**11. Surgical intervention for tumors of the pancreatic head**

**9. Novel diagnostic imaging modalities**

a vehicle to deliver anti-cancer therapies [75].

clinical use.

236 Updates on Cancer Treatment

**10. Treatment**

**10.1. Surgical intervention**

diagnostic imaging [77]:

Because pancreatic cancer might metastasize at an early stage, an ideal imaging modality is one that would predict the biological behavior of the tumor. Understanding the molecular aspects of pancreatic cancer has facilitated use of investigational modalities in this area. Imaging agents such as peptides that bind to specific factors on the surface of pancreatic tumors have been developed and include: plectin 1 (Plec 1), integrin αvβ6, cathepsin E and claudin-4 [70-73]. Early studies have shown promising results, but more work is needed before routine

A similar approach, but by interrogating normal tissue has also been investigated. Montet *et al.* demonstrated that as pancreatic tumors do not express receptors for bombesin, a bombesin peptide-coupled nanoparticle (BN-CLIO[Cy5.5]) can be used to image normal pancreas and hence, differentiate it from pancreatic tumors [74]. Similarly, a novel concept of microbubbles, small gas –filled microspheres, has been used in preliminary studies to image the peri-tumoral vasculature with the assistance of ultrasound. Moreover, this technology can also be used as

Surgery offers the only possibility for long term survival, however the majority (>85%) of patients with pancreatic cancer will present with unresectable or metastatic disease [76]. Removal of all disease offers the patient the only chance of long-term survival. Those who undergo surgical resection have a disappointing ~20% 5-year survival. Over the years it has become clear that the indications for surgical intervention have been substantially widened. Typically, the current criteria dictates possible resection for tumors stage I-A to II-B [77]. There are no randomized trials that assess resectability criteria to guide surgical intervention. In the absence of controlled trials, the best recommendations emanate from consensus guidelines [40, 78, 79]. It is practical to classify pancreatic tumors into one of three categories following

**i. Resectable Tumors**: These are tumors localized to the pancreas. In this case, there is

**ii. Borderline Resectable Tumors**: There is a dynamic criteria for resection of these

no evidence of SMV or portal vein involvement of any kind. A plane of dissection indicated by a fat pad between the SMA, celiac axis, and hepatic artery and the pancreas has to be identified by CT scan as well as absent involvement of the SMV and portal vein [40, 78]. These patients should proceed with surgical intervention.

tumors that continues to change based on the ability of specialized centers to perform complex arterial/venous/portal resection and reconstruction [79]. These tumors include those that have (A) Severe SMV-portal impingement (unilateral or bilateral), (B) SMA/celiac artery involvement, but less than 180°, (C) Hepatic artery involvement with the possibility of reconstruction, and (D) SMV occlusion or involvement with

Extirpation of pancreatic tumors at the head of the pancreas require pancreatic and duodenal resection as well as common bile duct re-implantation with reconstruction. The pacreatico‐ duodenectomy procedure (Figure 9) was first described in 1909 by Walter Kausch. Twenty six years later, the success with the procedure in three patients was reported at the American Surgical Association by Allen O. Whipple and Parson. The pancreaticodudenectomy proce‐ dure then became widely performed and it is commonly referred to as the Whipple procedure. Although, it's original description was a two-stage operative approach, it was rapidly modified [80]. The commonly known one-stage Whipple operation is credited to Trimble's group from John Hopkins in 1941 [81]. The drastic increase in the number of operations performed today is represented by the experience at Mass General where between 1940 and 1950, twenty pancreaticoduodenectomies were performed; while, between 2005-2011 813 were described (~125 per year) [82].

Technical considerations for standard pancreaticoduodenectomy (PD) have been reviewed extensively [83]. The proposed lines of resection are shown in (Figure 9). The general explo‐ ration of the abdomen includes careful inspection of the peritoneal surfaces and liver for metastases, which can be more accurately determined by intra-operative liver ultrasonogra‐ phy. Suspicious lymph nodes need to be submitted for frozen section histology to evaluate for metastatic disease. The presence of peritoneal implants and liver metastases render the patient incurable. Similarly, histologically proven metastases in lymph nodes accessible during the initial abdominal exploration makes the chance of cure highly remote.

Following abdominal exploration, the right colon is mobilized and retracted medially; a technique known as the Cattell-Braasch maneuver. The lesser sac is entered and posterior attachments of the stomach are divided. The superior mesenteric vein is identified by tracing the middle colic vein proximally, or after Kocherization by following the sweep of the duodenum medially. The gallbladder is mobilized and the common hepatic duct and gastro‐ duodenal arteries are divided. These maneuvers allow exposure of the anterior surface of the portal vein. The portal vein and superior mesenteric vein are carefully separated from the overlying pancreas. The stomach (or duodenum in cases of pylorus-preserving pancreatico‐ duodenectomy [PPPD]), small bowel, and pancreas are then divided sequentially. The uncinate process is liberated from its retroperitoneal attachments to complete the dissection. Gastrointestinal continuity is re-established by a pancraticojejunostomy (or pancreaticogas‐ trostomy), choledocojejunostomy, and gastrojejunostomy (or duodenojejunostomy in the case of PPPD). Anastomoses are done in sequence: pancreas, then bile duct, then stomach (or duodenum in the case of PPPD) (Figure 9).

**Figure 9.** Lines of resection of the typical pancreaticodoudenectomy. Reconstruction is performed in order from A to C.

PPPD is a modification of the standard Whipple procedure in which the entire stomach, including the pylorus, and 2 cm to 3 cm of the duodenal cuff, are preserved. This modification retains the entire stomach as a reservoir and may prevent the development of postgastrectomy syndromes, marginal ulceration, and enterogastric reflux. PPPD is touted to result in shorter operative times, less blood loss, and fewer transfusions. PPPD was first described by Dr. Warshaw in 1981 and has been the largest variation of the procedure since the one-stage approach was introduced in clinical practice [83]. However, delayed gastric emptying without much further benefit has led to a change back to the gastrojejunostomy approach in some centers, but this remains a point of controversy [84, 85].

Pancreaticojejunostomy may be performed as an end to-end "dunking" procedure, an end-toside anastomosis between pancreas and jejunum, or an end-to-side duct-to-mucosa anasto‐ mosis. A duct-to mucosa anastomosis may be performed over a stent and left in place for pancreatic ducts less than 5 mm. The primary theoretical advantage of duct-to-mucosa pancreaticojejunostomy is long-term patency. Pancreaticogastrostomy (PG) is performed in an end-to-side fashion. There is no evidence that the type of pancreatic-enteric anastomosis affects the rate of pancreatic fistula. Because pancreatic fistulas remain the most serious complication of the operation, a pancreaticogastrostomy (PG) instead of a pancreaticojejunos‐ tomy (PJ) has been performed by some surgeons. Randomized controlled trials (n=3) have not shown a difference in complications with these two approaches. However, thirteen non‐ randomized observational clinical studies have been in favor of PG [86]. Further studies are needed to clarify these findings.

The biliary and pancreatic anastomoses are drained and jejunostomy (for feeding) and gastrostomy (for decompression) tubes are placed prior to closure. Routine placement of feeding and decompression tubes is paramount in the postoperative management of patients following a pancreaticodudodenectomy.

Total pancreatectomy for pancreatic cancer is rarely performed. Total pancreatectomy had been proposed to obtain superior tumor margins and provide a more extensive lymph node dissection. In practice, total pancreatectomy is associated with increased postoperative mortality and no change in survival compared to standard pancreaticodudenectomy. Postop‐ erative diabetes is extremely difficult to manage in patients undergoing total pancreatectomy. Similarly, extensive lymph node dissection does not improve survival and leads to a higher complication rate [87].

Fifteen percent of pancreatic adenocarcinomas occur in the body and the tail of the pancreas. Because these tumors typically do not cause biliary obstruction, its diagnosis is not made until the disease is advanced and unresectable. Only 5% to 7% of individuals with adenocarcinoma of the body or the tail of the pancreas undergo resection and their survival is much worse compared to patients with adenocarcinoma of the head of the pancreas [77]. Distal pancrea‐ tectomy with splenectomy is reserved for rare instances when the tumor located in the body or the tail of the pancreas is resectable.

#### **11.1. Laparoscopic Pancreaticoduodenectomy**

attachments of the stomach are divided. The superior mesenteric vein is identified by tracing the middle colic vein proximally, or after Kocherization by following the sweep of the duodenum medially. The gallbladder is mobilized and the common hepatic duct and gastro‐ duodenal arteries are divided. These maneuvers allow exposure of the anterior surface of the portal vein. The portal vein and superior mesenteric vein are carefully separated from the overlying pancreas. The stomach (or duodenum in cases of pylorus-preserving pancreatico‐ duodenectomy [PPPD]), small bowel, and pancreas are then divided sequentially. The uncinate process is liberated from its retroperitoneal attachments to complete the dissection. Gastrointestinal continuity is re-established by a pancraticojejunostomy (or pancreaticogas‐ trostomy), choledocojejunostomy, and gastrojejunostomy (or duodenojejunostomy in the case of PPPD). Anastomoses are done in sequence: pancreas, then bile duct, then stomach (or

**Figure 9.** Lines of resection of the typical pancreaticodoudenectomy. Reconstruction is performed in order from A to C.

PPPD is a modification of the standard Whipple procedure in which the entire stomach, including the pylorus, and 2 cm to 3 cm of the duodenal cuff, are preserved. This modification retains the entire stomach as a reservoir and may prevent the development of postgastrectomy syndromes, marginal ulceration, and enterogastric reflux. PPPD is touted to result in shorter operative times, less blood loss, and fewer transfusions. PPPD was first described by Dr. Warshaw in 1981 and has been the largest variation of the procedure since the one-stage approach was introduced in clinical practice [83]. However, delayed gastric emptying without much further benefit has led to a change back to the gastrojejunostomy approach in some

Pancreaticojejunostomy may be performed as an end to-end "dunking" procedure, an end-toside anastomosis between pancreas and jejunum, or an end-to-side duct-to-mucosa anasto‐ mosis. A duct-to mucosa anastomosis may be performed over a stent and left in place for pancreatic ducts less than 5 mm. The primary theoretical advantage of duct-to-mucosa pancreaticojejunostomy is long-term patency. Pancreaticogastrostomy (PG) is performed in an end-to-side fashion. There is no evidence that the type of pancreatic-enteric anastomosis affects the rate of pancreatic fistula. Because pancreatic fistulas remain the most serious complication of the operation, a pancreaticogastrostomy (PG) instead of a pancreaticojejunos‐ tomy (PJ) has been performed by some surgeons. Randomized controlled trials (n=3) have not shown a difference in complications with these two approaches. However, thirteen non‐ randomized observational clinical studies have been in favor of PG [86]. Further studies are

duodenum in the case of PPPD) (Figure 9).

238 Updates on Cancer Treatment

centers, but this remains a point of controversy [84, 85].

needed to clarify these findings.

While the formidable Whipple remains one of the most complex abdominal operations performed today, at some centers it has become common practice where several open opera‐ tions are performed in a week at Johns Hopkins or Mass General. With the continued ad‐ vancement in laparoscopic technique and popularity of this approach to surgical intervention, there has been a rapid acceptance of more advanced laparoscopic approaches to patients with cancer. The first total laparoscopic pancreaticoduedenectomy was described by Gagner and Pomp in 1994 and constitutes one of the most advanced laparoscopic procedures today [88;89]. Between the time it was first described to 2009, 146 laparoscopic pancreaticoduodenectomies were performed worldwide. A large series has been reported by Palanivelu and colleagues which included 45 pancreaticoduodenectomies between 1998 and 2010 of which 18 were for pancreatic adenocarcinoma [90]. Another large report from the U.S. included 65 cases of laparoscopic pancreaticoduodenectomy and documented a morbidity of 42% and a mortality of 1.5% [89]. A more recent review reported 10 case series totaling 150 totally laparoscopic pancreaticoduodenectomies. In this review, mortality and morbidity have been comparable to the open approach. Operative time for this cohort has been 483 minutes and length of hospital stay 14.1 days [91]. The leading authors on these studies have concluded that the laparoscopic Whipple is feasible and safe. However, in the absence of controlled trials this approach remains experimental.

#### **11.2. Robotic pancreaticoduodenectomy**

The first pancreaticoduodenectomy was described in 1909 by Kausch. In 1935 AO Whipple described three successful cases via a two-stage approach [80]. One-stage Whipple was introduced in 1941 by Trimble [81]. No major variations occurred in technique until preser‐ vation of the pylorus was introduced by Warshaw in 1981 [85]. These changes in operative technique were not as radical as the introduction of the minimally invasive approach. The laparoscopic pancreaticoduodenectomy was introduced by Gagner and Pomp in 1994 [88]. Almost 100 years later, the first human robotic surgery was described by Himpens in 1997 [92] and the first robotic pancreaticoduodenectomy is credited to Giulianotti in 2000 [93]. While several limitations still exist, robotic surgery is the most innovative technology brought to the operating room in the last century.

A recent systematic review of the robotic approach demonstrated that up to date, 203 patients have had an intention to treat approach to a pancreaticoduodenectomy [94]. While the technical approach is wide and not clearly defined, the number of reported cases appears to be increasing over the past few years. In Cirocchi's review, the conversion rate was 14%, overall morbidity 58% and reoperation occurred in 7.3% of the cases [94]. Totally robotic technique has been reported by several surgeons [93;95-98]. While oncologic operations (R0) have been performed with similar morbidity and mortality to the open Whipple, the innovative nature of this approach makes it highly experimental and should only be undertaken in specialized centers. Similarly, cost analysis must be addressed in subsequent studies.

#### **12. Outcomes**

In the United States, there has been a substantial increase in the number of pancreaticoduo‐ denectomies performed. The average age of patients undergoing surgical intervention has also increased from 1991 to 2005. Similarly, more patients with a higher index of comorbidities underwent Whipples during this time. In spite of this, perioperative morbidity remained unchanged (53%) and 30-day mortality decreased from 6% to 3% in this cohort of patients [1].

The mortality rate in high volume centers performing pancreaticoduodenectomies is 2-4% [99]. However, perioperative morbidity remains substantially high (15% to 50%) even at high volume centers [100]. In patients undergoing resection for cure and treated with neoadjuvant chemoradiation, the 5-year survival is still disappointingly low (10% to 20%) [101-106]. In a study using the Surveillance, Epidemiology, and End Results-Medicare data inclusive of 2,461 patients investigating outcomes and use of adjuvant therapy between 1991 and 2005 in the USA, the median survival of patients treated for cure was 14 months, the 1-, 3-, and 5- year survival was 53.2%, 19.7%, and 12.6%, respectively. This study, demonstrated that the use of adjuvant chemoradiotherapy led to a 2 month increase in overall survival [1]. A study from Johns Hopkins examining temporal variation in morbid‐ ity and mortality following pancreaticoduodenectomy found a magnificent decrease in mortality to 4% (1981-1986) from 24% (1969-1980) with an accompanying decrease in morbidity from 59% to 36% during the same periods. The 5-year survival in patients with pancreatic cancer was 18% [107]. Thus, while the number of patients undergoing pancrea‐ ticoduodenectomy has increased with a variable decrease in complications, the overall mortality has not improved in most high volume centers [108].
