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Pancreatic Cancer
CHAPTER 41
PANCREATIC CANCER Martin D. McCarter, MD, FACS
1. What is the magnitude of the problem? For the year 2016, there were an estimated 53,000 new cases of pancreatic cancer in the United States, and more than 41,790 deaths, making this arguably one of the most lethal tumors. It is now the third most common cause of cancer death in the United States for both men and women, with an annual incidence of approximately 12.3 cases/100,000. 2. What are the histologic types of pancreatic cancer? Adenocarcinoma is far and away the most common (and lethal) type. Neuroendocrine tumors, making up approximately 1%–5% of cases, generally have a more indolent course. Other rare tumor types such as sarcoma, lymphoma, pseudopapillary, and intraductal papillary mucinous (IPMN) tumor can occur as well. 3. What are the presenting signs of pancreatic cancer? • Painless jaundice: 40% of patients • Pain (epigastric, right upper quadrant, back) with jaundice: 40% • Metastatic disease (e.g., hepatomegaly, ascites, lung nodules) with or without jaundice: 20% Most patients also have other nonspecific gastrointestinal symptoms such as bloating, food intolerance, or pancreatic insufficiency, and weight loss. 4. What is the estimated survival for pancreatic cancer patients? Overall 5-year survival for those undergoing a complete resection ranges from 5% to 25%. Stage
At Diagnosis
Estimated Median Survival
Resectable Locally Advanced Metastatic
10%–20% 40%–45% 40%–45%
18–24 months 9–12 months 6–9 months
5. Why is there such a high rate of advanced disease at diagnosis? The pancreas is retroperitoneal, relatively insensate, and symptoms of disease do not manifest themselves until local obstruction of duodenum, pancreatic, or biliary duct forms. About 80% arise in the head of the gland, 10% arise in the body, and 10% in the tail. 6. What is IPMN? IPMN is a type of neoplasm, or precancerous tissue that grows within the pancreas ducts and is characterized by the production of a thick mucinous fluid. IPMNs are classified as main duct, side branch, or a mixed type based on their radiographic appearance. IPMNs are analogous to adenomatous colon polyps in that they have malignant potential, but not all IPMNs will transform into an invasive cancer. 7. What are the indications to operate on IPMNs? The concern for a current occult malignancy or the risk of developing a malignancy drives much of the decision making around when to operate. In general, the indications to operate on IPMNs are for those that are symptomatic (i.e., causing pancreatitis or digestive problems from pancreatic insufficiency), those that involve the main pancreatic duct with >10 mm dilation (higher risk), those associated with mural nodules or high-grade dysplasia, side branch IPMNs associated with cysts >3 cm, or those that rapidly change under surveillance. 8. What is the significance of a “double-duct” sign? This refers to the presence of a dilated pancreatic and biliary ductal system identified on computed tomography (CT) scan or endoscopic retrograde cholangiopancreatography (ERCP). In the absence of a biliary stone, this nearly always implies the presence of an underlying cancer as the etiology.
185
186 ABDOMINAL SURGERY 9. What in the world is CA 19-9? CA 19-9 stands for carbohydrate antigen 19-9. It is a tumor marker associated with pancreatic and biliary tumors, which is measured in the patient’s serum. It is nonspecific (may be elevated in inflammation and other benign conditions), but may be helpful in monitoring a patient’s progress/response to therapy. Its sensitivity and specificity can be limited by certain conditions. For example, the blood test for CA 19-9 is dependent on the Lewis blood group antigen phenotype and is not detectable in patients with Lewis AB- phenotype (approximately 5%–10% of the population). In addition, inflammatory conditions and biliary obstruction cause artificial elevation and therefore limit its usefulness under these conditions. 10. What do you do when the ultrasound (US), ERCP, and CT scan show dilated extrahepatic bile ducts, a mass in the head of the pancreas, and no obvious cause other than cancer? The tumor seems separate from the portal vein and mesenteric arteries, and there are no liver metastases. What should be done next? Make an assessment of operative risk. If the patient is a poor operative risk, one should consider percutaneous or endoscopic US-guided fine-needle aspiration (FNA) to document cancer, if possible, and endoscopic stenting of the bile duct; surgery probably is not a good option. If the patient is a good operative risk, the next step is surgery. The clinical picture is accurate in at least 90% of cases, and FNA adds no useful information at this time. If no malignant tissue is obtained, surgery is still indicated to relieve the jaundice and because a negative biopsy does not rule out a cancer. 11. We are in the operating room, the abdomen is open, and the discussion revolves around taking out the tumor. What is a Whipple procedure? Pancreaticoduodenectomy involves the removal of the gallbladder, distal common duct, duodenum, gastric antrum, and the portion of pancreas to the right of the portal vein; in essence, a proximal pancreatectomy. 12. What is distal pancreatectomy? A total pancreatectomy? Distal pancreatectomy removes the portion of gland to the left of the portal vein, along with the spleen. Total pancreatectomy combines both procedures, again, with antrectomy in some centers. 13. Why remove the gallbladder, duodenum, and stomach if the problem is in the pancreas? After the ampulla of Vater is removed, the gallbladder does not function well and forms gallstones. The second and third portions of the duodenum share a blood supply with the head of the pancreas and are usually devascularized when the head is removed. Historically, the gastric antrum was removed to improve resection margins. Removing the antrum adds little to the scope of the operation, however, and marginal ulceration can be prevented by placing the gastrojejunostomy downstream from where bile and pancreatic secretions enter the gut. Thus, many surgeons choose to perform a pylorus-preserving Whipple procedure when feasible. 14. How does one determine whether to perform a Whipple procedure, distal pancreatectomy, or total pancreatectomy? What is the cure rate? Whipple procedures are used for mobile tumors in the head of the pancreas and periampullary region. Distal pancreatectomy is used for lesions of the body and tail unaccompanied by signs of spread. Total pancreatectomy is generally reserved for a few rare situations in which a diffuse cancer involves most of the gland but nowhere else. Median survival with each procedure is about 18–24 months, and 5-year survival is about 5%–25%. This procedure has about 1%–3% operative mortality and 25%–40% morbidity in centers with extensive experience; in other settings, the operative risk and complication rate can be much higher. 15. What should be done if there is tumor extension or nodal metastases along the aorta or root of mesentery? The patient cannot be cured with surgery, so the goal is palliation. If obstructive jaundice is present, a biliary-enteric bypass or endoscopic stenting should be performed. If a tumor obstructs the duodenum, a gastroenterostomy should also be carried out. Some surgeons believe gastroenterostomy
Pancreatic Cancer 187 should be done routinely for cancers of the pancreatic head, regardless of whether duodenal compromise is present because up to 20% of patients without this problem at the time of surgery may require intervention for poor gastric emptying in the future. 16. What are other signs of inoperability? General contraindications to resection include metastatic disease, invasion of the inferior vena cava, or major local arteries (celiac axis, hepatic artery, superior mesenteric artery). Relative contraindications to resection include invasion of the portal or superior mesenteric vein. Resection of the portal vein and reconstruction can be done with less morbidity than in the past, but it is debatable whether this technical exercise has led to improved survival or just better patient selection. 17. What is a borderline resectable pancreatic cancer? Borderline resectable pancreas cancer refers to a locally advanced tumor (not overtly metastatic) that abuts or involves a short segment of the portal vein, superior mesenteric vein, or, in some cases, abuts the hepatic artery or superior mesenteric artery. The evolving concept is to assess the tumor biology by treating these patients with some combination of chemotherapy, then reassess for response, and then treat with local radiation therapy and reassess with imaging again. If the disease has not progressed and no new lesions are found, some patients seem to benefit from an aggressive operative approach with planned vascular reconstruction. 18. A patient is found to have unsuspected spread to the celiac axis. You carry out a biliary and gastric bypass. What other palliative options can you consider? Some of these patients, if suffering from preoperative back pain, can be relieved of this by intraoperative alcohol celiac ganglion block. Alternatively, such treatment can be carried out postoperatively by gastroenterology or interventional radiology. Palliative chemotherapy and radiation therapy can also provide pain relief. 19. Are there any other treatments (chemotherapy, radiation therapy, pet therapy) that improve outcomes in resected pancreatic cancer? Marginally. This is not as a result of a lack of interest or effort. There is some evidence that chemotherapy (gemcitabine) or a combination of chemotherapy and radiation therapy may add a few months to overall survival following resection. The vast majority of prospective adjuvant trials have failed to make a significant difference in overall survival, though retrospective studies suggest some benefit. Here is a genuine opportunity for bright students such as the present reader to make a difference! 20. With high morbidity and low cure rates, why are surgeons so eager to do Whipple procedures? Resection represents the only chance for cure. In addition, pancreatic resection—when carried out safely—probably offers the best long-term palliation in those destined to die of their disease. Finally, future advances in adjuvant therapy may provide hope for improvement in overall survival.
K EY POIN T S: D IAGN OS T I C W O R K -UP O F A PAT I E N T WIT H J AU NDICE 1. Liver function tests: Determine degree of jaundice (obstructive versus nonobstructive) and hepatic dysfunction. 2. US of right upper quadrant: Rules out gallstones, evaluates intrahepatic versus extrahepatic ductal dilatation. 3. If hepatic ducts are dilated: ERCP or percutaneous transhepatic cholangiography to delineate site of mechanical obstruction. 4. CT: Evaluates size of tumor if present, degree of regional spread, or liver metastases.
WEB SIT E S • www.nccn.org • www.cancer.org
188 ABDOMINAL SURGERY Bibliography 1. Christians KK, Heimler JW, George B, et al. Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. Surgery. 2016;159(3):893–900. 2. Tanaka M. International consensus on the management of intraductal papillary mucinous neoplasm of the pancreas. Ann Transl Med. 2015;3(19):286. 3. Helmink BA, Snyder RA. Advances in the surgical management of resectable and borderline resectable pancreas cancer. Surg Oncol Clin N Am. 2016;25(2):287–310. 4. Giuliani J, Bonetti A. The role of palliative surgery in the management of advanced pancreatic cancer in patients with biliary and duodenal obstruction. Eur J Surg Oncol. 2016;42(4):581–583. 5. Tsuchikawa T, Hirano S. Concomitant major vessel resection in pancreatic adenocarcinoma. Postgrad Med. 2015;127(3):273–276. 6. Hüttner FJ, Fitzmaurice C, Schwarzer G, et al. Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma. Cochrane Database Syst Rev. 2016;16:2. 7. Sinha R, Gardner T. Double-duct sign in the clinical context. Pancreas. 2015;44(6):967–970. 8. Verbesey JE, Munson JL. Pancreatic cystic neoplasms. Surg Clin North Am. 2010;90(2):411–425. 9. Wargo JA, Warshaw AL. Surgical approach to pancreatic exocrine neoplasms. Minerva Chir. 2005;60(6):445–468. 10. Roeder F. Neoadjuvant radiotherapeutic strategies in pancreatic cancer. World J Gastrointest Oncol. 2016;8(2):186–197.
PANCREATIC CANCER Martin D. McCarter, MD, FACS
1. What is the magnitude of the problem? For the year 2016, there were an estimated 53,000 new cases of pancreatic cancer in the United States, and more than 41,790 deaths, making this arguably one of the most lethal tumors. It is now the third most common cause of cancer death in the United States for both men and women, with an annual incidence of approximately 12.3 cases/100,000. 2. What are the histologic types of pancreatic cancer? Adenocarcinoma is far and away the most common (and lethal) type. Neuroendocrine tumors, making up approximately 1%–5% of cases, generally have a more indolent course. Other rare tumor types such as sarcoma, lymphoma, pseudopapillary, and intraductal papillary mucinous (IPMN) tumor can occur as well. 3. What are the presenting signs of pancreatic cancer? • Painless jaundice: 40% of patients • Pain (epigastric, right upper quadrant, back) with jaundice: 40% • Metastatic disease (e.g., hepatomegaly, ascites, lung nodules) with or without jaundice: 20% Most patients also have other nonspecific gastrointestinal symptoms such as bloating, food intolerance, or pancreatic insufficiency, and weight loss. 4. What is the estimated survival for pancreatic cancer patients? Overall 5-year survival for those undergoing a complete resection ranges from 5% to 25%. Stage
At Diagnosis
Estimated Median Survival
Resectable Locally Advanced Metastatic
10%–20% 40%–45% 40%–45%
18–24 months 9–12 months 6–9 months
5. Why is there such a high rate of advanced disease at diagnosis? The pancreas is retroperitoneal, relatively insensate, and symptoms of disease do not manifest themselves until local obstruction of duodenum, pancreatic, or biliary duct forms. About 80% arise in the head of the gland, 10% arise in the body, and 10% in the tail. 6. What is IPMN? IPMN is a type of neoplasm, or precancerous tissue that grows within the pancreas ducts and is characterized by the production of a thick mucinous fluid. IPMNs are classified as main duct, side branch, or a mixed type based on their radiographic appearance. IPMNs are analogous to adenomatous colon polyps in that they have malignant potential, but not all IPMNs will transform into an invasive cancer. 7. What are the indications to operate on IPMNs? The concern for a current occult malignancy or the risk of developing a malignancy drives much of the decision making around when to operate. In general, the indications to operate on IPMNs are for those that are symptomatic (i.e., causing pancreatitis or digestive problems from pancreatic insufficiency), those that involve the main pancreatic duct with >10 mm dilation (higher risk), those associated with mural nodules or high-grade dysplasia, side branch IPMNs associated with cysts >3 cm, or those that rapidly change under surveillance. 8. What is the significance of a “double-duct” sign? This refers to the presence of a dilated pancreatic and biliary ductal system identified on computed tomography (CT) scan or endoscopic retrograde cholangiopancreatography (ERCP). In the absence of a biliary stone, this nearly always implies the presence of an underlying cancer as the etiology.
185
186 ABDOMINAL SURGERY 9. What in the world is CA 19-9? CA 19-9 stands for carbohydrate antigen 19-9. It is a tumor marker associated with pancreatic and biliary tumors, which is measured in the patient’s serum. It is nonspecific (may be elevated in inflammation and other benign conditions), but may be helpful in monitoring a patient’s progress/response to therapy. Its sensitivity and specificity can be limited by certain conditions. For example, the blood test for CA 19-9 is dependent on the Lewis blood group antigen phenotype and is not detectable in patients with Lewis AB- phenotype (approximately 5%–10% of the population). In addition, inflammatory conditions and biliary obstruction cause artificial elevation and therefore limit its usefulness under these conditions. 10. What do you do when the ultrasound (US), ERCP, and CT scan show dilated extrahepatic bile ducts, a mass in the head of the pancreas, and no obvious cause other than cancer? The tumor seems separate from the portal vein and mesenteric arteries, and there are no liver metastases. What should be done next? Make an assessment of operative risk. If the patient is a poor operative risk, one should consider percutaneous or endoscopic US-guided fine-needle aspiration (FNA) to document cancer, if possible, and endoscopic stenting of the bile duct; surgery probably is not a good option. If the patient is a good operative risk, the next step is surgery. The clinical picture is accurate in at least 90% of cases, and FNA adds no useful information at this time. If no malignant tissue is obtained, surgery is still indicated to relieve the jaundice and because a negative biopsy does not rule out a cancer. 11. We are in the operating room, the abdomen is open, and the discussion revolves around taking out the tumor. What is a Whipple procedure? Pancreaticoduodenectomy involves the removal of the gallbladder, distal common duct, duodenum, gastric antrum, and the portion of pancreas to the right of the portal vein; in essence, a proximal pancreatectomy. 12. What is distal pancreatectomy? A total pancreatectomy? Distal pancreatectomy removes the portion of gland to the left of the portal vein, along with the spleen. Total pancreatectomy combines both procedures, again, with antrectomy in some centers. 13. Why remove the gallbladder, duodenum, and stomach if the problem is in the pancreas? After the ampulla of Vater is removed, the gallbladder does not function well and forms gallstones. The second and third portions of the duodenum share a blood supply with the head of the pancreas and are usually devascularized when the head is removed. Historically, the gastric antrum was removed to improve resection margins. Removing the antrum adds little to the scope of the operation, however, and marginal ulceration can be prevented by placing the gastrojejunostomy downstream from where bile and pancreatic secretions enter the gut. Thus, many surgeons choose to perform a pylorus-preserving Whipple procedure when feasible. 14. How does one determine whether to perform a Whipple procedure, distal pancreatectomy, or total pancreatectomy? What is the cure rate? Whipple procedures are used for mobile tumors in the head of the pancreas and periampullary region. Distal pancreatectomy is used for lesions of the body and tail unaccompanied by signs of spread. Total pancreatectomy is generally reserved for a few rare situations in which a diffuse cancer involves most of the gland but nowhere else. Median survival with each procedure is about 18–24 months, and 5-year survival is about 5%–25%. This procedure has about 1%–3% operative mortality and 25%–40% morbidity in centers with extensive experience; in other settings, the operative risk and complication rate can be much higher. 15. What should be done if there is tumor extension or nodal metastases along the aorta or root of mesentery? The patient cannot be cured with surgery, so the goal is palliation. If obstructive jaundice is present, a biliary-enteric bypass or endoscopic stenting should be performed. If a tumor obstructs the duodenum, a gastroenterostomy should also be carried out. Some surgeons believe gastroenterostomy
Pancreatic Cancer 187 should be done routinely for cancers of the pancreatic head, regardless of whether duodenal compromise is present because up to 20% of patients without this problem at the time of surgery may require intervention for poor gastric emptying in the future. 16. What are other signs of inoperability? General contraindications to resection include metastatic disease, invasion of the inferior vena cava, or major local arteries (celiac axis, hepatic artery, superior mesenteric artery). Relative contraindications to resection include invasion of the portal or superior mesenteric vein. Resection of the portal vein and reconstruction can be done with less morbidity than in the past, but it is debatable whether this technical exercise has led to improved survival or just better patient selection. 17. What is a borderline resectable pancreatic cancer? Borderline resectable pancreas cancer refers to a locally advanced tumor (not overtly metastatic) that abuts or involves a short segment of the portal vein, superior mesenteric vein, or, in some cases, abuts the hepatic artery or superior mesenteric artery. The evolving concept is to assess the tumor biology by treating these patients with some combination of chemotherapy, then reassess for response, and then treat with local radiation therapy and reassess with imaging again. If the disease has not progressed and no new lesions are found, some patients seem to benefit from an aggressive operative approach with planned vascular reconstruction. 18. A patient is found to have unsuspected spread to the celiac axis. You carry out a biliary and gastric bypass. What other palliative options can you consider? Some of these patients, if suffering from preoperative back pain, can be relieved of this by intraoperative alcohol celiac ganglion block. Alternatively, such treatment can be carried out postoperatively by gastroenterology or interventional radiology. Palliative chemotherapy and radiation therapy can also provide pain relief. 19. Are there any other treatments (chemotherapy, radiation therapy, pet therapy) that improve outcomes in resected pancreatic cancer? Marginally. This is not as a result of a lack of interest or effort. There is some evidence that chemotherapy (gemcitabine) or a combination of chemotherapy and radiation therapy may add a few months to overall survival following resection. The vast majority of prospective adjuvant trials have failed to make a significant difference in overall survival, though retrospective studies suggest some benefit. Here is a genuine opportunity for bright students such as the present reader to make a difference! 20. With high morbidity and low cure rates, why are surgeons so eager to do Whipple procedures? Resection represents the only chance for cure. In addition, pancreatic resection—when carried out safely—probably offers the best long-term palliation in those destined to die of their disease. Finally, future advances in adjuvant therapy may provide hope for improvement in overall survival.
K EY POIN T S: D IAGN OS T I C W O R K -UP O F A PAT I E N T WIT H J AU NDICE 1. Liver function tests: Determine degree of jaundice (obstructive versus nonobstructive) and hepatic dysfunction. 2. US of right upper quadrant: Rules out gallstones, evaluates intrahepatic versus extrahepatic ductal dilatation. 3. If hepatic ducts are dilated: ERCP or percutaneous transhepatic cholangiography to delineate site of mechanical obstruction. 4. CT: Evaluates size of tumor if present, degree of regional spread, or liver metastases.
WEB SIT E S • www.nccn.org • www.cancer.org
188 ABDOMINAL SURGERY Bibliography 1. Christians KK, Heimler JW, George B, et al. Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. Surgery. 2016;159(3):893–900. 2. Tanaka M. International consensus on the management of intraductal papillary mucinous neoplasm of the pancreas. Ann Transl Med. 2015;3(19):286. 3. Helmink BA, Snyder RA. Advances in the surgical management of resectable and borderline resectable pancreas cancer. Surg Oncol Clin N Am. 2016;25(2):287–310. 4. Giuliani J, Bonetti A. The role of palliative surgery in the management of advanced pancreatic cancer in patients with biliary and duodenal obstruction. Eur J Surg Oncol. 2016;42(4):581–583. 5. Tsuchikawa T, Hirano S. Concomitant major vessel resection in pancreatic adenocarcinoma. Postgrad Med. 2015;127(3):273–276. 6. Hüttner FJ, Fitzmaurice C, Schwarzer G, et al. Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma. Cochrane Database Syst Rev. 2016;16:2. 7. Sinha R, Gardner T. Double-duct sign in the clinical context. Pancreas. 2015;44(6):967–970. 8. Verbesey JE, Munson JL. Pancreatic cystic neoplasms. Surg Clin North Am. 2010;90(2):411–425. 9. Wargo JA, Warshaw AL. Surgical approach to pancreatic exocrine neoplasms. Minerva Chir. 2005;60(6):445–468. 10. Roeder F. Neoadjuvant radiotherapeutic strategies in pancreatic cancer. World J Gastrointest Oncol. 2016;8(2):186–197.