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Surgical techniques for improving outcomes in pancreatic ductal adenocarcinoma Expert Rev. Gastroenterol. Hepatol. 8(3), 241–246 (2014)
Tamara MH Gall*, Zoe Thompson, Eoin P Dinneen, Mikael Sodergren, Madhava Pai, Adam E Frampton and Long R Jiao Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, W12 0HS, UK *Author for correspondence: Tel.: +44 208 383 3937 Fax: +44 208 383 3212 [email protected]
Pancreatic ductal adenocarcinoma is a devastating disease with extremely poor survival despite patients undergoing potentially curative resections and improvements in chemotherapeutic agents. Surgery for operable cancer in the head of the pancreas typically involves an open pancreaticoduodenectomy with a post-operative median survival of 21 months. Newer surgical techniques, however, aim to improve patient outcomes in terms of both their hospital experience and better oncological results. This article focuses on the evidence to date for some of these surgical techniques including laparoscopic and robotic surgery, the no-touch technique, venous and arterial resection, intra-operative radiofrequency ablation and intra-operative irreversible electroporation. With the increased use of these techniques we hope to see better quality of life and survival for these patients. KEYWORDS: irreversible electroporation therapy . laparoscopic surgery . no-touch technique . pancreatic cancer .
pancreaticoduodenectomy
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radiofrequency ablation
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robotic surgery
Discussion
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease and one of the top five causes of cancer-related death in the UK. Despite considerable oncological and surgical advances over the last 50 years, there has been almost no improvement in the survival statistics for PDAC, which remains less than 5% at 5 years [1]. Indeed, mortality still closely matches incidence. It is estimated that there were 266,000 deaths worldwide from pancreatic cancer in 2008 [2]. Symptom onset is often late in PDAC patients and many present with inoperable disease at diagnosis [3]. Features that preclude surgery in PDAC include distant metastatic disease and invasion of the tumor into local arteries, namely, the celiac axis or the superior mesenteric artery (SMA). However, with advances in radiological techniques, PDAC is being identified at an earlier stage [4–6], thus more patients are suitable for surgical resection. Removal of the head of the pancreas involves a pancreaticoduodenectomy (PD): either a Whipple procedure or pylorus preserving PD informahealthcare.com
10.1586/17474124.2014.881251
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venous and arterial resection
(PPPD). Both operations are well described and these open procedures have become the gold standard technique in pancreatic centers. The technique, however, is evolving. Usually, the surgeon will start by establishing a dissection plane along the lateral aspect of the portal vein (PV). However, venous involvement is no longer an absolute contraindication to surgery and thus the SMA first approach has been developed and used in borderline resectable disease identified on pre-operative staging. Currently, involvement of the SMA or celiac axis is considered as unresectable disease. The technique involves early dissection of the peripancreatic arteries so that resectability status can be determined quickly and the patient with unresectable disease does not undergo an unnecessary resection without survival benefit. Various approaches to the SMA have been used, including the posterior approach, the medial uncinate approach, the mesenteric approach, the anterior approach and the superior approach. Long-term evidence for this technique is sparse, but it is feasible, safe and has many potential advantages [7]. As surgical skill and postoperative care continue to
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improve, the morbidity and mortality for these procedures has become much better. However, despite resections with curative intent and the use of newer adjuvant chemotherapies, the 5-year survival has only improved marginally. Median survival following pancreatic resection at a specialist center is only 21 months [8]. Even those with R0 resection margins only live for a median of 28.7 months [8]. A new era of surgery has concentrated on improving patient outcomes postoperatively. Minimally invasive techniques have transformed recovery times across all surgical specialties and are now also used by some in pancreatic cancer surgery. Furthermore, there has been recent research energy invested into the development of novel surgical techniques and equipment, which may allow the pancreatic surgeon to grant improved recovery and outcomes to their patients compared with the standard traditional PD. This article discusses some of these new surgical techniques, which may benefit patients treated for PDAC. Laparoscopic PD
Laparoscopic PD (LPD) was first described by Gagner and Pomp in 1994 [9]. Technically, LPD is quite a demanding operation. As such, historical opposition of LPD has focused on concerns such as the difficulty in accessing and adequately exposing the pancreas, the lack of ability to control hemorrhage from major vessels and the feasibility of performing sophisticated anatomical reconstructions and anastomoses with laparoscopic instruments. These worries have been voiced in concert with suggestions that LPD may compromise patient outcomes, by the inability to maintain oncologic surgical principles due to surgeon fatigue secondary to prolonged operative times and by the inability to palpate the tumor itself and/or surrounding vasculature [10]. Some concerns about the technical demands of PD laparoscopically persist as LPD becomes increasingly difficult when the pancreas is particularly adherent to adjacent structures, notably the PV, secondary to pancreatitis, cholangitis and tumor invasion. Further, laparoscopic surgery does not currently allow for any vascular resection. There is a lack of level I evidence to prove the safety and benefits of LPD, and to date, there have been no randomized controlled trials (RCTs) of laparoscopic versus open PD (OPD) reported in the literature. Available evidence ranges from case reports to non-randomized comparative studies with relatively small numbers, which generally fail to reach statistical significance for the majority of findings. Many of the LPD series reported in the literature exclude patients with significant co-morbidities or those likely to have difficult PDs, such as those with large tumors, vascular involvement, non-dilated ducts and extension of tumor to the uncinate process [10]. Furthermore, patient preference for laparoscopic or OPD introduces selection bias to potentially confound the reliability of these findings [11,12]. Interpretation of the literature on LPD is made more difficult by the wide variety of technical practices at different centers. For instance, some report an 242
entirely laparoscopic completion of LPD, while others may perform the anastomoses through a small midline incision [12,13]. Despite reservations about the quality of data available, a meta-analysis of LPD published in 2011 is cause for optimism. Of the 126 patients included in the review, none had positive tumor resection margins [10]. Subsequently, it has been found that in spite of longer operations, the mean estimated blood loss, number of units of red blood cells transfused perioperatively, length of postoperative intensive care unit stay and length of overall hospital stay are better after LPD than after OPD, with comparable morbidity and mortality [11]. There is also no significant difference in tumor size, tumor/node stage, number of positive lymph nodes or R0 resections between either group [11]. A lower positive lymph-node to negative lymph-node ratio and a significantly higher total number of lymph nodes harvested is also seen after LPD, a positive predictor of better long-term survival [13]. As alluded to above, a small number of centers have reported their experience of robotic LPD, with some promising early results. Studies have detected an increase in R0 resections [14,15], with one study quoting an increase from 58 to 87% with the introduction of robotic PD [15]. Similar to LPD, robotic LPD has been reported to increase the number of lymph nodes harvested and reduce operative blood loss when compared with open operations [14,15]. Interestingly, robotic LPD may actually have shorter operative times than OPD [16]. Any consideration of the prospective benefits of robotic LPD should, however, take into account the fact that the costs of the robotic operation are estimated at more than twice that of the non-robotic LPD and appreciably more expensive than OPD [12,17]. A RCT comparing LPD with OPD is clearly required to assess surgical and oncologic parameters. Although the number of centers offering LPD and the number of patients suitable for LPD are both increasing, the institution of a sufficiently powered RCT comparing LPD with OPD poses sizeable logistical issues. We estimated the sample size required to detect a 25% difference in margin positivity at 80% power and 5% level of confidence to be 102 in each group, based on 73.6% of patients having a positive R1/R2 resection margin with the open technique [18]. However, the literature to date, demonstrates that LPD is feasible, safe and very promising in selected patients. No-touch technique PD
In 1967, Turnbull reported a no-touch technique in the operative management of colon cancer [19]. They adopted a technique deliberately avoiding any tumor manipulation until lymphovascular ligation was complete. Using this technique on 460 patients with colorectal cancer compared with standard colectomy on 120 patients, the 5-year survival improved from 34 to 50 months. It was postulated that limiting the handling of the tumor prevents the spread of cancer cells. Subsequently, Expert Rev. Gastroenterol. Hepatol. 8(3), (2014)
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Surgical techniques for improving outcomes in PDAC
it was noted that using this technique for colorectal cancer, liver metastases appeared later, and in fewer patients [20]. More recently, Kobayashi et al. applied the no-touch technique to PD in 10 patients with peri-ampullary tumors [21]. Briefly, the no-touch technique mandates that the tumor in the head of the pancreas must not be touched until complete ligation and division of the venous drainage. In the original paper by Kobayashi et al., there was no operative mortality and none of the patients developed liver metastases after a follow-up of between 5 months and 7 years. Further corroboration of the no-touch PD came from Hirota et al., who used this technique on 8 patients with pancreatic cancer and compared it with the conventional technique used with 10 patients [22]. The authors measured PV carcinoembryonic antigen (CEA) messenger RNA before and after tumor manipulation. No patients had detectable levels before resection but PV CEA messenger RNA was detected in only 13% (1/8) of those undergoing the no-touch technique compared with 50% (5/10) of patients having the standard PD. Patients in the no-touch group had a significantly lower recurrence rate (38% compared with 90%; p = 0.043) and longer overall survival (41.5 ± 5.6; 95% CI: 30.5–52.5) months compared with 21.2 ± 5.8 (95% CI: 9.9–32.5; p = 0.018) months. The authors later published a report showing a 40% morbidity rate and no operative mortality using this technique for PD in 42 patients [23]. For the 17 patients with PDAC, 14 (82%) had R0 resection margins and 3 (18%) had R1 resections, comparable with findings reported with conventional PD. At our center, we undertook a small RCT comparing the no-touch technique with conventional OPD in six versus six patients [24]. In brief, the no-touch technique is performed as follows. Following dissection of the liver hilum to identify the common bile duct and PV, the common bile duct is divided below the junction of hepatic ducts and the gastroduodenal artery is ligated and divided. Next, the lesser sac is entered by dividing the gastrocolic ligament with the LigaSure Vessel Sealing System (Valleylab, Boulder, CO, USA). After division of jejunum 5–10 cm from the duodenal–jejunal flexure with a 45 mm stapler, the pancreas is tunneled at the superior mesenteric vein (SMV) and PV and divided with a surgical scalpel. Superior, middle and inferior pancreatic veins are identified, ligated and divided. The SMV and PV are freed completely from pancreas. All lymphatic drainage to the portal hilus is divided. Finally, kocherization is performed and the crural tissue between the uncinate process of pancreas and SMA is divided by LigaSure to complete the PD. At no time during the procedure is the head of the pancreas grasped by the surgeon, and transection of pancreatic crura is performed only after ligation and division of the venous drainage. In our study, blood was collected from the PV before and after tumor resection. The CellSearch system (Veridex, NJ, USA) was used to detect circulating tumor cells, which are thought to be responsible for tumor metastases and poor prognosis. There was no difference between the two groups with informahealthcare.com
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regards to age, operative time, length of hospital stay, complication rate, metastatic:examined lymph-node ratio, tumor size or operative morbidity and mortality. However, following resection, an increase in the number of circulating tumor cells was seen in 5/6 (83%) patients in the conventional group versus 0/6 in the no-touch group (p = 0.003). The no-touch group also trended toward a better survival (13.0 months compared with 16.7 months; p = 0.328). There are limited data on the no-touch technique with small numbers of patients in each group. However, as we have briefly reviewed, the technique is possible for PD, does not increase morbidity or mortality and appears to have the possibility of improving oncological outcomes in PDAC patients who undergo PD. Although it should be mentioned that, given the poor prognosis after surgery, PDAC may be a systemic disease before resection and thus further validation regarding the notouch technique and oncological outcome is certainly required. PV resection in PD
A previous contraindication to PD was local invasion of the tumor into the PV or SMV. However, more recently some specialist high-volume pancreatic centers are performing PV/SMV resection routinely in patients with probable venous invasion. This element of PD remains somewhat controversial as it adds considerably to the complexity of the operation, thereby increasing the possibility of bleeding, PV thrombosis, morbidity and mortality for the patient without conferring major improvement in long-term survival. There are currently no RCTs analyzing the safety of performing PV/SMV resection in patients with PDAC. Although some have found higher rates of post-operative complications in those undergoing venous resection [25], operative morbidity and mortality have mostly been reported as not significantly different between PD with versus without PV/SMV resection [26–34]. This is despite those with PV/SMV resection having larger tumors [26]. Furthermore, the potential benefit of PV/SMV resection was evaluated in a systematic review of 1458 patients from 28 level III evidence studies [35]. Median survival was 15 months (9–23 months) and the authors concluded that in high-volume centers, vascular resection has acceptable morbidity, mortality and survival outcomes and should not be seen as a contraindication to curative surgery. By pooling results from studies reporting resection margin status after PD [8,18,36–41], a positive medial resection margin was reported in 38.2% of 701 patients. However, following PD with PV/SMV resection, the medial resection margin is only positive in 16% of patients, and it is well recognized that an R0 medial resection margin is a predictor of improved survival [8]. Of further considerable interest was a recently published paper by a group in Marseille [42], who performed PV/SMV resection with curative intent on 34 patients with pancreatic adenocarcinoma. Histopathological examination found that 19 patients had no tumor invasion of the resected vein. These were compared with patient- and tumor-matched controls, that is, patients who had PD without PV/SMV resection, all with 243
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negative resection margins. Of note, median survival was 42 months in the PV/SMV resection group compared with 22 months (p = 0.02). The group’s finding inevitably now generates the question as to whether the PV/SMV resection should be performed routinely in PD, even when there is no suspected venous tumor infiltration.
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Expert commentary & five-year view
Pancreatic cancer has a dismal outlook without surgery, and prognosis is still poor even after extensive operation aiming for a curative resection. Given the paucity of successful chemotherapeutic options currently available, the onus remains on surgeons to make every effort to investigate new techniques and operative approaches that can lead to improvements in the outcomes of their patients. These efforts become even more important, if we consider that it is likely more patients will be diagnosed with PDAC and at even earlier stages, that more patients will be deemed fit for major surgery and that everspecializing surgical centers are demonstrating that tumors previously deemed inoperable are now amenable to surgery with good results. Further, there is increasing evidence that patients with borderline resectable disease or with small metastases may benefit from neoadjuvant chemotherapy and/or radiotherapy, following which they can undergo resection with 83% having an R0 resection margin status [43]. In addition to the techniques described above, there are some newer ‘cutting-edge’ techniques, which have been developed and may have a part to play in pancreatic cancer surgery. Radiofrequency ablation (RFA), or microwave ablation, has been successfully used in the treatment of solid tumors in the liver, lung, breast, kidney and many other tumor types. This technique has also been demonstrated to be safe and promising when performed percutaneously or endoscopically for locally advanced PDAC [44–47]. Increasingly, there is evidence from series around the world that open intra-operative RFA is a safe and feasible way to provide tumor cytoreduction and partial necrosis in locally advanced pancreatic tumors, leading to good survival rates and an improvement in quality of life [46,48]. Another exciting emerging modality for treatment of PDAC is irreversible electroporation therapy (IRE), or NanoKnifeÒ technology. IRE is an ablation technology, which unlike RFA is not based on thermal damage to tissue, and has shown to be safe near vascular and ductal structures. IRE uses focused electrical energy to alter the transmembrane potential of the cell membranes, creating nanoscale pores within the cell membranes of precisely targeted tissues, after which the cells die due to loss of homeostasis. The potential for use in PDAC where the tumor is adjacent or involved in key local vascular structures is clear. To date, IRE has been demonstrated to be safe, feasible and of value to patients as an intra-operative adjunct for open curative PD tumor margin accentuation, and in open intraoperative tumor palliative ablation [49,50]. There are several
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complications that may develop following this procedure. The National Institute for Health and Clinical Excellence looked at one case series, one case report and six conference abstracts involving 241 patients [51]. Complications included pancreatitis (n = 1), partial splenic infarction (n = 1), PV thrombosis (n = 2), renal failure (n = 1), bile leak (n = 2), pancreatic fistula (n = 1), transient ascites (n = 1), mild pain (n = 1) and intraprocedural hypertension (n = 1). Our experience with IRE on two cases in our unit has been poor, with a rapid progression of disease with liver metastases within 6 weeks of IRE. This clinical manifestation of disease progression after intervention may be explained by dissemination of circulating tumor cells [52]. The benefit and usefulness of IRE and RFA in pancreatic cancer remains debatable. In the absence of effective systemic chemotherapy, local treatment for unresectable pancreatic cancer does not offer any survival benefit to patients. Lastly, although local arterial invasion of PDAC has traditionally been treated as an absolute contraindication to surgery, there is now burgeoning observational data to suggest that PD can be performed with resection of the SMA or celiac artery. Although this carries significantly worse peri-operative mortality compared with those who undergo PD without arterial resection, in highly selected cases it may be justifiable to perform PD with arterial resection, given it is associated with more favorable long-term survival compared with patients who did not undergo resection for locally advanced disease [53]. Complications related to arterial resection include bleeding, vascular thrombosis and ischemic complications to the liver or stomach. Further, patients can develop mild-to-severe chronic diarrhea following resection of the SMA [54]. None of the techniques discussed have been evaluated with the unique rigor of RCTs. However, the evidence for the LPD, the no-touch technique and portal/superior mesenteric venous resection does show some promise for the future. Furthermore, the more recent novel techniques including RFA, IRE and PD with arterial resection may allow patients with locally advanced and previously unresectable disease to undergo resection, perhaps leading to improved survival. There is cause for cautious optimism, as many of the new surgical techniques reviewed here may continue to advance and with increased use and surgical skill, enable those with PDAC to have a better quality of life for longer period of time. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Gastroenterol. Hepatol. 8(3), (2014)
Surgical techniques for improving outcomes in PDAC
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Key issues .
Pancreatic ductal adenocarcinoma has a dismal prognosis.
.
Despite potentially curative resection and anticancer therapies, survival rates are still poor.
.
Laparoscopic and robotic pancreaticoduodenectomy results in better post-operative recovery, without compromising oncological
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outcome. .
There have been limited trials involving the no-touch surgical technique, but this may lead to better disease-free and overall survival.
.
Pancreaticoduodenectomy with venous resection is increasingly used without worsening perioperative morbidity or mortality.
.
Venous resection enables patients previously thought to have unresectable disease, or those who would have positive medial resection margins, to undergo R0 resection.
.
Some novel surgical techniques for pancreatic ductal adenocarcinoma are being tried and developed resulting in more patients deemed suitable for surgery and may lead to better outcomes.
.
With all the above-mentioned techniques, there is a paucity of level I and II evidence; therefore, the conclusions are not robust.
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Expert Rev. Gastroenterol. Hepatol. 8(3), (2014)
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Surgical techniques for improving outcomes in pancreatic ductal adenocarcinoma Expert Rev. Gastroenterol. Hepatol. 8(3), 241–246 (2014)
Tamara MH Gall*, Zoe Thompson, Eoin P Dinneen, Mikael Sodergren, Madhava Pai, Adam E Frampton and Long R Jiao Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, W12 0HS, UK *Author for correspondence: Tel.: +44 208 383 3937 Fax: +44 208 383 3212 [email protected]
Pancreatic ductal adenocarcinoma is a devastating disease with extremely poor survival despite patients undergoing potentially curative resections and improvements in chemotherapeutic agents. Surgery for operable cancer in the head of the pancreas typically involves an open pancreaticoduodenectomy with a post-operative median survival of 21 months. Newer surgical techniques, however, aim to improve patient outcomes in terms of both their hospital experience and better oncological results. This article focuses on the evidence to date for some of these surgical techniques including laparoscopic and robotic surgery, the no-touch technique, venous and arterial resection, intra-operative radiofrequency ablation and intra-operative irreversible electroporation. With the increased use of these techniques we hope to see better quality of life and survival for these patients. KEYWORDS: irreversible electroporation therapy . laparoscopic surgery . no-touch technique . pancreatic cancer .
pancreaticoduodenectomy
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radiofrequency ablation
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robotic surgery
Discussion
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease and one of the top five causes of cancer-related death in the UK. Despite considerable oncological and surgical advances over the last 50 years, there has been almost no improvement in the survival statistics for PDAC, which remains less than 5% at 5 years [1]. Indeed, mortality still closely matches incidence. It is estimated that there were 266,000 deaths worldwide from pancreatic cancer in 2008 [2]. Symptom onset is often late in PDAC patients and many present with inoperable disease at diagnosis [3]. Features that preclude surgery in PDAC include distant metastatic disease and invasion of the tumor into local arteries, namely, the celiac axis or the superior mesenteric artery (SMA). However, with advances in radiological techniques, PDAC is being identified at an earlier stage [4–6], thus more patients are suitable for surgical resection. Removal of the head of the pancreas involves a pancreaticoduodenectomy (PD): either a Whipple procedure or pylorus preserving PD informahealthcare.com
10.1586/17474124.2014.881251
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venous and arterial resection
(PPPD). Both operations are well described and these open procedures have become the gold standard technique in pancreatic centers. The technique, however, is evolving. Usually, the surgeon will start by establishing a dissection plane along the lateral aspect of the portal vein (PV). However, venous involvement is no longer an absolute contraindication to surgery and thus the SMA first approach has been developed and used in borderline resectable disease identified on pre-operative staging. Currently, involvement of the SMA or celiac axis is considered as unresectable disease. The technique involves early dissection of the peripancreatic arteries so that resectability status can be determined quickly and the patient with unresectable disease does not undergo an unnecessary resection without survival benefit. Various approaches to the SMA have been used, including the posterior approach, the medial uncinate approach, the mesenteric approach, the anterior approach and the superior approach. Long-term evidence for this technique is sparse, but it is feasible, safe and has many potential advantages [7]. As surgical skill and postoperative care continue to
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improve, the morbidity and mortality for these procedures has become much better. However, despite resections with curative intent and the use of newer adjuvant chemotherapies, the 5-year survival has only improved marginally. Median survival following pancreatic resection at a specialist center is only 21 months [8]. Even those with R0 resection margins only live for a median of 28.7 months [8]. A new era of surgery has concentrated on improving patient outcomes postoperatively. Minimally invasive techniques have transformed recovery times across all surgical specialties and are now also used by some in pancreatic cancer surgery. Furthermore, there has been recent research energy invested into the development of novel surgical techniques and equipment, which may allow the pancreatic surgeon to grant improved recovery and outcomes to their patients compared with the standard traditional PD. This article discusses some of these new surgical techniques, which may benefit patients treated for PDAC. Laparoscopic PD
Laparoscopic PD (LPD) was first described by Gagner and Pomp in 1994 [9]. Technically, LPD is quite a demanding operation. As such, historical opposition of LPD has focused on concerns such as the difficulty in accessing and adequately exposing the pancreas, the lack of ability to control hemorrhage from major vessels and the feasibility of performing sophisticated anatomical reconstructions and anastomoses with laparoscopic instruments. These worries have been voiced in concert with suggestions that LPD may compromise patient outcomes, by the inability to maintain oncologic surgical principles due to surgeon fatigue secondary to prolonged operative times and by the inability to palpate the tumor itself and/or surrounding vasculature [10]. Some concerns about the technical demands of PD laparoscopically persist as LPD becomes increasingly difficult when the pancreas is particularly adherent to adjacent structures, notably the PV, secondary to pancreatitis, cholangitis and tumor invasion. Further, laparoscopic surgery does not currently allow for any vascular resection. There is a lack of level I evidence to prove the safety and benefits of LPD, and to date, there have been no randomized controlled trials (RCTs) of laparoscopic versus open PD (OPD) reported in the literature. Available evidence ranges from case reports to non-randomized comparative studies with relatively small numbers, which generally fail to reach statistical significance for the majority of findings. Many of the LPD series reported in the literature exclude patients with significant co-morbidities or those likely to have difficult PDs, such as those with large tumors, vascular involvement, non-dilated ducts and extension of tumor to the uncinate process [10]. Furthermore, patient preference for laparoscopic or OPD introduces selection bias to potentially confound the reliability of these findings [11,12]. Interpretation of the literature on LPD is made more difficult by the wide variety of technical practices at different centers. For instance, some report an 242
entirely laparoscopic completion of LPD, while others may perform the anastomoses through a small midline incision [12,13]. Despite reservations about the quality of data available, a meta-analysis of LPD published in 2011 is cause for optimism. Of the 126 patients included in the review, none had positive tumor resection margins [10]. Subsequently, it has been found that in spite of longer operations, the mean estimated blood loss, number of units of red blood cells transfused perioperatively, length of postoperative intensive care unit stay and length of overall hospital stay are better after LPD than after OPD, with comparable morbidity and mortality [11]. There is also no significant difference in tumor size, tumor/node stage, number of positive lymph nodes or R0 resections between either group [11]. A lower positive lymph-node to negative lymph-node ratio and a significantly higher total number of lymph nodes harvested is also seen after LPD, a positive predictor of better long-term survival [13]. As alluded to above, a small number of centers have reported their experience of robotic LPD, with some promising early results. Studies have detected an increase in R0 resections [14,15], with one study quoting an increase from 58 to 87% with the introduction of robotic PD [15]. Similar to LPD, robotic LPD has been reported to increase the number of lymph nodes harvested and reduce operative blood loss when compared with open operations [14,15]. Interestingly, robotic LPD may actually have shorter operative times than OPD [16]. Any consideration of the prospective benefits of robotic LPD should, however, take into account the fact that the costs of the robotic operation are estimated at more than twice that of the non-robotic LPD and appreciably more expensive than OPD [12,17]. A RCT comparing LPD with OPD is clearly required to assess surgical and oncologic parameters. Although the number of centers offering LPD and the number of patients suitable for LPD are both increasing, the institution of a sufficiently powered RCT comparing LPD with OPD poses sizeable logistical issues. We estimated the sample size required to detect a 25% difference in margin positivity at 80% power and 5% level of confidence to be 102 in each group, based on 73.6% of patients having a positive R1/R2 resection margin with the open technique [18]. However, the literature to date, demonstrates that LPD is feasible, safe and very promising in selected patients. No-touch technique PD
In 1967, Turnbull reported a no-touch technique in the operative management of colon cancer [19]. They adopted a technique deliberately avoiding any tumor manipulation until lymphovascular ligation was complete. Using this technique on 460 patients with colorectal cancer compared with standard colectomy on 120 patients, the 5-year survival improved from 34 to 50 months. It was postulated that limiting the handling of the tumor prevents the spread of cancer cells. Subsequently, Expert Rev. Gastroenterol. Hepatol. 8(3), (2014)
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Surgical techniques for improving outcomes in PDAC
it was noted that using this technique for colorectal cancer, liver metastases appeared later, and in fewer patients [20]. More recently, Kobayashi et al. applied the no-touch technique to PD in 10 patients with peri-ampullary tumors [21]. Briefly, the no-touch technique mandates that the tumor in the head of the pancreas must not be touched until complete ligation and division of the venous drainage. In the original paper by Kobayashi et al., there was no operative mortality and none of the patients developed liver metastases after a follow-up of between 5 months and 7 years. Further corroboration of the no-touch PD came from Hirota et al., who used this technique on 8 patients with pancreatic cancer and compared it with the conventional technique used with 10 patients [22]. The authors measured PV carcinoembryonic antigen (CEA) messenger RNA before and after tumor manipulation. No patients had detectable levels before resection but PV CEA messenger RNA was detected in only 13% (1/8) of those undergoing the no-touch technique compared with 50% (5/10) of patients having the standard PD. Patients in the no-touch group had a significantly lower recurrence rate (38% compared with 90%; p = 0.043) and longer overall survival (41.5 ± 5.6; 95% CI: 30.5–52.5) months compared with 21.2 ± 5.8 (95% CI: 9.9–32.5; p = 0.018) months. The authors later published a report showing a 40% morbidity rate and no operative mortality using this technique for PD in 42 patients [23]. For the 17 patients with PDAC, 14 (82%) had R0 resection margins and 3 (18%) had R1 resections, comparable with findings reported with conventional PD. At our center, we undertook a small RCT comparing the no-touch technique with conventional OPD in six versus six patients [24]. In brief, the no-touch technique is performed as follows. Following dissection of the liver hilum to identify the common bile duct and PV, the common bile duct is divided below the junction of hepatic ducts and the gastroduodenal artery is ligated and divided. Next, the lesser sac is entered by dividing the gastrocolic ligament with the LigaSure Vessel Sealing System (Valleylab, Boulder, CO, USA). After division of jejunum 5–10 cm from the duodenal–jejunal flexure with a 45 mm stapler, the pancreas is tunneled at the superior mesenteric vein (SMV) and PV and divided with a surgical scalpel. Superior, middle and inferior pancreatic veins are identified, ligated and divided. The SMV and PV are freed completely from pancreas. All lymphatic drainage to the portal hilus is divided. Finally, kocherization is performed and the crural tissue between the uncinate process of pancreas and SMA is divided by LigaSure to complete the PD. At no time during the procedure is the head of the pancreas grasped by the surgeon, and transection of pancreatic crura is performed only after ligation and division of the venous drainage. In our study, blood was collected from the PV before and after tumor resection. The CellSearch system (Veridex, NJ, USA) was used to detect circulating tumor cells, which are thought to be responsible for tumor metastases and poor prognosis. There was no difference between the two groups with informahealthcare.com
Perspective
regards to age, operative time, length of hospital stay, complication rate, metastatic:examined lymph-node ratio, tumor size or operative morbidity and mortality. However, following resection, an increase in the number of circulating tumor cells was seen in 5/6 (83%) patients in the conventional group versus 0/6 in the no-touch group (p = 0.003). The no-touch group also trended toward a better survival (13.0 months compared with 16.7 months; p = 0.328). There are limited data on the no-touch technique with small numbers of patients in each group. However, as we have briefly reviewed, the technique is possible for PD, does not increase morbidity or mortality and appears to have the possibility of improving oncological outcomes in PDAC patients who undergo PD. Although it should be mentioned that, given the poor prognosis after surgery, PDAC may be a systemic disease before resection and thus further validation regarding the notouch technique and oncological outcome is certainly required. PV resection in PD
A previous contraindication to PD was local invasion of the tumor into the PV or SMV. However, more recently some specialist high-volume pancreatic centers are performing PV/SMV resection routinely in patients with probable venous invasion. This element of PD remains somewhat controversial as it adds considerably to the complexity of the operation, thereby increasing the possibility of bleeding, PV thrombosis, morbidity and mortality for the patient without conferring major improvement in long-term survival. There are currently no RCTs analyzing the safety of performing PV/SMV resection in patients with PDAC. Although some have found higher rates of post-operative complications in those undergoing venous resection [25], operative morbidity and mortality have mostly been reported as not significantly different between PD with versus without PV/SMV resection [26–34]. This is despite those with PV/SMV resection having larger tumors [26]. Furthermore, the potential benefit of PV/SMV resection was evaluated in a systematic review of 1458 patients from 28 level III evidence studies [35]. Median survival was 15 months (9–23 months) and the authors concluded that in high-volume centers, vascular resection has acceptable morbidity, mortality and survival outcomes and should not be seen as a contraindication to curative surgery. By pooling results from studies reporting resection margin status after PD [8,18,36–41], a positive medial resection margin was reported in 38.2% of 701 patients. However, following PD with PV/SMV resection, the medial resection margin is only positive in 16% of patients, and it is well recognized that an R0 medial resection margin is a predictor of improved survival [8]. Of further considerable interest was a recently published paper by a group in Marseille [42], who performed PV/SMV resection with curative intent on 34 patients with pancreatic adenocarcinoma. Histopathological examination found that 19 patients had no tumor invasion of the resected vein. These were compared with patient- and tumor-matched controls, that is, patients who had PD without PV/SMV resection, all with 243
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negative resection margins. Of note, median survival was 42 months in the PV/SMV resection group compared with 22 months (p = 0.02). The group’s finding inevitably now generates the question as to whether the PV/SMV resection should be performed routinely in PD, even when there is no suspected venous tumor infiltration.
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Expert commentary & five-year view
Pancreatic cancer has a dismal outlook without surgery, and prognosis is still poor even after extensive operation aiming for a curative resection. Given the paucity of successful chemotherapeutic options currently available, the onus remains on surgeons to make every effort to investigate new techniques and operative approaches that can lead to improvements in the outcomes of their patients. These efforts become even more important, if we consider that it is likely more patients will be diagnosed with PDAC and at even earlier stages, that more patients will be deemed fit for major surgery and that everspecializing surgical centers are demonstrating that tumors previously deemed inoperable are now amenable to surgery with good results. Further, there is increasing evidence that patients with borderline resectable disease or with small metastases may benefit from neoadjuvant chemotherapy and/or radiotherapy, following which they can undergo resection with 83% having an R0 resection margin status [43]. In addition to the techniques described above, there are some newer ‘cutting-edge’ techniques, which have been developed and may have a part to play in pancreatic cancer surgery. Radiofrequency ablation (RFA), or microwave ablation, has been successfully used in the treatment of solid tumors in the liver, lung, breast, kidney and many other tumor types. This technique has also been demonstrated to be safe and promising when performed percutaneously or endoscopically for locally advanced PDAC [44–47]. Increasingly, there is evidence from series around the world that open intra-operative RFA is a safe and feasible way to provide tumor cytoreduction and partial necrosis in locally advanced pancreatic tumors, leading to good survival rates and an improvement in quality of life [46,48]. Another exciting emerging modality for treatment of PDAC is irreversible electroporation therapy (IRE), or NanoKnifeÒ technology. IRE is an ablation technology, which unlike RFA is not based on thermal damage to tissue, and has shown to be safe near vascular and ductal structures. IRE uses focused electrical energy to alter the transmembrane potential of the cell membranes, creating nanoscale pores within the cell membranes of precisely targeted tissues, after which the cells die due to loss of homeostasis. The potential for use in PDAC where the tumor is adjacent or involved in key local vascular structures is clear. To date, IRE has been demonstrated to be safe, feasible and of value to patients as an intra-operative adjunct for open curative PD tumor margin accentuation, and in open intraoperative tumor palliative ablation [49,50]. There are several
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complications that may develop following this procedure. The National Institute for Health and Clinical Excellence looked at one case series, one case report and six conference abstracts involving 241 patients [51]. Complications included pancreatitis (n = 1), partial splenic infarction (n = 1), PV thrombosis (n = 2), renal failure (n = 1), bile leak (n = 2), pancreatic fistula (n = 1), transient ascites (n = 1), mild pain (n = 1) and intraprocedural hypertension (n = 1). Our experience with IRE on two cases in our unit has been poor, with a rapid progression of disease with liver metastases within 6 weeks of IRE. This clinical manifestation of disease progression after intervention may be explained by dissemination of circulating tumor cells [52]. The benefit and usefulness of IRE and RFA in pancreatic cancer remains debatable. In the absence of effective systemic chemotherapy, local treatment for unresectable pancreatic cancer does not offer any survival benefit to patients. Lastly, although local arterial invasion of PDAC has traditionally been treated as an absolute contraindication to surgery, there is now burgeoning observational data to suggest that PD can be performed with resection of the SMA or celiac artery. Although this carries significantly worse peri-operative mortality compared with those who undergo PD without arterial resection, in highly selected cases it may be justifiable to perform PD with arterial resection, given it is associated with more favorable long-term survival compared with patients who did not undergo resection for locally advanced disease [53]. Complications related to arterial resection include bleeding, vascular thrombosis and ischemic complications to the liver or stomach. Further, patients can develop mild-to-severe chronic diarrhea following resection of the SMA [54]. None of the techniques discussed have been evaluated with the unique rigor of RCTs. However, the evidence for the LPD, the no-touch technique and portal/superior mesenteric venous resection does show some promise for the future. Furthermore, the more recent novel techniques including RFA, IRE and PD with arterial resection may allow patients with locally advanced and previously unresectable disease to undergo resection, perhaps leading to improved survival. There is cause for cautious optimism, as many of the new surgical techniques reviewed here may continue to advance and with increased use and surgical skill, enable those with PDAC to have a better quality of life for longer period of time. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Gastroenterol. Hepatol. 8(3), (2014)
Surgical techniques for improving outcomes in PDAC
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Key issues .
Pancreatic ductal adenocarcinoma has a dismal prognosis.
.
Despite potentially curative resection and anticancer therapies, survival rates are still poor.
.
Laparoscopic and robotic pancreaticoduodenectomy results in better post-operative recovery, without compromising oncological
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outcome. .
There have been limited trials involving the no-touch surgical technique, but this may lead to better disease-free and overall survival.
.
Pancreaticoduodenectomy with venous resection is increasingly used without worsening perioperative morbidity or mortality.
.
Venous resection enables patients previously thought to have unresectable disease, or those who would have positive medial resection margins, to undergo R0 resection.
.
Some novel surgical techniques for pancreatic ductal adenocarcinoma are being tried and developed resulting in more patients deemed suitable for surgery and may lead to better outcomes.
.
With all the above-mentioned techniques, there is a paucity of level I and II evidence; therefore, the conclusions are not robust.
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