Surgical palliation in patients with pancreatic cancer

Transcription

1 Langenbecks Arch Surg (2007) 392:13 21 DOI /s CURRENT CONCEPTS IN CLINICAL SURGERY Surgical palliation in patients with pancreatic cancer Jörg Köninger & Moritz N. Wente & Michael W. Müller & Carsten N. Gutt & Helmut Friess & Markus W. Büchler Received: 24 May 2006 / Accepted: 11 August 2006 / Published online: 11 November 2006 # Springer-Verlag 2006 Abstract Background The aim of palliative strategies in patients with pancreatic cancer is the relief of tumor-associated symptoms such as biliary and duodenal obstruction and tumor growth. Due to high mortality and morbidity rates of surgery, treatment of patients with advanced pancreatic cancer is mainly in the hand of gastroenterologists. Rationale In recent years, surgery of pancreatic cancer in specialized centres developed strongly, which makes it a viable option even in the treatment of advanced disease. Conclusion We advocate for an aggressive strategy in the treatment of pancreatic cancer with surgical exploration and tumor resection whenever possible. Keywords Pancreatic cancer. Palliative surgery. Whipple procedure. Curative resection. Palliative treatment Introduction Pancreatic cancer is the fourth to fifth most common reason for cancer-associated death in the western world, with rising incidence and a still-dismal prognosis [1]. Median survival time without any therapy is 3 4 months after diagnosis, and only 20% of all patients with pancreatic cancer will survive for more than 1 year [2]. Survival after surgery is also disappointing, with 5-year survival rates ranging from 10 29% [3]. Pancreatic cancer has the worst prognosis and highest lethality among all gastrointestinal tumors. Unfortunately, at the time of diagnosis, around 85% J. Köninger : M. N. Wente : M. W. Müller : C. N. Gutt : H. Friess : M. W. Büchler (*) Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany Markus_Buechler@med.uni-heidelberg.de of the patients are unsuitable for curative resection and are potential candidates for palliative treatment [4, 5]. The aim of palliative treatment is to improve the quality of life by treating the most common syndromes of patients with tumors in the pancreatic head or the periampullary region, such as jaundice, duodenal obstruction, and pain. In the 1980s, due to the high morbidity and mortality of surgical procedures and the appearance of endoscopic procedures, palliative treatment was mainly in the hands of gastroenterologists [6]. Over the years, however, there have been many developments in surgical techniques, and today, even extended resections can be performed with low perioperative morbidity and mortality. Therefore, further discussion of the advantages of the different strategies of surgical palliation is required [7, 8]. Biliary obstruction and jaundice Around two thirds of pancreatic tumors arise in the head of the organ, in close proximity to the common bile duct. As a consequence, jaundice is a common, and often the first, symptom of pancreatic cancer [5, 9]. Relief of obstructive jaundice is essential, as untreated biliary stasis leads to pruritus, recurrent attacks of cholangitis, anorexia and progressive malnutrition, liver malfunction and failure, and early death. Biliary decompression in patients with cancer-related jaundice can be achieved with both surgical and nonsurgical approaches. Only a minority of patients with pancreatic cancer are candidates for a successful curative surgical intervention, however. Most of the patients present with vascular infiltration and metastatic disease, which may be regarded as contraindications for curative surgery. Because of its efficacy and low short-term morbidity and mortality, endoscopic stenting of the common bile duct may

2 14 Langenbecks Arch Surg (2007) 392:13 21 be considered as a first-line treatment in the case of incurable pancreatic cancer and jaundice. It has been shown that palliative endoscopic stenting is useful in improving the quality of life in jaundiced patients with inoperable malignant diseases. The impact of successful biliary drainage on different components of the quality of life was assessed in a cohort of inoperable patients with malignant obstruction of the common bile duct [10]. Before endoscopic treatment, 98% were jaundiced and 70% complained of itching. Weight loss and rising bilirubin level had the greatest impact on quality of life domains in different analyses. One month after stenting, baseline bilirubin of greater than 14 mg/dl was associated with a lack of improvement in social function, while decreasing bilirubin levels were associated with improvements in social function and mental health. Different studies compare endoscopic with percutaneous stent placement in patients with malignant biliary obstruction and clearly showed that endoscopic placement is safer and more effective than the transcutaneous, transhepatic technique [11]. Up to now, in most of the centers where both techniques are applicable, the endoscopic route is regarded as the first choice, while transhepatic access is used in case of endoscopic failure or inapplicability [12, 13]. Compared to surgical biliary bypass, lower complication rates and shorter hospital stays are reported for the endoscopic techniques (Table 1). However, severe complications, usually due to stent dysfunction, are more likely to occur in patients treated endoscopically [14, 15], which restricts the indication for this interventional technique. Whether new generations of self-expanding metallic stents will reduce stent-associated complication rates is uncertain. As a consequence, endoscopic stenting should be restricted to well-defined patient groups. It may be indicated in jaundiced patients prior to surgery, as high serum bilirubin levels cause a higher perioperative complication rate, and it should be restricted to patients with advanced irresectable disease and a short expected survival or patients with concurrent medical conditions and contraindications for anesthesia or major surgery. Surgical bypass of the biliary system establishes continuity between the biliary tract proximal to the stenosis and the gastrointestinal tract. It has been advocated in patients with longer projected survival, as well as in patients whose intra-abdominal findings reveal unresectable disease at the time of laparotomy and planned tumor resection [16, 17]. If the gallbladder is intact and the cystic duct not infiltrated by the tumor, fashioning an anastomosis to the gallbladder may be technically easier than bypassing the common bile duct. This and the fact that this technique can be performed endoscopically are the main reasons why cholecystojejunostomy remains in the armamentarium of some surgeons. However, while short-term outcomes of gallbladder and common bile duct enteroanastomoses do not differ significantly from choledochojejunostomy, it is well documented that, in the long run, common bile duct anastomosis provides more durable palliation of obstructive jaundice than gall bladder anastomosis. Gall bladder bypass is associated with a substantially greater risk of subsequent biliary drainage procedures than bile duct bypass in patients with pancreatic cancer [18]. The reason for this lies in the frequently occurring inclusion of the cystic duct in the case of tumor progression. A retrospective evaluation of endoscopic retrograde findings in patients with pancreatic head cancer and jaundice revealed that only a minority of patients would have been suitable for cholecystojejunostomy. Tarnasky et al. examined 218 patients in an endoscopic retrograde cholangiopancreatography-based study to estimate the potential role of laparoscopic cholecystojejunostomy for palliation of patients with malignant obstructive jaundice by judging their cystic duct patency. Only 50/218 patients had a radiologically unaltered hepaticocystic junction, and only in 22/218 patients was the gastrocystic junction >1 cm away from the upper tumor margin. The authors concluded that before a cholecystjejunostomy is performed, the situation in the region around the hepaticocystic junction should be clarified [19], which may be impossible using laparoscopic techniques. Taking this into account, one has to state that laparoscopic bypass surgery in the case of jaundice may not fulfill Table 1 Biliary stent vs surgical bypass Study Study type Patients Success Complications Survival Stent Surgery Stent (%) Surgery (%) Stent (%) Surgery (%) Stent (weeks) Surgery (weeks) Bornman et al [54] RCT Shepherd et al [55] RCT Andersen et al [14] RCT Smith et al [15] RCT Success functional biliary decompression, Survival median overall survival, RCT randomized controlled trial

3 Langenbecks Arch Surg (2007) 392: the principle of best clinical practice, as it appears to provide inferior long-term palliation of jaundice compared to the open technique. Thus, if a surgeon decides to perform the technically simpler or so-called minimally invasive approach to relieve the symptoms of biliary obstruction, he/she must weigh this against an increased risk of further interventions. However, trends in the management of malignant pancreatic diseases over the past decades have generally favored a shift towards minimally invasive palliation and stent placement. A typical algorithm for the treatment of patients with pancreatic cancer and jaundice would exclude all patients from surgical (even minimally invasive) bypass techniques, except those in whom a laparotomy is performed with the definite aim of a potentially curative pancreatic resection. Laparoscopically active surgeons, however, argue that the situation has changed since the introduction of the laparoscopic techniques [20]. The most widely applied form of laparoscopic biliary bypass, a stapled anastomosis between the gall bladder and a loop of small bowel in the sense of a cholecystojejunostomy [21, 22], could be integrated in staging laparoscopy when evidence of irresectability is present. In these cases, laparoscopic cholecystojejunostomy could represent an alternative to stenting techniques. However, there are no randomized trials available supporting this concept at this time. Laparoscopy may be regarded as a final staging procedure in patients already selected for surgery by radiological and other imaging techniques. The question is whether preoperative diagnostic laparoscopy could help to avoid unnecessary surgery and improve the patient s outcome and quality of life. Nieveen van Dijkum et al. investigated the efficacy of diagnostic laparoscopy in 297 patients with peripancreatic cancer scheduled for laparoscopic staging, and found the benefit of this procedure to be lower than expected [23]. Hennig et al. found that not more than 14% of patients benefit from diagnostic laparoscopy when a state-of-the-art CT scan has already been performed. Therefore, they conclude that routine diagnostic laparoscopy is not justified in all patients with pancreatic cancer. According to the authors, selective use is appropriate, especially in patients in whom ascites is an indirect sign of peritoneal metastases, or if liver metastases cannot be excluded preoperatively [24]. In conclusion, diagnostic laparoscopy may not be a viable tool in patients with pancreatic cancer [25]. A clear statement on the resectability of a tumor cannot be made based on laparoscopy, and in addition, conventional surgical palliation seems to be more effective than endoscopic techniques. Gastric outlet obstruction Malignant gastric obstruction is a common complication in patients with pancreatic cancer. However, as not all patients with pancreatic cancer will develop gastric or duodenal obstruction, there is some controversy as to whether and when a gastroenterostomy should be performed (Table 2). Whereas, at the time of diagnosis, only about 19% of patients present with gastroduodenal obstruction due to advanced tumor growth, 30 50% of the patients will develop gastroduodenal obstruction during the course of their disease, with the necessity for endoscopic or surgical intervention [6]. However, before interventional or surgical treatment, motility dysfunction of the stomach and duodenum due to infiltration of the celiac nerve plexus has to be distinguished from mechanical obstruction, which requires pharmaceutical treatment [26]. Traditionally, the palliation of gastric outlet syndrome in patients with mechanical obstruction of the stomach or duodenum due to direct infiltration of the tumor is performed by open gastrojejunostomy. Performed together with a biliary bypass, this procedure does not increase the risk of the primary surgical intervention. If performed separately when the patient presents with symptomatic gastroduodenal stenosis, the morbidity of this second intervention is high, with mortality rates around 22% [27, 28]. Various trials have examined the indication for prophylactic gastrojejunostomy in patients with unresect- Table 2 Double bypass vs single bypass Study Study type Patients Morbidity Gastric outlet obstruction Survival DB BB DB (%) BB (%) DB (%) BB (%) DB (months) BB (months) Lillemoe et al [29] RCT Van Heek et al [30] RCT Shyr et al [56] a OS N/A Mortenson et al [57] OS Survival median overall survival, RCT randomized controlled trial, OS observational study, DB: double bypass, BB biliary bypass a Patients with gastric outlet obstruction received a double bypasses, patients without gastric outlet obstruction received only biliary bypasses; 32% of biliary bypass patients developed gastric outlet obstruction in the postoperative period.

4 16 Langenbecks Arch Surg (2007) 392:13 21 able pancreatic cancer. Lillemoe et al. investigated 87 patients with unresectable tumors. Patients who were thought not to be at risk for duodenal obstruction received either a biliary bypass alone or double bypass in the form of prophylactic gastrojejunostomy and biliary bypass [29]. The combination of biliary and gastric bypass did not increase surgery-related morbidity and mortality or hospital stay. In addition, none of the patients with double bypass developed gastric outlet obstruction, whereas 19% of the patients with only biliary bypass did in the late follow-up. Van Heek et al. validated these results in a multicenter randomized trial [30]. In this cohort of patients, 5.5% with double bypass developed gastric outlet obstruction, compared to 41.4% of patients with only biliary bypass. In accordance with our personal experience, these two studies support the conclusion that a combination of biliary and gastric bypass is preferable in the treatment of patients with unresectable pancreatic head tumors at the time of surgical exploration [31, 32]. With the development of laparoscopic procedures in the past 15 years, even the option of palliative bypass surgery for pancreatic cancer has emerged. However, up to now there have been no randomized trials showing any advantage of minimally invasive surgery procedures in the palliative treatment of pancreatic cancer. Most of the studies evaluate minimally invasive gastric bypass procedures in combination with biliary bypass. Minimally invasive biliary bypass is usually performed as a cholecystojejunostomy. Although this type of bypass surgery is simpler to perform than open choledochojejunostomy, it is considered less effective in the long run, as already discussed [33, 34]. In addition, it is well documented in the literature that a definitive statement on the resectability of pancreatic tumors can only be made with explorative laparotomy and accurate investigation of the intraoperative situs. Thus, conventional double bypass surgery, even in the absence of gastroduodenal obstruction, may be the strategy of choice in patients with intraoperatively proven nonresectability. Duodenal stenting using self-expandable metallic stents is another minimally invasive option in the treatment of gastro-duodenal obstruction. Up to now, this relatively new technique has only been described in nonrandomized trials [35, 36]. Holt et al. investigated 28 patients with nonresectable gastric or pancreatic cancer and symptoms of gastroduodenal obstruction [37]. Stent deployment was successful in 26 patients within min, and the authors concluded that this simple and less invasive technique may represent a viable alternative in cases of advanced disease and frail patients. Mittal et al. retrospectively compared the outcomes of traditional surgical management of pyloroduodenal obstruction (both conventional and laparoscopic) and endoscopic placement of self-expandable metallic stents [38]. This study included a total of 181 patients, of whom 56 had open gastrojejunostomy, 14 had laparoscopic gastrojejunostomy, and 16 had endoscopic stent placement. Although only a small number of patients were treated endoscopically, the authors concluded that the endoscopic procedure has marked advantages over gastrojejunostomy as either an open or laparoscopic procedure for the palliation of malignant gastric outlet obstruction. Pain Around 40 80% of patients with pancreatic cancer present with pain at the time of diagnosis. In the course of the disease, nearly all patients will suffer from abdominal pain, with varying intensity [39]. The etiopathogenesis of pain in pancreatic cancer has not been fully clarified; however, in most of the patients with advanced disease, pain will result from infiltration of the mesenteric or celiac nerve plexus, with pain located in the upper abdomen and in the back. It is clear that initial pain treatment should be pharmacological. The first-line analgesics are nonsteroidal antiinflammatory drugs (NSAIDs) depending on the intensity of pain in combination with opioids, ideally applied transdermally. However, the management of pain especially in the case of advanced cancer and retroperitoneal tumor infiltration may be difficult and unsatisfactory [40]. Simply augmenting the dose of opioids will lead to considerable side effects and can be counterproductive. In these cases, other treatment options should be discussed, such as thoracic splanchnicectomy and celiac and mesenteric nerve block. The principle behind these techniques is to interrupt the transmission of painful stimuli from the organ to the central nervous system. Thoracic splanchnicectomy is a treatment option in patients with pancreatic cancer and untractable pain. In a prospective study, 44 patients with pancreatic cancer or chronic pancreatitis were treated by bilateral thoracoscopic splanchnicectomy. It was shown that this procedure led to a 50% reduction in the pain score within 1 week of the intervention, and this result remained stable throughout the mean follow-up of 4 months [41]. Despite the fact that it can be performed minimally invasively by thoracoscopy, the procedure is complex and associated with considerable risk. Nine percent of the patients required a thoracotomy due to intraoperative bleeding. To our understanding, so far, thoracic splanchnicectomy cannot be regarded as a standard treatment in patients with untractable pain due to pancreatic carcinoma. In contrast to thoracic splanchnicectomy, celiac plexus nerve block represents a viable option in the treatment of pain in patients with advanced, nonresectable pancreatic

5 Langenbecks Arch Surg (2007) 392: cancer. This technique can be performed transcutaneously, or even during laparotomy. While it is well described that this technique achieves good results with regard to pain relief, it also produces undesirable side effects, such as diarrhea and orthostatic problems, in up to 40% of the patients [42]. Various authors have described a correlation between pain and poor prognosis for pancreatic cancer [43]. Lillemoe et al. performed a randomized trial comparing the outcomes of patients in whom chemical splanchnicectomy was performed during laparotomy, either with 50% alcohol or saline solution as a placebo [44]. Good results regarding reduction of pain score after 2, 4, and 6 months could be achieved with this technique; however, no statement was made about side effects. An interesting finding was that a subgroup of patients with severe pain had improved survival after successful pain relief compared to patients with pain and sham treatment. This confirms the observation of other authors that high levels of pain are associated with poor prognosis in pancreatic cancer [43]. In another randomized trial by Wong et al., patients received either neurolytic celiac plexus blockade (NCPB) or standardized analgesic therapy according to the World Health Organization guidelines. In this trial, it was shown that NCPB, compared to optimized analgesic therapy, did not increase the quality of life in these patients. In addition, there was no significant difference between the groups with regard to consumption of analgesics or survival, although pain relief was significantly better with NCPB [45]. These results suggest that effective pain control is possible without splanchnicectomy in most cases, with the consequence that NCPB should be an option for rescue intervention in individual patients with pharmacologically untractable pain. In addition, it is likely that it is not NCBP but aggressive pain management regardless of the technique that is a major factor in prolonging patient survival. Palliative resection Substantial progress has been made in the surgical therapy for pancreatic cancer. However, while perioperative mortality in specialized centers has decreased to around 1 2%, the overall prognosis is still disappointing. Since the 1970s, specialized centers have increased the overall resection rate in patients with pancreatic cancer to 40 50%; however, only a portion of these patients will have complete tumor removal in terms of an R0 resection [7, 46, 47]. Despite impressive advances in imaging techniques, surgical exploration in case of doubt remains the only way to definitively prove diagnosis and to finally exclude resectability. Johnstone and Sindelar reported on 29 patients in whom resectability of pancreatic cancer was excluded in other institutions by explorative laparotomy [48]. All of these patients were reoperated, and only 13 proved to be definitively nonresectable. Sixteen patients could be resected, and their disease-free survival was significantly longer compared to the other patients. Two of these 16 patients who had undergone definitive surgery after palliation elsewhere were long-term survivors (53 and >103 months). The Johnstone study suggests that there may be a relatively high number of patients in whom a complete resection cannot be definitively excluded intraoperatively, as the extent of the pancreatic tumor is not clearly definable due to the degree of accompanying pancreatitis. In these cases, depending on the progression of the surgical intervention, the surgeon must decide either to give up trying to resect the tumor entirely and continue with biliary and/or gastric bypass, or to continue with the resection and eventually arrive at an R1 or even an R2 resection [8, 27]. The resectability of pancreatic tumors depends to a great extent on the experience of the individual surgeon and the case load of the institution. However, it is clear that the number of possible resections will be higher if the surgeon accepts possible R1 or R2 situations. The more aggressive the approach to ultimately try to obtain an R0 resection, the greater the number of incomplete and palliative resections. But as these palliative resections can be performed with extremely low complication and mortality rates, at least in specialized centers, it is worth discussing whether this may represent an acceptable strategy in individual cases (Table 3). Lillemoe et al. retrospectively compared two groups of patients with intraoperatively proven nonresectable pan- Table 3 Palliative resection vs surgical bypass Study Study type Patients Morbidity Survival Resection Bypass Resection (%) Bypass (%) Resection (months) Bypass (months) Reinders et al [47] OS Lillemoe et al [49] OS Kuhlmann et al [58] OS Survival median overall survival, OS observational study

6 18 Langenbecks Arch Surg (2007) 392:13 21 creatic cancer but without evidence of metastatic disease. While the first group underwent palliative resection in the form of a pancreaticoduodenectomy, combined biliary and gastric bypass was performed in 87% of the second group. It was shown that palliative resection can be performed with similar perioperative mortality and complication rates and only a minimal increase in length of hospital stay compared to traditional surgical palliation. Hospital mortality was 1.6% in both groups. While hospital stay was slightly longer in the pancreaticoduodenectomy group (18 vs 15 days), overall survival in this group was significantly improved. The authors concluded that pancreaticoduodenectomy represents a viable palliative option in patients with nonresectable pancreatic cancer, and they recommended using a more aggressive approach in these patients [49]. Similarly, Huguier et al. reported on a retrospective multicenter study in which they analyzed the outcomes of 3,241 patients with histologically proven adenocarcinoma of the pancreas who underwent resection or palliative surgery [50]. Of these, 787 underwent resection, whereas in 2,444, a palliative procedure was performed. The aim of this retrospective multicentric study was to compare the results of resections with those of surgical palliative procedures to determine variables having an impact on postoperative mortality. Surprisingly, postoperative mortality was significantly lower after resection compared to bypass procedures (10% vs 15%; P<0.001). In addition, mean survival times were significantly higher after resective procedures compared to palliative bypass (19.5 vs 8.8 months; P<0.001). Even in patients with involvement of lymph nodes adjacent to or distant from the tumor, survival was better after resection than after bypass (P=0.001). The authors concluded that, in spite of the retrospectively collected data, these results support the idea that in patients with pancreatic cancer without metastases, resection should be attempted whenever possible. This strategy is supported by the observation that lymph node involvement and even cancer-positive resection margins although clearly negative prognostic findings do not preclude 5-year survival. In the Johns Hopkins study [5], the median survival of lymph node-positive patients was 13 months after resection, and 5-year survival was 14%, in accordance with data from the Memorial Sloan-Kettering Cancer Centre, where the 5-year survival rate of node-positive patients was 9% [51]. Most surprisingly, even positive resection margins did not exclude long-term survival. Yeo et al. showed 5-year survival of 26% in patients with negative margins, compared to 8% in patients with positive resection margins [52], and astonishingly, data from Memorial Sloan-Kettering Cancer Centre revealed no difference in mean survival for patients with positive and negative resection margins [51]. In another study, Reinders et al. investigated 240 patients with suspected tumors in the region of the pancreatic head who underwent laparotomy [47]. Of the 196 patients with apparently resectable cancer, 164 underwent a Whipple procedure and 32 underwent a total pancreaticoduodenectomy. In 56 patients, after the Whipple procedure, histologic examination revealed tumor infiltration of resection margins, with the consequence that these resections were considered palliative. A matched group of patients after palliative Whipple (n=36, group B) was compared with another group of patients who underwent palliative biliary or gastric bypass due to unresectable pancreatic head tumors (n=24, group A); hospital mortality, morbidity, and long-term survival were compared. Hospital stay was significantly longer in group A, but there was no significant difference between the two groups regarding severe complications and hospital mortality. However, 1- and 2-year survival was significantly longer after palliative Whipple (group B; 44 and 24%, respectively) than after bypass surgery (group A; 22 and 2%, respectively). Maximum duration of survival in group A was 26 months. In comparison, at the conclusion of the study, 12 patients of group B were still alive, with the maximal survival time being 45 months. In a recent randomized, multicenter trial, Imamura et al. [53] compared surgical resection with radiochemotherapy alone in patients with resectable and locally invasive pancreatic cancer. Inclusion criteria were invasiveness of the tumor into the organ capsule without infiltration of the superior mesenteric or common hepatic artery and the absence of distant metastasis. Patients assigned to the resection group underwent pancreaticoduodenectomy or distal pancreatectomy for resection of the pancreatic tumor. In these patients, no postoperative adjuvant treatment was performed unless recurrence was obvious, at which point the selection of another therapy was permitted. In patients assigned to the radiochemotherapy group, the abdomen was closed once a biopsy had been taken to confirm the diagnosis, although the surgeon was free to perform biliary or gastric bypass. There was a significant difference favoring surgical resection with regard to 1-year survival (62 vs 32%, P=0.05), mean survival time (>17 vs 11 months, P<0.03), and hazard ratio (0.46, P<0.04), while there was no difference in quality of life score apart from diarrhea after surgical resection [53]. Together with data from the other studies mentioned, these data suggest that tumor resection should be performed whenever possible, even in patients with advanced pancreatic cancer. Despite the fact that, intraoperatively, pancreatic cancer very often presents at a stage where R0 resection is unlikely, an aggressive surgical approach to the tumor may represent a viable option to improve patient prognosis [32].

7 Langenbecks Arch Surg (2007) 392: Conclusion The aim of every palliative strategy in patients with pancreatic cancer must be to relieve the symptoms of further tumor growth, such as pain and duodenal and biliary obstruction. However, decisions about resectability and curability of pancreatic cancer must be clear and well founded in every single patient. In the 1980s, due to the development of sophisticated endoscopic procedures, palliative concepts in pancreatic cancer were mainly based on stent placement by gastroenterologists. This trend was enforced by the fact that increasingly elaborate endoscopic and radiologic diagnostic tools and imaging techniques seemed to allow for an increasingly exact estimation of whether a surgical intervention was potentially curative. As a consequence, radiologically diagnosed advanced tumor growth led primarily to conservative treatment, mostly without any surgical statement on potential resectability. Another factor that supported such therapeutic nihilism was the myth about pancreatic resections, especially the Whipple procedure or palliative resections, where mortality rates of around 14 17% were cited in the 1980s and even in the 1990s [15, 28]. For example, in 1994, Smith cited a 30-day mortality of 14% after surgical palliation compared to 3% after an interventional technique numbers that are no longer acceptable. Meanwhile, several recent studies have shown that, if performed in specialized centers, even palliative resections can be performed with an extremely low morbidity rate. In comparisons of long-term outcome, surgical biliary and gastric bypass is clearly superior to endoscopic stenting, and even patients with palliative resection seem to benefit from the reduction of tumor mass, in particular if combined with (neo-)adjuvant radiochemotherapy. One of the central difficulties in the treatment of pancreatic cancer is how to decide whether a tumor is resectable. Even with an armamentarium of diagnostic tools, surgical exploration remains the only approach to definitively exclude the possibility of tumor resection. The crucial point is that, very often, the final decision can only be made during extensive surgical exploration, which means that the surgeon will have to operate with the knowledge that an R1 or R2 situation may result postoperatively. With this concept, we advocate a relatively aggressive approach to treating patients with advanced pancreatic cancer. Only patients with preoperatively proven distant metastases or peritoneal disease should be excluded from surgical exploration. For each of these patients, it must be individually decided whether surgical biliary and gastric bypass should be performed or whether limited prognosis or advanced disease make interventional palliation techniques more suitable. All other patients will undergo surgical exploration, in certain cases in combination with neoadjuvant treatment. Intraoperatively, every attempt should be made to resect the tumor. Suspected infiltration of the mesenteric radix and portal vein is often due to inflammatory side reactions, and appraisal is only possible after meticulous dissection of these regions. Only intraoperatively detected distant metastasizing disease or peritoneal carcinosis may be regarded as a definite contraindication for resective surgery. References 1. Warshaw AL, Swanson RS (1988) Pancreatic cancer in Possibilities and probabilities. Ann Surg 208: Gudjonsson B (1987) Cancer of the pancreas. 50 years of surgery. Cancer 60: Mosca F, Giulianotti PC, Balestracci T, Di Candio G, Pietrabissa A, Sbrana F, Rossi G (1997) Long-term survival in pancreatic cancer: pylorus-preserving versus Whipple pancreatoduodenectomy. Surgery 122: Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med 326: Yeo CJ (1998) Pancreatic cancer: 1998 update. J Am Coll Surg 187: Lillemoe KD (1998) Palliative therapy for pancreatic cancer. Surg Oncol Clin N Am 7: Sohn TA, Lillemoe KD, Cameron JL, Huang JJ, Pitt HA, Yeo CJ (1999) Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188: van Wagensveld BA, Coene PP, van Gulik TM, Rauws EA, Obertop H, Gouma DJ (1997) Outcome of palliative biliary and gastric bypass surgery for pancreatic head carcinoma in 126 patients. Br J Surg 84: Tan HP, Smith J, Garberoglio CA (1996) Pancreatic adenocarcinoma: an update. J Am Coll Surg 183: Abraham NS, Barkun JS, Barkun AN (2002) Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life. Gastrointest Endosc 56: Speer AG, Cotton PB, Russell RC, Mason RR, Hatfield AR, Leung JW, MacRae KD, Houghton J, Lennon CA (1987) Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 2: Classen M, Hagenmuller F (1983) Biliary drainage. Endoscopy 15 (Suppl 1): Stanley J, Gobien RP, Cunningham J, Andriole J (1986) Biliary decompression: an institutional comparison of percutaneous and endoscopic methods. Radiology 158: Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P (1989) Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 30: Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB (1994) Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction. Lancet 344: Taylor MC, McLeod RS, Langer B (2000) Biliary stenting versus bypass surgery for the palliation of malignant distal bile duct obstruction: a meta-analysis. Liver Transpl 6: Wagner M, Egger B, Kulli C, Redaelli CA, Krahenbuhl L, Seiler CA, Buchler MW (2000) Stent or surgical bypass as palliative therapy in obstructive jaundice. Swiss Surg 6: Urbach DR, Bell CM, Swanstrom LL, Hansen PD (2003) Cohort study of surgical bypass to the gallbladder or bile duct for the

8 20 Langenbecks Arch Surg (2007) 392:13 21 palliation of jaundice due to pancreatic cancer. Ann Surg 237: Tarnasky PR, England RE, Lail LM, Pappas TN, Cotton PB (1995) Cystic duct patency in malignant obstructive jaundice. An ERCP-based study relevant to the role of laparoscopic cholecystojejunostomy. Ann Surg 221: Ammori BJ (2003) Pancreatic surgery in the laparoscopic era. JOP 4: Fletcher DR, Jones RM (1992) Laparoscopic cholecystjejunostomy as palliation for obstructive jaundice in inoperable carcinoma of pancreas. Surg Endosc 6: Rhodes M, Nathanson L, Fielding G (1995) Laparoscopic biliary and gastric bypass: a useful adjunct in the treatment of carcinoma of the pancreas. Gut 36: Nieveen van Dijkum EJ, Romijn MG, Terwee CB, de Wit LT, van der Meulen JH, Lameris HS, Rauws EA, Obertop H, van Eyck CH, Bossuyt PM, Gouma DJ (2003) Laparoscopic staging and subsequent palliation in patients with peripancreatic carcinoma. Ann Surg 237: Hennig R, Tempia-Caliera AA, Hartel M, Buchler MW, Friess H (2002) Staging laparoscopy and its indications in pancreatic cancer patients. Dig Surg 19: Friess H, Kleeff J, Silva JC, Sadowski C, Baer HU, Buchler MW (1998) The role of diagnostic laparoscopy in pancreatic and periampullary malignancies. J Am Coll Surg 186: Yeo CJ, Barry MK, Sauter PK, Sostre S, Lillemoe KD, Pitt HA, Cameron JL (1993) Erythromycin accelerates gastric emptying after pancreaticoduodenectomy. A prospective, randomized, placebo-controlled trial. Ann Surg 218: Sarr MG, Cameron JL (1984) Surgical palliation of unresectable carcinoma of the pancreas. World J Surg 8: Watanapa P, Williamson RC (1992) Surgical palliation for pancreatic cancer: developments during the past two decades. Br J Surg 79: Lillemoe KD, Cameron JL, Hardacre JM, Sohn TA, Sauter PK, Coleman J, Pitt HA, Yeo CJ (1999) Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg 230: Van Heek NT, De Castro SM, van Eijck CH, van Geenen RC, Hesselink EJ, Breslau PJ, Tran TC, Kazemier G, Visser MR, Busch OR, Obertop H, Gouma DJ (2003) The need for a prophylactic gastrojejunostomy for unresectable periampullary cancer: a prospective randomized multicenter trial with special focus on assessment of quality of life. Ann Surg 238: Heinicke JM, Buchler MW, Laffer UT (2002) Bilio-digestive double bypass for nonresectable pancreatic cancer. Dig Surg 19: Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW (2004) Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 91: Rhodes M, Nathanson L, Fielding G (1995) Laparoscopic biliary and gastric bypass: a useful adjunct in the treatment of carcinoma of the pancreas. Gut 36: Rothlin MA, Schob O, Weber M (1999) Laparoscopic gastro- and hepaticojejunostomy for palliation of pancreatic cancer: a case controlled study. Surg Endosc 13: Maetani I, Akatsuka S, Ikeda M, Tada T, Ukita T, Nakamura Y, Nagao J, Sakai Y (2005) Self-expandable metallic stent placement for palliation in gastric outlet obstructions caused by gastric cancer: a comparison with surgical gastrojejunostomy. J Gastroenterol 40: Tsukada K (2005) Metallic stent placement or gastroenterostomy for gastric outlet obstruction caused by gastric cancer? J Gastroenterol 40: Holt AP, Patel M, Ahmed MM (2004) Palliation of patients with malignant gastroduodenal obstruction with self-expanding metallic stents: the treatment of choice? Gastrointest Endosc 60: Mittal A, Windsor J, Woodfield J, Casey P, Lane M (2004) Matched study of three methods for palliation of malignant pyloroduodenal obstruction. Br J Surg 91: Kuhlmann KF, De Castro SM, Wesseling JG, ten Kate FJ, Offerhaus GJ, Busch OR, van Gulik TM, Obertop H, Gouma DJ (2004) Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 40: Caraceni A, Portenoy RK (1996) Pain management in patients with pancreatic carcinoma. Cancer 78: Ihse I, Zoucas E, Gyllstedt E, Lillo-Gil R, Andren-Sandberg A (1999) Bilateral thoracoscopic splanchnicectomy: effects on pancreatic pain and function. Ann Surg 230: Eisenberg E, Carr DB, Chalmers TC (1995) Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis. Anesth Analg 80: Kelsen DP, Portenoy R, Thaler H, Tao Y, Brennan M (1997) Pain as a predictor of outcome in patients with operable pancreatic carcinoma. Surgery 122: Lillemoe KD, Cameron JL, Kaufman HS, Yeo CJ, Pitt HA, Sauter PK (1993) Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 217: Wong GY, Schroeder DR, Carns PE, Wilson JL, Martin DP, Kinney MO, Mantilla CB, Warner DO (2004) Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. JAMA 291: Allema JH, Reinders ME, van Gulik TM, Koelemay MJ, Van Leeuwen DJ, de Wit LT, Gouma DJ, Obertop H (1995) Prognostic factors for survival after pancreaticoduodenectomy for patients with carcinoma of the pancreatic head region. Cancer 75: Reinders ME, Allema JH, van Gulik TM, Karsten TM, de Wit LT, Verbeek PC, Rauws EJ, Gouma DJ (1995) Outcome of microscopically nonradical, subtotal pancreaticoduodenectomy (Whipple s resection) for treatment of pancreatic head tumors. World J Surg 19: Johnstone PA, Sindelar WF (1996) Radical reoperation for advanced pancreatic carcinoma. J Surg Oncol 61: Lillemoe KD, Cameron JL, Yeo CJ, Sohn TA, Nakeeb A, Sauter PK, Hruban RH, Abrams RA, Pitt HA (1996) Pancreaticoduodenectomy. Does it have a role in the palliation of pancreatic cancer? Ann Surg 223: Huguier M, Baumel H, Manderscheid JC (1996) Cancer of the exocrine pancreas. A plea for resection. Hepatogastroenterology 43: Geer RJ, Brennan MF (1993) Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 165: Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, Dooley WC, Coleman J, Pitt HA (1995) Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg 221: Imamura M, Doi R, Imaizumi T, Funakoshi A, Wakasugi H, Sunamura M, Ogata Y, Hishinuma S, Asano T, Aikou T, Hosotani R, Maetani S (2004) A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer. Surgery 136: Bornman PC, Harries-Jones EP, Tobias R, Van Stiegmann G, Terblanche J (1986) Prospective controlled trials of transhepatic biliary endoprothesis versus bypass surgery for incurable carcinoma of head of pancreas. Lancet 1:69 71

9 Langenbecks Arch Surg (2007) 392: Shepherd HA, Royle G, Ross AP, Diba A, Arthur M, Colin-Jones D (1988) Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg 75: Shyr YM, Su CH, Wu CW, Lui WY (2000) Prospective study of gastric outlet obstruction in unresectable periampullary adenocarcinoma. World J Surg 24: Mortenson MM, Ho HS, Bold RJ (2005) An analysis of cost and clinical outcome in palliation for advanced pancreatic cancer. Am J Surg 190: Kuhlmann K, de Castro S, van Heek T, Busch O, van Gulik T, Obertop H, Gouma D (2006) Microscopically incomplete resection offers acceptable palliation in pancreatic cancer. Surgery 139: