The impact of different types of surgery in pancreatic cancer

European Journal of Surgical Oncology 1999; 25: 124–131

The impact of different types of surgery in pancreatic cancer H. Friess, J. Kleeff, C. Kulli, M. Wagner, H. Sawhney and M. W. Bu¨chler Department of Visceral and Transplantation Surgery, University of Bern, 3010 Bern, Switzerland

Introduction Pancreatic cancer has a mortality rate roughly equal to its incidence rate.1 Because of its extremely poor prognosis, it represents the fourth to fifth leading cause of cancer-related death in Western industrialized countries.2,3 In recent years, molecular analysis has substantially contributed to a better understanding of the growth behaviour of pancreatic cancer. A significant number of pancreatic cancers over-express growth factor receptors such as the epidermal growth factor (EGF) receptor, c-erbB-2, c-erbB-3, fibroblast growth factor (FGF) receptor, c-met, transforming growth factor-beta (TGF-b) receptors, and activin receptors, as well as growth factors such as EGF, TGF-a, amphiregulin, hepatocyte growth factor (HGF), TGF-bs, and activins/inhibins.4–14 Furthermore, pancreatic cancers often exhibit gene mutations of p53 and k-ras, alterations in the expression of metastasis genes such as KAI1, and upregulation of factors such as urokinase plasminogen activator and its receptor, which enhances tumour invasion.15–19 These molecular alterations enhance the aggressiveness of pancreatic cancer cells and lead to the fast spread of the disease. Contributing to the high death rate is the fact that pancreatic cancer is often diagnosed at a fairly late stage (when the tumour has already metastasized), which greatly prevents the possibility of a curative resection, and its unresponsiveness to conventional oncological treatment options. Although chemotherapy has improved the prognosis in many malignancies, its impact in pancreatic cancer is limited.20 The same is true for intraoperative or external radiotherapy, anti-hormonal treatment or immunotherapy.21–24 Due to the lack of effective adjuvant treatment protocols, the median survival time following diagnosis in non-resectable tumours is only about 4–6 months. If diagnosis is in fact established at an early stage, the only chance for cure, to date, is offered via resection. In pancreatic cancers without distant metastases resectability rates have increased steadily during the past several decades, due in part to enhanced diagnostic techniques and lower post-operative mortality and morbidity in experienced centres.25–39 Long-term survival

Correspondence to: Markus W. Bu¨chler, M.D., Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, CH-3010 Bern, Switzerland. Fax: +41 31 382 4772; Email: [email protected] 0748–7983/99/020124+08 $12.00/0

after resection, however, continues to be low, and recent studies reveal that the 5-year survival rate after resection is only around 10%,27,30–32 with a range of between 0.4 and 33%.26–33 Attempts to improve surgical treatment for pancreatic cancer have led to the development of various resection modifications.30,34–42 In this overview, we compare the different surgical approaches for the resection of pancreatic cancer and present our experience with these techniques.

Standard Whipple and pylorus-preserving Whipple procedures In the years preceding 1935, most surgeons favoured the use of a gastroenterostomy in dealing with pancreatic malignancies. Although Walter Kausch of Berlin had already reported the first successful duodenopancreatectomy in 1912,43 this procedure was not immediately accepted by surgeons due to the high mortality rates of 20–40% associated with it,44 and for the next two decades surgeons were hesitant to employ it. Interest in pancreatic resections was renewed, however, when Allen O. Whipple reported three successful duodenopancreatectomies in 1935. The procedure came to be known and standardized as the Whipple procedure in honour of this surgeon who performed 37 resections in his lifetime.45,46 The Whipple resection still remains the standard operation for pancreatic, ampullary, duodenal and distal bile duct cancers. Two-thirds of all pancreatic head resections in the USA employ the Whipple procedure, as disclosed by a survey conducted among surgeons in the USA.47,48 The operation involves the removal of the pancreatic head, the duodenum with a short segment of the proximal jejunum, the peripancreatic and the hepatoduodenal ligament lymph nodes, the distal stomach with the right half of the great omentum and the gall bladder with the distal common bile duct (Fig. 1a, b). A more conservative alternative to the classical Whipple’s procedure is the pylorus-preserving duodenopancreatectomy (Fig. 1a, c). This procedure was pioneered by Kenneth Watson, an assistant surgeon in East Surrey in the UK, who performed the operation in 1942 in a patient with carcinoma of the ampulla of Vater.49 Although Walter Kausch had also performed the procedure earlier in 1909, he did not actually exploit the advantage of preserving the  1999 W.B. Saunders Company Limited

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Pancreatic cancer—matters for debate (a)

(b)

(c)

(d)

Fig. 1. (a) Pre-operative situation before pancreatic resection. (b) Post-operative situation following classical Whipple’s resection. (c) Postoperative situation following pylorus-preserving Whipple’s resection. (d) Post-operative situation following total duodenopancreatectomy for pancreatic cancer.

pylorus since the reconstruction was performed through a gastroenterostomy. Watson suggested that this more conservative procedure would be beneficial to the patient because preservation of the stomach and pylorus would minimize post-operative jejunal ulceration as well as the side-effects of partial gastrectomy.49 In 1978, almost 40 years after Watson’s achievement, Traverso and Longmire finally publicised the procedure when they published a report about their two initial, not to mention successful, operations.50 They, like Watson, reasoned that leaving the entirety of the stomach unimpaired, including the pylorus, would not only enhance gastrointestinal function but would also eradicate the side-effects correlated with a gastroenterostomy.51 The pylorus-preserving duodenopancreatectomy has been adopted by many surgeons for treating chronic pancreatitis as well as cancer of the pancreatic head and particularly of the periampullary region. The pylorus-preserving procedure and classical Whipple’s resection both have advantages and drawbacks. The two procedures show no difference in the occurrence of pancreatic fistulae and haemorrhage, the two most feared complications following duodenopancreatectomy.52,53 In the past, classical Whipple’s resection was associated with mortality rates of about 20%. However, due to advances

Table 1. Mortality and survival rates after standard Whipple’s procedure Reference

Year

Patients (n)

Hospital mortality (%)

5-year survival (%)

Bodner54 Lygidakis et al.55 Funovics et al.56 Condie et al.57 Trede et al.30 Cameron et al.58 Roder et al.53 Baumel et al.59 Beger et al.25 Nitecki et al.60 Wade et al.61 Yeo et al.62 Patel et al.63 Sperti et al.64 Chou et al.65 Iacono et al.66 Bern (this report)

1988 1989 1989 1989 1990 1991 1992 1994 1994 1995 1995 1995 1995 1996 1996 1997 1998

274 111 100 13 133 52 31 555 101 123 252 201 52 77 93 23 37

6 2 13 31 2 9 2 8 4 3 8 5 0 15 8 4.3 2.7

11 — 5 7.7 24 19 3 15 9 7 9 21 — 10 — — —

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Table 2. Mortality and survival rates after pylorus-preserving Whipple’s procedure Reference

Year

Patients (n)

Hospital mortality (%)

5-year survival (%)

Cameron et al.58 Klinkenbijl et al.52 Roder et al.53 Friess et al.27 Kozuschek et al. in Beger et al.68 Takada et al.69 Mosca et al.70 Tsao et al.71 Heise et al.72 Nitecki et al.60 Patel et al.63 Yeo et al.73∗ Bern (this report)

1991 1992 1992 1993 1993

37 25 22 19 24

9 2 2 5 8

19 — 0 9 19

1993 1994 1994 1994 1995 1995 1997 1998

16 76 22 18 16 15 282 51

— 7.5 2 0 3 1.6 1.4 1.9

35 12 7 3 7 — 18 —

∗ Sub-analysis of 650 patients with pancreaticoduodenectomies.

in surgical technique and intensive care, mortality has dropped tremendously in the last few decades (Table 1).25,30,53–66 The mortality rates for the pylorus-preserving procedure appeared at first considerably lower than those of Whipple’s resection, with a range of 2–9% as reported by different institutions (Table 2).31,41,42,53,58,60,67–74 However, peri-operative mortality for both procedures has declined to 5% or less and is approaching zero in some major institutions performing pancreatic surgery.30,31 The use of the pylorus-preserving duodenopancreatectomy for pancreatic cancer has nevertheless been disputed, as the resection field is reduced in this procedure. The rudimentary norm in oncological surgery is to remove the primary tumour without leaving any tumour tissue at the resection borders. However, no outgrowths of tumour tissue adjacent to the pylorus and no lymph-node involvement along the minor and major curvatures of the stomach were found in a pathological examination of 140 operative specimens from people with cancer of the pancreatic head.75 When considering the long-term survival of patients, the outcomes attributable to the pyloruspreserving procedure do not show significant deviation from those of the standard duodenopancreatectomy. Obviously, the generalization that the two procedures have similar survival rates only has grounds when the malignancies of the pancreatic head are in comparable tumour stages.40,51,52,58,68 The results of these studies coincide with our own observations and it is now widely accepted that the pylorus-preserving duodenopancreatectomy is a suitable operation for most periampullary and pancreatic head cancers. However, despite the improved 5-year survival rates of about 15–36% after resection,32,58,59 the outcomes for pancreatic cancer patients appear much less encouraging when all tumour stages are considered. Overall, long-term survival rates following resection are only about 10%.27,32,48 Thus, we have learned from our own and others’ experience that due to the high recurrence rates after a radical tumour resection, resection of pancreatic cancer is often only a palliative procedure.

An area that continues to cause dispute and controversy is the effect of the pylorus-preserving Whipple on gastrointestinal function. Some gastric retention is a common outcome after any duodenopancreatectomy. However, delayed gastric emptying has been reported to occur with a higher frequency after preservation of the pylorus.53,75,76 This led to the argument that pylorus preservation impairs gastric function by preventing the stomach from emptying adequately. However, other authors were unable to find any significant difference in gastric emptying following the two procedures.40,77 It has also been revealed by a number of studies that gastric emptying is normalized within a period of 2–4 weeks following pyloruspreserving treatment.78,79 In the above-mentioned studies, only five (8.6%) of the patients showed continual delayed gastric emptying several months after resection.75 A possible explanation for this temporary malfunction of gastric emptying lies in the formation of an anastomotic oedema in the initial post-operative period and in the destruction of the crucial neurovascular supply. This has led to the proposition that accurate preservation of pyloric innervation and perfusion should hinder long-term impairment of gastric function. This theory coincides with our own observations: in a 15-month period, in which more than 130 pancreatic operations were performed, only 18% of the patients who underwent pylorus-preserving Whipple’s resection suffered from delayed gastric emptying, whereas 40% of patients who underwent the classical Whipple’s resection showed delayed gastric emptying. Hence, the argument that the pylorus-preserving Whipple causes an increased incidence of delayed gastric emptying does not appear to be validated by the evidence. However, controlled randomized trials to evaluate gastric emptying delay, quality of life and long-term survival are under way and will give definitive answers.

Total and subtotal pancreatectomy Total pancreatectomy Total pancreatectomy was first described by Ross and then later by Porter, both in 1954.34,35 In 1960, Howard reported a mortality rate of 37% for this procedure, which led most surgeons to abandon it.80 However, when Whipple’s procedure did not fulfill initial expectations due to its high mortality and inadequate long-term survival, interest in total pancreatectomy was renewed. A total pancreatectomy combines a standard duodenopancreatectomy and a distal pancreatectomy including the spleen. The entire pancreas is removed along with the lymph nodes around the left gastric artery, the splenic artery and the coelical truncus. An end-to-side hepaticojejunostomy is applied for reconstruction (Fig. 1a, d). Initially, a total pancreatectomy appeared to offer certain advantages. Some authors found that multicentricity of the tumour within the pancreas was a regular occurrence81–83 and thus removing the whole pancreas as the primary tumour site would make sense.84,85 In addition, as a total pancreatectomy would eliminate a pancreatic anastomosis, it would prevent the substantial morbidity and mortality

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Pancreatic cancer—matters for debate that was associated with leakage of the anastomosis, which at the time was a common occurrence. It was also believed that a more complete lymphadenectomy would be possible with wider margins, which would confer yet another advantage to total pancreatectomy. It soon became apparent, however, that a total pancreatectomy also had many drawbacks. Not only was mortality as high as that following Whipple’s procedure, but there was also no impact on long-term survival in comparison to a standard duodenopancreatectomy.86,87 Another quite serious disadvantage was the deterioration of health that occurred due to disturbed nutritional and metabolic functions.88 For instance, in patients who had undergone total pancreatectomy, Dresler et al. found an increase in the frequency of liver disease and osteopenia.89 Even more importantly, some patients died due to unmanageable diabetes mellitus, a condition which inevitably results following total pancreatectomy.83 Keeping all this in mind, in addition to the fact that pancreatic anastomosis is no longer considered a risky procedure, total pancreatectomy seems to offer no definite advantage and thus should only be performed under special, particularly relevant circumstances.87,90,91 In our clinical practice a total duodenopancreatectomy is only performed when the pathologist does not find tumour-free resection margins intraoperatively in the frozen sections or if a safe pancreaticojejunostomy cannot be performed due to the soft texture of the pancreatic remnant at the resection margin. Subtotal pancreatectomy It is noteworthy that the pancreatic tail and its lymph nodes are seldom affected by cancer.92,93 Utilizing this fact, subtotal pancreatectomy was developed with the intention of allowing wide resection margins while avoiding the metabolic side-effects associated with total pancreatectomy.92 The operation is similar to Whipple’s procedure but the resection of the pancreas is expanded distally, preserving only the last 5 cm of the pancreatic tail. As described by Gall et al.,92 the regional lymph nodes are also removed and the tail remnant is closed in a blind fashion so that the reconstruction comprises an end-to-side hepaticojejunostomy and gastroenterostomy. Morbidity and mortality of a subtotal pancreatectomy are similar to those reported after a classical Whipple’s procedure (Table 3).39,93–100 One of the greatest disadvantages of subtotal pancreatectomy, however, lies in the high occurrence of pancreatic fistulae—20% as reported by Ihse et al.81 As a standard duodenopancreatectomy is associated with an 8–10% occurrence of fistulae,30,101 the higher incidence involved with subtotal pancreatectomy has brought surgeons to question this procedure. To date, long-term results concerning this technique are lacking since only very few surgeons are utilizing this method.38,48,92 It is not possible, therefore, to evaluate the clinical significance of this procedure adequately. It would be necessary to carry out prospective, randomized trials comparing subtotal pancreatectomy to the standard Whipple’s or pylorus-preserving duodenopancreatectomy to judge whether this procedure has any survival advantage.

Table 3. Mortality and survival rates after extended radical pancreatectomy Reference

Year

Patients (n)

Hospital mortality (%)

5-year survival (%)

Manabe et al.93 Sindelar94 Nagakawa et al.95 Miyazaki et al.96 Gall et al. in Beger et al.97 Hanyu et al. in Beger et al.39 Takahashi et al.98 Fortner et al.99 Nagakawa et al.100

1989 1989 1991 1992 1993

32 20 43 32 139

6 20 14 — 7

33 5 14 28 8

1993

167

3

8

1994 1996 1996

137 26 53

10 4 15

7 12–13 27

As already mentioned, pancreatic anastomosis can now be performed safely38,39 and thus avoiding this procedure cannot be regarded as an advantage of subtotal pancreatectomy. Furthermore, as no increase in long-term survival has been observed following total pancreatectomy, a wider resection margin gives, from an oncological point of view, most probably no advantage to subtotal pancreatectomy. However, to avoid the high occurrence of pancreatic fistula following Gall’s inaugurated subtotal pancreatectomy,92 the small pancreatic remnant can be anastomosed with the jejunum or stomach as is done in Whipple’s procedure.

Pancreatectomy with extended lymph-node resection Regional pancreatectomy Joseph Fortner first introduced regional pancreatectomy for pancreatic cancer in 1973 with the hope of improving resectability rates and long-term survival. He presented two distinct strategies, type I and type II regional pancreatectomy. Type I consists of an en bloc resection of the pancreas with the intrapancreatic segment of the portal vein, the base of the transverse mesocolon, the soft tissue encompassing the pancreas and the regional lymph nodes. This represents a total or subtotal pancreatectomy, which leaves at least a 4-cm margin of uninvolved tissue at the borders of concern. The regional lymph-node dissection also includes the retroperitoneal lymph nodes from the diaphragm until the origin of the inferior mesenteric artery. The hepatic artery, the portal vein and the coeliac truncus, the superior mesenteric artery as well as the vena cava and the aorta are carefully skeletonized from soft tissue. A distal gastrectomy, duodenectomy, cholecystectomy and resection of the extrahepatic bile ducts to near the bifurcation are included.85 For venous reconstruction, a direct end-to-end anastomosis of the superior mesenteric vein to the portal vein is performed without inserting a graft. The distinction in the type II procedure is that it consists of additional removal of either a segment of the hepatic artery and the celiacal axis or a segment of the superior mesenteric artery. Reconstruction may involve shortening of the artery, a vein graft, or the insertion of an arterial substitute. As regional pancreatectomy has been associated with

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high peri-operative morbidity rates and correspondingly high mortality rates of up to 26%,85,94 this method is rarely employed by surgeons in Europe and North America.94 Recently reported resectability rates range from 28 to 42%.26,39,85,97 However, this method fails to show any advantage in long-term survival as compared to a classical Whipple’s or pylorus-preserving Whipple’s procedure and therefore this technique is rarely indicated for pancreatic cancer. Extended lymph-node resection Since 1973, when Fortner endorsed regional pancreatectomy, Japanese surgeons have increasingly preferred resection of the pancreatic tumour via an extended radical operation. This procedure consists of a regional lymphadenectomy and dissection of the nervous plexus around the retroperitoneum, followed by resection and reconstruction of the portal vein system and finally extended proximal pancreatectomy.102 This practice was adopted by many Japanese surgeons and was ultimately standardized by the Japanese Pancreatic Society. With the use of this technique, the resectability rates for patients increased significantly from a mere 20 up to 60%, as reported in a study by Hanyu et al.102 For small and early pancreatic cancers in particular, radical extended pancreatectomy attains 5-year survival rates of 28–46%.26,39,93,95,98,103,104 Reported mortality rates range between 3 and 14%. It appears that with adequate surgical experience and the use of enhanced technology, mortality rates for extended lymphnode resection resemble those of Whipple’s resection.39,95 Even though the Japanese have much experience and expertise in this particular type of operation, it is difficult to make final conclusions from their studies. First, the Japanese staging system for pancreatic cancer differs from that used in Europe and the USA, and thus their studies cannot properly be compared. Furthermore, their surgical technique is rarely employed in Europe and the USA and therefore sufficient data for statistical analysis are not readily available. A recently conducted study by an Italian centre suggested that an extended lymphadenectomy only improved prognosis in a subgroup of patients with lymphnode involvement, rather than in the whole population of resected patients.105 Controlled clinical trials encompassing a large number of patients need to be conducted to reach reliable conclusions.

Table 4. Surgical treatment of pancreatic cancer in Bern (195 patients): November 1993 to May 1998 Procedure

n (%)

Exploration Laparotomy Laparoscopy

38 (20) 35 3

Bypass procedure Biliodig. bypass Gastroenterostomy

47 (24) 36 11

Resection Pylorus-preserving Whipple Classical Whipple Total pancreatectomy Left resection

110 (56) 51 37 14 8

cancers become symptomatic at a much later stage than do pancreatic head carcinomas and distant metastases are frequently present at the time of the establishment of the diagnosis.106 As another inevitable consequence of their late presentation, adenocarcinomas of the pancreatic body and tail are rendered unresectable at a higher rate than cancers of the pancreatic head.107–109 Johnson et al. reported a resection rate of only 12% (13/105) in patients with cancer of the pancreatic body and tail.108 The reported median survival was 13 months following resection, with only five patients surviving for more than 2 years.108 Howard et al. reported that only two patients have ever been cured of disease via left resection,109 although no other therapy presents a better chance of survival or relief from symptoms. It has been suggested that the incidence of resection should increase with more accurate diagnostic techniques and more aggressive surgery, both of which are now possible.109 Conventionally, a distal pancreatectomy is always accompanied by a splenectomy. However, because the spleen plays an important role in host defence, arguments have been made in favour of its preservation.110 Although spleen preservation during distal pancreatectomy may offer advantages for indications such as chronic pancreatitis or pancreatic trauma, it seems to offer no advantage when dealing with adenocarcinomas of the pancreas. Therefore in Bern we routinely perform a splenectomy along with a distal pancreatectomy in pancreatic cancer. Treatment of pancreatic cancer: the Bern experience

Distal pancreatectomy A distal pancreatectomy is the operation of choice for lesions of the pancreatic body and tail. This technique, also known as the left resection, involves the removal of the pancreatic body and tail together with the peripancreatic lymph nodes and the spleen. The pancreatic stump is sutured in a blind fashion. Since cancers in the body and tail of the pancreas occur quite infrequently in comparison to carcinomas of the pancreatic head, the left resection is a rarely employed surgical procedure. Another factor that contributes to the rare employment of the left resection is the unfortunate delay in the diagnosis of cancers of the pancreatic body and tail. This is due to the fact that these

Between November 1993 and May 1998 in the Department of Visceral and Transplantation Surgery at the University of Bern, 195 patients (82 women, 113 men; median age 67 years, range 36–87 years) were operated on for pancreatic cancer. At the time of operation, 67% of the patients were already in advanced tumour stages, with lymph-node metastasis (stage III, 41%) or distant metastasis (stage IV, 26%). Only 10% of the pancreatic cancer patients had stage I disease and 23% stage II disease according to UICC criteria. In 56% of the pancreatic cancer patients a tumour resection could be performed (Table 4). Forty-seven patients (24%) required a bypass operation due to unresectability of

Pancreatic cancer—matters for debate Table 5. Morbidity and mortality following pancreatic resection for pancreatic cancer in Bern (110 patients): November 1993 to May 1998 n (%) Morbidity Delayed gastric emptying Wound infection Pancreatic fistula Other

43 (40) 24 4 3 14

Mortality

2 (1.9)

Re-operation

5 (4.7)

the primary tumour or due to tumour spread. Exploratory laparotomy or laparoscopy without further surgical treatment was done in 38 patients (20%) (Table 4).111 Following tumour resection post-operative mortality was 1.9% (2/110 patients) and hospital morbidity was 40% (43/ 110 patients) (Table 5). In five of 110 (4.7%) patients undergoing major pancreatic resection a re-laparotomy was required due to post-operative complications.

Conclusion In recent decades, remarkable efforts have been made to improve the prognosis for pancreatic cancer. Surgical techniques have evolved from a simple gastroenterostomy to several specific types of pancreatic resections, including Whipple’s resection, the pylorus-preserving resection, total and subtotal pancreatectomies, regional pancreatectomy and the extended lymph-node resection. Of these, Whipple’s resection must be considered the standard procedure for cancer of the pancreatic head, along with its derivative, the pylorus-preserving resection. Although each successive type of operation was developed and refined in order to produce a better outcome, studies have shown that, in general, none seem to produce significantly improved results in terms of survival, mortality and resection rates compared to the standard Whipple’s and pylorus-preserving duodenopancreatectomies. Despite the progress in the surgical treatment of pancreatic cancer, the overall prognosis following resection remains unsatisfactory. Surgery will most probably remain the primary option for the cure of pancreatic cancer. However, one hopes that progress in alternative therapies resulting from both clinical and basic research will improve the prognosis of this malignancy in the future.

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24.

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29. 30. 31.

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