**4. Therapeutic approaches for pancreato-biliary cancers**

Patients with suspected or confirmed diagnosis of pancreato-biliary malignancy should be assessed by a multidisciplinary team and stratified as resectable, borderline resectable,

Pancreato-Biliary Cancers – Diagnosis and Management 467

Surgical resection remains the only possibility of cure for pancreato-biliary cancers as chemotherapy and radiotherapy offering only a modest survival benefit. Patients who undergo complete surgical resection for localized, non-metastatic adenocarcinoma of the pancreas have a 5-year survival rate of approximately 20 to 25%, and a median survival of 22 months (Cameron et al., 2006). Unfortunately less than 20% of patients with pancreatic cancer have disease amendable to surgical resection at the time of presentation (Yeo et al., 1997) because patients often present at an advanced stage with widespread metastatic or locally advanced disease. The type of resection depends on the location of the tumours with Whipple's procedures are most commonly performed as most cancers locate in the head of

Similarly, the type and extend of resection for cholangiocarcinoma depends on the location of the tumour. The indication and type of resection of intra-hepatic cholangiocarcinoma is similar to those of liver cancers. In contrast, curative surgery for extra-hepatic cholangiocarcinoma is rare and is only possible for distal ductal tumours (Witzigmann et al., 2008; Lang et al., 2009). Hilar tumours involving the bifurcation are usually contraindicated for surgery and have very poor prognosis. Even in patients whose resection is considered successful, the overall five-year survival rate in the range of 25–30% (Lang et al., 2009).

Given the high loco-regional recurrence rate and a tendency towards early liver metastasis after pancreatic resection, adjuvant chemotherapy has been employed though its benefits remain controversial with mixed results until recently (Brennan, 2004; Zuckerman and Ryan, 2008). Of the six randomized controlled trials that examined the effects of adjuvant chemotherapy after pancreatic resection (Kalser and Ellenberg, 1985; Moertel et al., 1994; Neoptolemos et al., 2001; Neoptolemos et al., 2004; Oettle et al., 2007; Regine et al., 2008), only two trials were able to demonstrate a survival benefit of adjuvant chemotherapy (Neoptolemos et al., 2001; Neoptolemos et al., 2004). In the ESPAC-1 study, the survival of patients treated with adjuvant 5-Fluorouracil (5-FU) was significantly longer than that without adjuvant chemotherapy (20.1 months vs 15.5 months) (Neoptolemos et al., 2001; Neoptolemos et al., 2004). Subsequent meta-analysis supports the results of ESPAC-1 trial and indicated that 5-FU reduced the risk of death by 25% (Stocken et al., 2005). More recently, German investigators (Oettle et al., 2007) have demonstrated a disease-free survival advantage of patients who received gemcitabine adjuvant chemotherapy (13.4 months vs 6.9 months), but not the overall survival (22.1 months vs 20.2 months). Given the encouraging data from these trials (Neoptolemos et al., 2001; Neoptolemos et al., 2004; Oettle et al., 2007), adjuvant chemotherapy with either 5- FU or gemcitabine or both is increasingly used in patients with resected pancreatic cancer (Fogelman et al., 2004; Goldstein et al., 2004). Compared with 5-FU, gemcitabine is better tolerated with lesser incidence of grade 3 and 4 haematological toxicity (Oettle et al., 2007;

Similarly, in order to convert borderline resectable to resectable tumors or to increase the probability of complete microscopic tumor resection, neo-adjuvant chemo-radiotherapy has also been evaluated (Gillen et al., 2010; Heinrich et al., 2010; van Tienhoven et al., 2011;

**4.1 Surgery** 

pancreas.

**4.2 Chemo-radiotherapy** 

Palmer et al., 2007).

Fig. 3. Cholangioscopic images from SpyScope for investigation of suspected biliary strictures. A case of a hepatoma causing a polypoid protrusion into the right hepatic duct at the hilum, mimicking a cholangiocarcinoma on cholangiography (panel A). A case of cholangiocarcinoma in the upper common bile duct (CBD) stricture, confirmed on SpyGlass guided biopsy (panel B). A case of mid-CBD stricture in a patient with primary sclerosing cholangitis, which appeared benign on SpyScope and was confirmed on biopsy (panel C).

locally advanced unresectable or metastatic disease. Treatment should be planned according to local expertise and established guidelines, as resectable and borderline patients should be referred to surgeons, unresectable and metastatic patients should be referred to medical and radiation oncologists and palliative care teams. Endoscopic interventions to alleviate biliary or duodenal obstruction are also important in improving the performance status and quality of life in these patients. A multidisciplinary approach to pancreato-biliary malignancy is necessary to improve the overall outcome of these patients, especially for borderline resectable or unresectable disease as neo-adjuvant chemo-radiation therapy may play a role in down-staging and the conversion to potentially resectable, and in some case "curable", disease (Verslype et al., 2007; Chang et al., 2008). The therapeutic approach for pancreatic cancers is summarized in Figure 1.

#### **4.1 Surgery**

466 New Advances in the Basic and Clinical Gastroenterology

Fig. 3. Cholangioscopic images from SpyScope for investigation of suspected biliary

cancers is summarized in Figure 1.

strictures. A case of a hepatoma causing a polypoid protrusion into the right hepatic duct at the hilum, mimicking a cholangiocarcinoma on cholangiography (panel A). A case of cholangiocarcinoma in the upper common bile duct (CBD) stricture, confirmed on SpyGlass guided biopsy (panel B). A case of mid-CBD stricture in a patient with primary sclerosing cholangitis, which appeared benign on SpyScope and was confirmed on biopsy (panel C).

locally advanced unresectable or metastatic disease. Treatment should be planned according to local expertise and established guidelines, as resectable and borderline patients should be referred to surgeons, unresectable and metastatic patients should be referred to medical and radiation oncologists and palliative care teams. Endoscopic interventions to alleviate biliary or duodenal obstruction are also important in improving the performance status and quality of life in these patients. A multidisciplinary approach to pancreato-biliary malignancy is necessary to improve the overall outcome of these patients, especially for borderline resectable or unresectable disease as neo-adjuvant chemo-radiation therapy may play a role in down-staging and the conversion to potentially resectable, and in some case "curable", disease (Verslype et al., 2007; Chang et al., 2008). The therapeutic approach for pancreatic Surgical resection remains the only possibility of cure for pancreato-biliary cancers as chemotherapy and radiotherapy offering only a modest survival benefit. Patients who undergo complete surgical resection for localized, non-metastatic adenocarcinoma of the pancreas have a 5-year survival rate of approximately 20 to 25%, and a median survival of 22 months (Cameron et al., 2006). Unfortunately less than 20% of patients with pancreatic cancer have disease amendable to surgical resection at the time of presentation (Yeo et al., 1997) because patients often present at an advanced stage with widespread metastatic or locally advanced disease. The type of resection depends on the location of the tumours with Whipple's procedures are most commonly performed as most cancers locate in the head of pancreas.

Similarly, the type and extend of resection for cholangiocarcinoma depends on the location of the tumour. The indication and type of resection of intra-hepatic cholangiocarcinoma is similar to those of liver cancers. In contrast, curative surgery for extra-hepatic cholangiocarcinoma is rare and is only possible for distal ductal tumours (Witzigmann et al., 2008; Lang et al., 2009). Hilar tumours involving the bifurcation are usually contraindicated for surgery and have very poor prognosis. Even in patients whose resection is considered successful, the overall five-year survival rate in the range of 25–30% (Lang et al., 2009).

#### **4.2 Chemo-radiotherapy**

Given the high loco-regional recurrence rate and a tendency towards early liver metastasis after pancreatic resection, adjuvant chemotherapy has been employed though its benefits remain controversial with mixed results until recently (Brennan, 2004; Zuckerman and Ryan, 2008). Of the six randomized controlled trials that examined the effects of adjuvant chemotherapy after pancreatic resection (Kalser and Ellenberg, 1985; Moertel et al., 1994; Neoptolemos et al., 2001; Neoptolemos et al., 2004; Oettle et al., 2007; Regine et al., 2008), only two trials were able to demonstrate a survival benefit of adjuvant chemotherapy (Neoptolemos et al., 2001; Neoptolemos et al., 2004). In the ESPAC-1 study, the survival of patients treated with adjuvant 5-Fluorouracil (5-FU) was significantly longer than that without adjuvant chemotherapy (20.1 months vs 15.5 months) (Neoptolemos et al., 2001; Neoptolemos et al., 2004). Subsequent meta-analysis supports the results of ESPAC-1 trial and indicated that 5-FU reduced the risk of death by 25% (Stocken et al., 2005). More recently, German investigators (Oettle et al., 2007) have demonstrated a disease-free survival advantage of patients who received gemcitabine adjuvant chemotherapy (13.4 months vs 6.9 months), but not the overall survival (22.1 months vs 20.2 months). Given the encouraging data from these trials (Neoptolemos et al., 2001; Neoptolemos et al., 2004; Oettle et al., 2007), adjuvant chemotherapy with either 5- FU or gemcitabine or both is increasingly used in patients with resected pancreatic cancer (Fogelman et al., 2004; Goldstein et al., 2004). Compared with 5-FU, gemcitabine is better tolerated with lesser incidence of grade 3 and 4 haematological toxicity (Oettle et al., 2007; Palmer et al., 2007).

Similarly, in order to convert borderline resectable to resectable tumors or to increase the probability of complete microscopic tumor resection, neo-adjuvant chemo-radiotherapy has also been evaluated (Gillen et al., 2010; Heinrich et al., 2010; van Tienhoven et al., 2011;

Pancreato-Biliary Cancers – Diagnosis and Management 469

Fig. 4. Examples of biliary obstruction from pancreatic cancer requiring biliary drainage

guidance, to pass a guide wire into the duodenum, which then allows successful canulation of the biliar tree via ERCP and stenting (Shami and Kahaleh, 2007). In cases of duodenal obstruction, direct biliary drainage from a dilated intrahepatic duct into the stomach or duodenum via a SEM is an effective alternative for palliation with reasonable safety profile (Iwamuro et al., 2010; Nguyen-Tang et al. 2010). Surgical biliary bypass is only considered for patients who have relatively preserved functional status with obstructive jaundice and

Although gastric bypass is commonly performed for unresectable patients with gastroduodenal obstruction, the introduction of self-expanding metallic duodenal stents has changed the options for palliation (Figure 5). Current data suggest that placement of selfexpandable metallic duodenal stents for malignant gastric outlet obstruction is successful in 98% of cases with a median duration of patency of 10 months (van Hooft et al., 2009). Serious complications from duodenal stenting, such as gastrointestinal bleeding or perforation, are rare with long-term stent dysfunction occurs in 14% of patients and migration in only 2% (van Hooft et al., 2009). Compared with palliative surgery, stent placement provides a shorter hospital stay, earlier resumption of oral intake, fewer complications and lower hospital costs (Maetani et al., 2004; Maetani et al., 2005). Currently, surgical palliation is often reserved for patients who are expected have a long life-

using plastic biliary stent (panel A) and SEM biliary stent (panel B).

have failed on endoscopic stent placement.

**5.2 Alleviation of gastro-duodenal obstruction** 

expectancy and need both biliary and gastric bypass.

Vinciguerra 2011). A recent systematic review evaluating retrospective and prospective studies on neo-adjuvant chemo-radiotherapy from 1966 to 2009 included a total of 111 studies and 4,394 patients suggests that up to one third of patients with previously borderline resectable cancers are eligible for resection after neoadjuvant treatment (Gillen et al. 2010). More importantly, these patients were found to have comparable median survival as those who undergoing resection followed by adjuvant therapy (20.1 vs. 23.6 months, respectively). In contrast, neoadjuvant therapy did not seem to improve overall outcome for patients with resectable cancer at presentation (Gillen et al. 2010).

In contrast to pancreatic cancer, cholangiocarcinoma has been shown to be resistant to common chemotherapy (Anderson and Kim, 2009). Numerous drugs have been tested alone and in combination, and thus far, the response rate has been unacceptably low. Although gemcitabine chemotherapy is often given to patients with unresectable cholangiocarcinoma, the survival benefit has not been proven in a randomised controlled trial (Gruenberger et al. 2010).
