the hepatoduodenal ligament12b1, 12b1, 12c
Posterior pancreaticoduodenal nodes13a, 13b
Nodes to the right side of the superior mesenteric artery from the origin of the superior mesenteric artery at the aorta to the inferior pancreatico-duodenal artery14a, 14b
Anterior pancreaticoduodenal nodes17a, 17b
Extended Lymphadenectomy
Skeletonization of the common and proper hepatic artery lymph nodesAll 8
Celiac axis nodes9
Lymph nodes of the left and right side of the hepatoduodenal ligamentAll 12
Circumferential skeletonization of the superior mesenteric artery between the aorta and the inferior pancreaticoduodenal arteryAll 14
All lymph nodes of the anterolateral aspect of the aorta and of the inferior vena cava, in continuity with Gerota’s fascia, between the celiac axis and the inferior mesenteric artery16a2, 16b1
Pancreatic body and tail cancers
Standard Lymphadenectomy
Celiac axis nodes9
Nodes of the hilum of the spleen10
Splenic artery lymph nodes11
Nodes along the inferior border of the body and tail of the pancreas18
Extended Lymphadenectomy
Anterior-superior region of the common hepatic artery8a
Circumferential skeletonization of the superior mesenteric artery between the aorta and the inferior pancreaticoduodenal arteryAll 14
Lymph nodes of the anterolateral aspect of the aorta and of the inferior vena cava, in continuity with Gerota’s fascia, between the celiac axis and the inferior mesenteric artery16a2, 16b1

Numerous studies have attempted to answer this question[8,61-77]. Table 3 lists the randomised controlled trials published to date comparing SL versus EL.

Table 3 Randomised controlled trials analysing the benefits of SL versus EL for pancreatic cancer.
Author (Ref) & yearNumber of patients randomisedMean lymph nodes harvested±SDAdjuvant CTMorbidity/MortalitySurvivalConclusions
Pedrazolli et al[61] 1998PD: 40 PD/EL: 41PD: 13.3 ± 8.3 PD/EL: 19.8 ± 15.1 (P < 0.03)-PD: 45%/5% PD/EL: 34%/4.8%4-YSR = (actuarial) PD: 12% PD/EL: 6%No difference in morbidity and mortality Trend toward longer survival in node positive patients treated with EL
Yeo et al[62] 2002PD: 146 PD/EL: 148PD: 17.0 ± 0.6 PD /EL: 28.5 ± 0.6 (P < 0.001)Both groupsPD: 29%/4% PD/EL: 43%/2%5-YSR = (actuarial) PD: 10% PD/EL: 25%Similar mortality but increased morbidity with no survival benefit
1Nimura et al[63] 2004PD: 51 PD/EL: 50PD: 13 PD/EL: 40 (P < 0.03)-PD: 12%/0% PD/EL: 20%/2%3-YSR = (actuarial) PD: 28.5% PD/EL: 16.6%No improvement in survival with EL
Farnell et al[64] 2005PD: 40 PD/EL: 39PD: 15 (3-31) 2PD/EL: 36 (6-74) (P < 0.0001)Both Groups (+ RT)PD: 35%/0% PD/EL: 45%/2.6%5-YSR = (actuarial) PD: 16.4% PD/EL: 16.5%No improvement in survival along with a decreased QOL with EL

In the last 2 years there have been 2 meta-analyses[78,79] published comparing SL with EL. The lymph node yield and the ability to achieve a complete resection improved with an extended resection that involved an EL. Both the meta-analyses concluded that while the extended procedure tended to be associated with a comparable morbidity and mortality (5.5% versus 3.8%)[79] (except for increased risk of delayed gastric emptying in the EL group; 9.4% vs 19.4% OR = 0.120)[78], the extended procedure did not impact on overall survival. They also concluded that more adequately powered studies are needed which should preferably be performed within the realms of controlled trials. Farnell et al[64] also reported a decreased quality of life in their patients who underwent EL. Interestingly in 2005, Pawlik et al[80] analysed the results of SL and EL from their own data and determined that only 3 in 1000 patients would benefit from an EL. Put differently, this would imply a 0.22% potential incremental improvement in survival following EL compared with SL. Based on a biostatistical model they determined that a definitive evaluation of the potential benefits of EL would require a prohibitively large sample size of 202,000 in each arm in a phase 3 randomized trial. This meant that even if an accrual of 200 patients per year in the trial was possible, it would take 1010 years to complete the trial! This led them to conclude that such a trial would be infeasible.

However, as the argument on the ideal lymphadenectomy for pancreatic cancer continues, some surgeons have focussed their attention on analysing another potential predictor of survival-lymph node ratio[81-85]. The lymph nodal ratio essentially is a ratio of metastatic to examined lymph nodes. Based on the results obtained using SL, the cut-off ratio indicative of adverse prognosis in the different studies varied between 0.15 and 0.3. What has also been shown to aid an accurate staging and in turn more precise prediction of survival has been the total number of lymph nodes harvested. In a large population-based cohort, Schwarz et al[86] found that lymph nodal yields of at least 15 in the histopathological specimen analysed would yield at least 10-15 negative lymph nodes resulting in a more accurate prediction of survival.

M1 RESECTIONS

The presence of distant metastases in patients with pancreatic cancer has generally been considered an indicator of terminal disease. However, there have been a number of reports (case reports and even some large series) highlighting attempts from surgical resection of distant metastases (liver, peritoneum)[7,87-91]. While some studies have demonstrated improved survival in patients with pancreatic cancer in whom metastasectomy was performed for adenocarcinoma[7,88,89,91], a more recent study in which resections were performed for liver and peritoneal metastases has indicated that such resections do not provide a survival benefit[90].

In one of the larger series of metastasectomies for pancreatic cancer published till date, Shrikhande et al[7] were able to achieve a median survival of 13.8 mo after R0/R1 (microscopically positive margins) surgery for advanced pancreatic cancer with M1 disease with a 1-year survival of 58.9%. While the median survival following resection of liver and peritoneal metastases was comparatively low (11.4 mo and 12.9 mo respectively) the median survival following removal of interaortocaval lymph nodal metastases was as high as 27 mo. Furthermore, the morbidity and mortality in their series was 24% and 0% respectively. Yamada et al[90] observed no difference in survival between those patients who had resections for liver and peritoneal metastases (n =11 and 6 respectively) as compared to those who did not. However, in the 48 patients who did undergo removal of the involved interaortocaval lymph nodes, survival appeared to be better than those who were not resected. The difference though did not attain statistical significance.

In 2008, Michalski et al[92] reviewed the available literature on liver resections for pancreatic ductal adenocarcinoma which included the results from 3 case reports and 21 studies (the largest had 11 patients undergoing liver resection). They concluded that while such resections were technically feasible in selected patients the actual benefit could be determined only from larger randomized controlled trials.

CONCLUSION

Available data on extended pancreatic resections for pancreatic ductal adenocarcinoma indicates that such major procedures are technically feasible and can be done with reasonable morbidity and mortality. However, the benefit of such surgery on more important variables such as overall survival and quality of life is lacking with the existence of conflicting and often confusing reports. Thus, till such time as more robust evidence from randomised controlled trials is available to support the performance of extended resections, standard PD, DP or TP should be considered as the best practice for resectable pancreatic ductal adenocarcinoma. The more complex resections should only be undertaken in high volume specialized centres of pancreatic surgery after a careful assessment of the risk benefit ratio in the individual patient.

Footnotes

Peer reviewers: Joseph Kim, MD, Department of Oncologic Surgery, City of Hope Medical Center, 1500 East Duarte Road Duarte, CA 91010, United States; Sonshin Takao, MD, Frontier Science Research Center, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

S- Editor Li LF L- Editor Roemmele A E- Editor Yang C

References
1.  Mendieta Zerón H, García Flores JR, Romero Prieto ML. Limitations in improving detection of pancreatic adenocarcinoma. Future Oncol. 2009;5:657-668.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Raut CP, Tseng JF, Sun CC, Wang H, Wolff RA, Crane CH, Hwang R, Vauthey JN, Abdalla EK, Lee JE. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246:52-60.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Mackenzie RP, McCollum AD. Novel agents for the treatment of adenocarcinoma of the pancreas. Expert Rev Anticancer Ther. 2009;9:1473-1485.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Fortner JG, Kim DK, Cubilla A, Turnbull A, Pahnke LD, Shils ME. Regional pancreatectomy: en bloc pancreatic, portal vein and lymph node resection. Ann Surg. 1977;186:42-50.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Martin RC 2nd, Scoggins CR, Egnatashvili V, Staley CA, McMasters KM, Kooby DA. Arterial and venous resection for pancreatic adenocarcinoma: operative and long-term outcomes. Arch Surg. 2009;144:154-159.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Abramson MA, Swanson EW, Whang EE. Surgical resection versus palliative chemoradiotherapy for the management of pancreatic cancer with local venous invasion: a decision analysis. J Gastrointest Surg. 2009;13:26-34.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Shrikhande SV, Kleeff J, Reiser C, Weitz J, Hinz U, Esposito I, Schmidt J, Friess H, Büchler MW. Pancreatic resection for M1 pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2007;14:118-127.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Massucco P, Ribero D, Sgotto E, Mellano A, Muratore A, Capussotti L. Prognostic significance of lymph node metastases in pancreatic head cancer treated with extended lymphadenectomy: not just a matter of numbers. Ann Surg Oncol. 2009;16:3323-3332.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Crippa S, Domínguez I, Rodríguez JR, Razo O, Thayer SP, Ryan DP, Warshaw AL, Fernández-del Castillo C. Quality of life in pancreatic cancer: analysis by stage and treatment. J Gastrointest Surg. 2008;12:783-793; discussion 793-794.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Büchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91:586-594.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Schafer PW, Kozy JS. Radical Pan- creatoduodenectomy with Resection of the. Patent Portal Vein. Surgery. 1947;22:959.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Milnes RF, Child CG 3rd. Acute occlusion by ligature of the portal vein in the Macacus rhesus monkey. Proc Soc Exp Biol Med. 1949;70:332-334.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Child CG 3rd, Holswade GR, Mcclure RD Jr, Gore AL, O'Neill EA. Pancreaticoduodenectomy with resection of the portal vein in the Macaca mulatta monkey and in man. Surg Gynecol Obstet. 1952;94:31-45.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Child CG III. Eck’s Fistula. Surg Gynecol Obst. 1953;96:375.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Mcdermott WV Jr. A one-stage pancreatoduodenectomy with resection of the portal vein for carcinoma of the pancreas. Ann Surg. 1952;136:1012-1018.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Monge JJ, Judd ES, Gage RP. Radical pancreatoduodenectomy: A 22-Year experience with the complications, mortality rate, and survival rate. Ann Surg. 1964;160:711-722.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Fortner JG. Regional resection of cancer of the pancreas: a new surgical approach. Surgery. 1973;73:307-320.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Fortner JG. Regional pancreatectomy for cancer of the pancreas, ampulla, and other related sites. Tumor staging and results. Ann Surg. 1984;199:418-425.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Kondo S, Katoh H, Hirano S, Ambo Y, Tanaka E, Okushiba S, Morikawa T. Results of radical distal pancreatectomy with en bloc resection of the celiac artery for locally advanced cancer of the pancreatic body. Langenbecks Arch Surg. 2003;388:101-106.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Sasson AR, Hoffman JP, Ross EA, Kagan SA, Pingpank JF, Eisenberg BL. En bloc resection for locally advanced cancer of the pancreas: is it worthwhile? J Gastrointest Surg. 2002;6:147-157; discussion 157-158.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Miyakawa S, Horiguchi A, Hanai T, Mizuno K, Ishihara S, Niwamoto N, Iwase Y, Asano Y, Furusawa K, Miura K. Monitoring hepatic venous hemoglobin oxygen saturation during Appleby operation for pancreatic cancer. Hepatogastroenterology. 2002;49:817-821.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Konishi M, Kinoshita T, Nakagori T, Inoue K, Oda T, Kimata T, Kikuchi H, Ryu M. Distal pancreatectomy with resection of the celiac axis and reconstruction of the hepatic artery for carcinoma of the body and tail of the pancreas. J Hepatobiliary Pancreat Surg. 2000;7:183-187.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Mayumi T, Nimura Y, Kamiya J, Kondo S, Nagino M, Kanai M, Miyachi M, Hamaguchi K, Hayakawa N. Distal pancreatectomy with en bloc resection of the celiac artery for carcinoma of the body and tail of the pancreas. Int J Pancreatol. 1997;22:15-21.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Kimura W, Han I, Furukawa Y, Sunami E, Futakawa N, Inoue T, Shinkai H, Zhao B, Muto T, Makuuchi M. Appleby operation for carcinoma of the body and tail of the pancreas. Hepatogastroenterology. 1997;44:387-393.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Makary MA, Fishman EK, Cameron JL. Resection of the celiac axis for invasive pancreatic cancer. J Gastrointest Surg. 2005;9:503-507.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Lin CC, Chen CL, Cheng YF. Modified extended distal pancreatectomy for carcinoma of body and tail of pancreas. Hepatogastroenterology. 2005;52:1090-1091.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Hirai I, Kimura W, Kamiga M, Mizutani M, Takeshita A, Watanabe T, Fuse A. The significance of intraoperative Doppler ultrasonography in evaluating hepatic arterial flow when assessing the indications for the Appleby procedure for pancreatic body cancer. J Hepatobiliary Pancreat Surg. 2005;12:55-60.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Liu B. Modified Appleby operation in treatment of distal pancreatic cancer. Hepatobiliary Pancreat Dis Int. 2003;2:622-625.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Yamaguchi K, Nakano K, Kobayashi K, Ogura Y, Konomi H, Sugitani A, Tanaka M. Appleby operation for pancreatic body-tail carcinoma: report of three cases. Surg Today. 2003;33:873-878.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Wu YL, Yan HC, Chen LR, Gao SL, Chen J, Dong X. Extended Appleby's operation for pancreatic cancer involving celiac axis. J Surg Oncol. 2007;96:442-446; discussion 447.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Gagandeep S, Artinyan A, Jabbour N, Mateo R, Matsuoka L, Sher L, Genyk Y, Selby R. Extended pancreatectomy with resection of the celiac axis: the modified Appleby operation. Am J Surg. 2006;192:330-335.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Nakano H, Bachellier P, Weber JC, Oussoultzoglou E, Dieng M, Shimura H, Boudjema K, Wolf P, Jaeck D. Arterial and vena caval resections combined with pancreaticoduodenectomy in highly selected patients with periampullary malignancies. Hepatogastroenterology. 2002;49:258-262.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Riediger H, Makowiec F, Fischer E, Adam U, Hopt UT. Postoperative morbidity and long-term survival after pancreaticoduodenectomy with superior mesenterico-portal vein resection. J Gastrointest Surg. 2006;10:1106-1115.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Siriwardana HP, Siriwardena AK. Systematic review of outcome of synchronous portal-superior mesenteric vein resection during pancreatectomy for cancer. Br J Surg. 2006;93:662-673.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Amano H, Miura F, Toyota N, Wada K, Katoh K, Hayano K, Kadowaki S, Shibuya M, Maeno S, Eguchi T. Is pancreatectomy with arterial reconstruction a safe and useful procedure for locally advanced pancreatic cancer? J Hepatobiliary Pancreat Surg. 2009;16:850-857.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Tseng JF, Raut CP, Lee JE, Pisters PW, Vauthey JN, Abdalla EK, Gomez HF, Sun CC, Crane CH, Wolff RA. Pancreaticoduodenectomy with vascular resection: margin status and survival duration. J Gastrointest Surg. 2004;8:935-949; discussion 949-950.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Shibata C, Kobari M, Tsuchiya T, Arai K, Anzai R, Takahashi M, Uzuki M, Sawai T, Yamazaki T. Pancreatectomy combined with superior mesenteric-portal vein resection for adenocarcinoma in pancreas. World J Surg. 2001;25:1002-1005.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  van Geenen RC, ten Kate FJ, de Wit LT, van Gulik TM, Obertop H, Gouma DJ. Segmental resection and wedge excision of the portal or superior mesenteric vein during pancreatoduodenectomy. Surgery. 2001;129:158-163.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Adham M, Mirza DF, Chapuis F, Mayer AD, Bramhall SR, Coldham C, Baulieux J, Buckels J. Results of vascular resections during pancreatectomy from two European centres: an analysis of survival and disease-free survival explicative factors. HPB (Oxford). 2006;8:465-473.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Jaeck D, Bachellier P, Oussoultzoglou E, Audet M, Rosso E, Wolf P. [Analysis of a series of 100 mesenterico-portal vein resections during pancreatic resection]. Bull Acad Natl Med. 2006;190:1495-1506; dsicussion 1506-1509.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Fukuda S, Oussoultzoglou E, Bachellier P, Rosso E, Nakano H, Audet M, Jaeck D. Significance of the depth of portal vein wall invasion after curative resection for pancreatic adenocarcinoma. Arch Surg. 2007;142:172-179; discussion 180.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Park DI, Lee JK, Kim JE, Hyun JG, Shim SG, Lee KT, Palk SW, Rhee JC, Choi KW, Lim JH. The analysis of resectability and survival in pancreatic cancer patients with vascular invasion. J Clin Gastroenterol. 2001;32:231-234.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Taschieri AM, Elli M, Rovati M, Sampietro GM, Cristaldi M, Danelli P, Pisacreta M. Surgical treatment of pancreatic tumors invading the spleno-mesenteric-portal vessels. An Italian Multicenter Survey. Hepatogastroenterology. 1999;46:492-497.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Toomey P, Hernandez J, Morton C, Duce L, Farrior T, Villadolid D, Ross S, Rosemurgy A. Resection of portovenous structures to obtain microscopically negative margins during pancreaticoduodenectomy for pancreatic adenocarcinoma is worthwhile. Am Surg. 2009;75:804-809; discussion 809-810.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Kaneoka Y, Yamaguchi A, Isogai M. Portal or superior mesenteric vein resection for pancreatic head adenocarcinoma: prognostic value of the length of venous resection. Surgery. 2009;145:417-425.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Shimada K, Sano T, Sakamoto Y, Kosuge T. Clinical implications of combined portal vein resection as a palliative procedure in patients undergoing pancreaticoduodenectomy for pancreatic head carcinoma. Ann Surg Oncol. 2006;13:1569-1578.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Hartel M, Niedergethmann M, Farag-Soliman M, Sturm JW, Richter A, Trede M, Post S. Benefit of venous resection for ductal adenocarcinoma of the pancreatic head. Eur J Surg. 2002;168:707-712.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Kure S, Kaneko T, Takeda S, Inoue S, Nakao A. Analysis of long-term survivors after surgical resection for invasive pancreatic cancer. HPB (Oxford). 2005;7:129-134.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Takahashi S, Ogata Y, Tsuzuki T. Combined resection of the pancreas and portal vein for pancreatic cancer. Br J Surg. 1994;81:1190-1193.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Varadhachary GR, Tamm EP, Abbruzzese JL, Xiong HQ, Crane CH, Wang H, Lee JE, Pisters PW, Evans DB, Wolff RA. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol. 2006;13:1035-1046.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Hartwig W, Hackert T, Hinz U, Hassenpflug M, Strobel O, Büchler MW, Werner J. Multivisceral resection for pancreatic malignancies: risk-analysis and long-term outcome. Ann Surg. 2009;250:81-87.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Nikfarjam M, Sehmbey M, Kimchi ET, Gusani NJ, Shereef S, Avella DM, Staveley-O'Carroll KF. Additional organ resection combined with pancreaticoduodenectomy does not increase postoperative morbidity and mortality. J Gastrointest Surg. 2009;13:915-921.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Trede M, Schwall G. [Multivisceral and extended resection in pancreatic cancer]. Langenbecks Arch Chir Suppl Kongressbd. 1992;61-65.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Klempnauer J, Ridder GJ, Bektas H, Pichlmayr R. Extended resections of ductal pancreatic cancer--impact on operative risk and prognosis. Oncology. 1996;53:47-53.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  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;7:946-952; discussion 952.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Adam U, Makowiec F, Riediger H, Schareck WD, Benz S, Hopt UT. Risk factors for complications after pancreatic head resection. Am J Surg. 2004;187:201-208.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Ozaki H, Kinoshita T, Kosuge T, Yamamoto J, Shimada K, Inoue K, Koyama Y, Mukai K. An aggressive therapeutic approach to carcinoma of the body and tail of the pancreas. Cancer. 1996;77:2240-2245.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Miller EM, Clagett OT. Survival five years after radical pancreatoduodenectomy for carcinoma of the head of the pancreas. Ann Surg. 1951;134:1013-1017.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Weber AO. Carcinoma of head of pancreas with spread to local lymph nodes. Five-year survival after radical pancreaticoduodenectomy. JAMA. 1963;186:150-151.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Pedrazzoli S, Beger HG, Obertop H, Andrén-Sandberg A, Fernández-Cruz L, Henne-Bruns D, Lüttges J, Neoptolemos JP. 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;16:337-345.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Pedrazzoli S, DiCarlo V, Dionigi R, Mosca F, Pederzoli P, Pasquali C, Klöppel G, Dhaene K, Michelassi F. 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;228:508-517.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, Coleman J, Abrams RA, Hruban RH. 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;236:355-366; discussion 366-368.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Nimura Y, Nagino M, Kato H, Miyagawa S, Yamaguchi A, Kinoshita T, Takao S, Takada T, Miyazaki K, Ishiyama S. Regional versus extended lymph node dissection in radical pancreatoduodenectomy for pancreatic cancer: A multicenter, randomized controlled trial. HPB (Oxford). 2004;6:2.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Farnell MB, Pearson RK, Sarr MG, DiMagno EP, Burgart LJ, Dahl TR, Foster N, Sargent DJ. A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery. 2005;138:618-628; discussion 628-630.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Yamada S, Nakao A, Fujii T, Sugimoto H, Kanazumi N, Nomoto S, Kodera Y, Takeda S. Pancreatic cancer with paraaortic lymph node metastasis: a contraindication for radical surgery? Pancreas. 2009;38:e13-e17.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Yoshida T, Matsumoto T, Sasaki A, Shibata K, Aramaki M, Kitano S. Outcome of paraaortic node-positive pancreatic head and bile duct adenocarcinoma. Am J Surg. 2004;187:736-740.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Shimada K, Sakamoto Y, Sano T, Kosuge T. The role of paraaortic lymph node involvement on early recurrence and survival after macroscopic curative resection with extended lymphadenectomy for pancreatic carcinoma. J Am Coll Surg. 2006;203:345-352.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Takamori H, Hiraoka T, Kanemitsu K, Tsuji T, Tanaka H, Chikamoto A, Horino K, Beppu T, Hirota M, Baba H. Long-term outcomes of extended radical resection combined with intraoperative radiation therapy for pancreatic cancer. J Hepatobiliary Pancreat Surg. 2008;15:603-607.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Yang YM, Wan YL, Tian XD, Zhuang Y, Huang YT. Outcome of pancreaticoduodenectomy with extended retroperitoneal lymphadenectomy for adenocarcinoma of the head of the pancreas. Chin Med J (Engl). 2005;118:1863-1869.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Yeo CJ, Cameron JL, Sohn TA, Coleman J, Sauter PK, Hruban RH, Pitt HA, Lillemoe KD. Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: comparison of morbidity and mortality and short-term outcome. Ann Surg. 1999;229:613-622; discussion 622-624.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Henne-Bruns D, Vogel I, Lüttges J, Klöppel G, Kremer B. Surgery for ductal adenocarcinoma of the pancreatic head: staging, complications, and survival after regional versus extended lymphadenectomy. World J Surg. 2000;24:595-601; discussion 601-602.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Henne-Bruns D, Vogel I, Lüttges J, Klöppel G, Kremer B. Ductal adenocarcinoma of the pancreas head: survival after regional versus extended lymphadenectomy. Hepatogastroenterology. 1998;45:855-866.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J, Abrams RA, Laheru D, Hruban RH, Yeo CJ. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival. J Gastrointest Surg. 2005;9:1191-204; discussion 1204-1206.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Popiela T, Kedra B, Sierzega M. Does extended lymphadenectomy improve survival of pancreatic cancer patients? Acta Chir Belg. 2002;102:78-82.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Ohigashi H, Ishikawa O, Tamura S, Imaoka S, Sasaki Y, Kameyama M, Kabuto T, Furukawa H, Hiratsuka M, Fujita M. Pancreatic invasion as the prognostic indicator of duodenal adenocarcinoma treated by pancreatoduodenectomy plus extended lymphadenectomy. Surgery. 1998;124:510-515.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Mukaiya M, Hirata K, Satoh T, Kimura M, Yamashiro K, Ura H, Oikawa I, Denno R. Lack of survival benefit of extended lymph node dissection for ductal adenocarcinoma of the head of the pancreas: retrospective multi-institutional analysis in Japan. World J Surg. 1998;22:248-252; discussion 252-253.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Nakagohri T, Kinoshita T, Konishi M, Takahashi S, Tanizawa Y. Clinical results of extended lymphadenectomy and intraoperative radiotherapy for pancreatic adenocarcinoma. Hepatogastroenterology. 2007;54:564-569.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Michalski CW, Kleeff J, Wente MN, Diener MK, Büchler MW, Friess H. Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br J Surg. 2007;94:265-273.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Iqbal N, Lovegrove RE, Tilney HS, Abraham AT, Bhattacharya S, Tekkis PP, Kocher HM. A comparison of pancreaticoduodenectomy with extended pancreaticoduodenectomy: a meta-analysis of 1909 patients. Eur J Surg Oncol. 2009;35:79-86.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Pawlik TM, Abdalla EK, Barnett CC, Ahmad SA, Cleary KR, Vauthey JN, Lee JE, Evans DB, Pisters PW. Feasibility of a randomized trial of extended lymphadenectomy for pancreatic cancer. Arch Surg. 2005;140:584-589; discussion 589-591.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Pawlik TM, Gleisner AL, Cameron JL, Winter JM, Assumpcao L, Lillemoe KD, Wolfgang C, Hruban RH, Schulick RD, Yeo CJ. Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery. 2007;141:610-618.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Benassai G, Mastrorilli M, Mosella F, Mosella G. Significance of lymph node metastases in the surgical management of pancreatic head carcinoma. J Exp Clin Cancer Res. 1999;18:23-28.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Riediger H, Keck T, Wellner U, zur Hausen A, Adam U, Hopt UT, Makowiec F. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest Surg. 2009;13:1337-1344.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Berger AC, Watson JC, Ross EA, Hoffman JP. The metastatic/examined lymph node ratio is an important prognostic factor after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am Surg. 2004;70:235-240; discussion 240.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Sierzega M, Popiela T, Kulig J, Nowak K. The ratio of metastatic/resected lymph nodes is an independent prognostic factor in patients with node-positive pancreatic head cancer. Pancreas. 2006;33:240-245.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Schwarz RE, Smith DD. Extent of lymph node retrieval and pancreatic cancer survival: information from a large US population database. Ann Surg Oncol. 2006;13:1189-1200.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Klempnauer J, Ridder GJ, Piso P, Pichlmayr R. [Is liver resection in metastases of exocrine pancreatic carcinoma justified?]. Chirurg. 1996;67:366-370.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Takamori H, Hiraoka T, Kanemitsu K, Tsuji T, Saito N, Nishida H, Sakaguchi H, Miyauchi Y. Treatment strategies for hepatic metastases from pancreatic cancer in patients previously treated with radical resection combined with intraoperative radiation therapy. HPB Surg. 1994;8:107-110.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Shimada K, Kosuge T, Yamamoto J, Yamasaki S, Sakamoto M. Successful outcome after resection of pancreatic cancer with a solitary hepatic metastasis. Hepatogastroenterology. 2004;51:603-605.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Yamada S, Fujii T, Sugimoto H, Kanazumi N, Kasuya H, Nomoto S, Takeda S, Kodera Y, Nakao A. Pancreatic cancer with distant metastases: a contraindication for radical surgery? Hepatogastroenterology. 2009;56:881-885.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Yamada H, Hirano S, Tanaka E, Shichinohe T, Kondo S. Surgical treatment of liver metastases from pancreatic cancer. HPB (Oxford). 2006;8:85-88.  [PubMed]  [DOI]  [Cited in This Article: ]
92.  Michalski CW, Erkan M, Hüser N, Müller MW, Hartel M, Friess H, Kleeff J. Resection of primary pancreatic cancer and liver metastasis: a systematic review. Dig Surg. 2008;25:473-480.  [PubMed]  [DOI]  [Cited in This Article: ]