Surgical Treatment of Various GI Tract Cancers

Surgical Treatment of Various GI Tract Cancers By James Ouellette, DO, FACS, Surgical Oncology, Hepatobiliary Surgery Surgical treatment for most gastrointestinal (GI) cancers requires multidisciplinary interaction and thorough planning. This review focuses on primary tumors of the liver, bile duct and pancreas. Treatment of these tumors requires detailed investigation of the potential for surgical therapy. Timing and operative planning are significantly influenced by tumor location as well as the presence of regional or distant metastatic disease. In the case of hepatocellular carcinoma, which is most frequently associated with cirrhosis, additional considerations are required. Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the fifth most common malignant neoplasm in men and the ninth most common in women, accounting for 500,000 to 1 million cases annually. HCC is relatively rare in the United States, with an annual incidence of fewer than 5 cases per 100,000 persons. The incidence in the U.S. is rising, however, apparently as the result of the increasing prevalence of hepatitis B and hepatitis C infection. Clinical presentation depends on the stage of disease. In the United States, where there is no systematic screening for HCC, patients usually present at a later stage. They frequently present with upper abdominal pain or discomfort, weight loss, ascites, or other sequela of portal hypertension. Jaundice is relatively uncommon but is an ominous sign if present. Tumor rupture at presentation occurs only about 5 percent of the time. Patients with known hepatitis C infection are generally screened for hepatocellular carcinoma, and typically present at earlier stages. Unfortunately, patients with hepatitis B infection, or no evidence of hepatitis, often present with larger tumors, but may in fact have fewer changes consistent with cirrhosis. Alpha-fetoprotein is a relatively reliable tumor marker for hepatocellular carcinoma, especially with levels >400ng/ml in the face of a large or rapidly growing tumor. Despite these general correlations AFP testing is not sensitive, nor specific, for HCC. In fact, a patient with a small hepatocellular carcinoma may have minimal or no elevation in AFP, while transient increases can be seen within inflammatory hepatic disease or cirrhosis. In general, an alpha-fetoprotein >200ng/ml in association with characteristic imaging findings is nearly 100 percent sensitive for HCC and therefore does not require biopsy to decide treatment. Various imaging modalities are used to diagnose HCC and typically include: CT scanning, ultrasound and MRI. Other more invasive tests can be used as well, although less often. Surgical treatment for hepatocellular carcinoma, in general, consists of surgical resection or orthotopic liver transplantation. However, most patients are not candidates for surgical resection. In fact only 10-30 percent of patients will be eligible for surgery. The options for treatment may be significantly limited due to a patient s underlying cirrhosis. In the case of orthotopic liver transplantation, there are defined selection criteria which must be adhered to as well as the issue of a limitation of organs available for transplant. Once a tumor has been determined to be resectable, the decision must then be based on the extent of liver resection that can be performed. One must carefully evaluate the extent of any resection, which will depend on the size of the mass, the number of nodules, and the tumor s proximity to major vascular structures. Historic goals for surgical resection required a 1 cm margin for adequate therapy. Currently, based on comparative studies, a negative margin is the goal. In cases where the functional liver remnant is in question, portal vein embolization is a technique used to increase the functional liver remnant. This is done in Interventional Radiology with pre- and post-procedure volume analysis to assess the ability of liver regeneration and measure the anticipated remnant post-surgery. In patients who are being considered for liver transplantation, relatively rigid criteria have been set forth based on the study published by Mazzaferro, et al from Milan. These Milan criteria identify patients with cirrhosis who Oncology Services Annual Report 3

may be candidates for liver transplantation when hepatocellular carcinoma is present. Limitations define a patient with either a single tumor less than 5 cm or 3 tumors less than 3 cm in maximum diameter. Survival of 5 years after transplantation exceeded 60 percent with disease free survival exceeding 50 percent. These criteria have been adopted at most centers in the United States. For patients found to be unresectable, there are alternative therapies available that are used routinely. At our institution we rely on liver-directed trans-arterial chemoembolization and radioembolization. These techniques allow regional treatment within the lobar divisions of the liver in hopes of delivering therapy to the tumor involved regions. This procedure has the ability to be repeated should it be found to be effective and treatment is required again in the future. Ablative therapies are the other mechanism by which unresectable tumors can be approached. Typical treatment uses radiofrequency ablation which uses heat to destroy tumors. A high frequency-altering current is generated which induces frictional heat and eventually coagulative necrosis. Radiofrequency ablation is relatively versatile and can be used in multiple locations within the liver. It can also be used in multiple modes including percutaneously, laparoscopically and during open surgery. Though ablation is most effective in tumors less than 3 cm, it is frequently used in tumors up to 4 or 5 cm when necessary. It is not uncommon to use a combination of approaches for unresectable tumors. In our institution patients frequently get liver directed therapy and ablative techniques during their Analytic Gastrointestinal Cancer Cases* Miami Valley Hospital, 2000-2008 2000 2001 2002 2003 2004 2005 2006 2007 2008 Total Liver and Intrahepatic Bile Duct 5 7 7 3 3 3 5 9 12 54 Pancreas 16 21 32 27 26 26 27 24 32 231 Extrahepatic Bile Duct 0 0 2 3 0 1 2 2 0 10 Ampulla of Vater 1 1 1 3 0 0 1 3 1 11 Biliary Tract, NOS 0 1 1 0 0 0 0 1 0 3 Total 22 30 43 36 29 30 35 39 45 309 *Includes stage unknown Gastrointestinal Cancer Location and Stage at Diagnosis Miami Valley Hospital, 2000-2008 AJCC Stage Subsite 1 2 3 4 Total Liver 9 3 14 18 44 Intrahepatic Bile Duct 2 2 2 4 10 Extrahepatic Bile Duct 6 1 2 2 11 Ampulla of Vater 4 4 1 2 11 Biliary Tract, NOS 0 0 0 2 2 Pancreas, head 17 40 17 49 123 Pancreas, body 0 3 3 16 22 Pancreas, tail 1 6 1 22 30 Pancreas, duct 0 1 0 0 1 Pancreas, other specified parts 0 2 0 0 2 Pancreas, overlapping lesions 1 1 2 15 19 Pancreas, NOS 1 2 2 29 34 Total 41 65 44 159 309 4 Miami Valley Hospital

course of treatment. A further description of these interventional techniques can be found in the Radiology section of this report. Other therapies that have been used include percutaneous ethanol injection, which is relatively uncommon with the widespread availability of radiofrequency or microwave ablation. Cryotherapy is no longer used as an ablation technique for the liver because of serious complications which occurred in the past. All ablative therapies carry some risk. Complications from RFA are relatively rare, and this appears to be a safe outpatient procedure whether done percutaneously or via laparoscopy. Care must be taken to avoid heated ablation close to major biliary structures to avoid injury to the biliary tree. Cancer of the Intra- and Extrahepatic Bile Duct Cholangiocarcinoma (CCA) is an extremely rare tumor comprising only 2 percent of all the cancers in the United States. It has an equal male to female ratio, and most patients are greater than 60 years of age. People of Asian descent have almost twice the incidence of other ethnicities; this is likely because of endemic chronic parasitic infestation. The etiology of the cholangiocarcinoma is not known. Increased risk for these tumors is associated with several diseases including ulcerative colitis and sclerosing cholangitis. Other factors include choledochal cysts and thorotrast exposure. There also appears to be an increased incidence in patients with parasitic infestations or hepatolithiasis. These findings indicate chronic inflammation of the bile duct likely plays a role. Adenocarcinoma is the most common histologic type of biliary cancer and cholangiocarcinoma can be divided into papillary, nodular or sclerosing types. The most common type is sclerosing, which represents 70 percent of tumors and is also more likely to be poorly differentiated with a poor prognosis. Papillary types, less than 5 percent of cases, carry the most favorable prognosis. The most common presenting findings include obstructive jaundice, which occurs in almost 90 percent of patients with extrahepatic cholangiocarcinoma. Other associated findings include weight loss, vague abdominal pain, fatigue and nausea. Elevation in liver enzymes is typically seen along with an elevated carbohydrate antigen 19-9 and carcinoembryonic antigen which can function as tumor markers for disease. Diagnostic imaging studies are typically performed to assess the location of the lesion. The location of cholangiocarcinoma dictates whether any surgical approach would be feasible. Typically, the first test performed is an ultrasound looking for ductal dilation. Further cross-sectional imaging is then necessary and includes CT scan, MRI, MRCP, and frequently ERCP which is required to attempt to perform ductal decompression. As discussed earlier, location is the most significant concern for defining the possibility of resection. Extrahepatic bile duct tumors occur near the hilum (Klatskin tumors), in mid-duct (rare), or in the distal bile duct. The definitive therapy for all extrahepatic bile duct carcinomas is complete resection. Unfortunately the overall resectability rates range anywhere from 10-85 percent, depending on the location of the lesion. Hilar cholangiocarcinomas are the most technically challenging to resect, and contributing to this is the difficulty in preoperative imaging to determine the extent of disease in some cases. Hilar cholangiocarcinomas are defined according to the Bismuth-Corlette System which describes the common patterns as they occur in the biliary tree. Type 1 tumors approach the right and left bifurcation of the common hepatic duct. Type 2 tumors extend slightly to involve the proximal portion of both right and left ducts. Type 3a lesions extend into the right bile duct, whereas 3b tumors extend into the left bile duct. Lesions that extend up and into both right and left biliary trees are unresectable without liver transplantation. Vascular involvement of the hepatic artery and portal vein also need to be considered when assessing these tumors. Frequently vascular resection is required with reconstruction in order to allow margin negative resection. Because of the need for extended hepatic resections in these cases, assessment of the functional liver remnant is important. These assessments are made in similar fashion to those for hepatocellular carcinoma with similar imaging techniques. Distal cholangiocarcinomas are treated typically with surgical resection, Oncology Services Annual Report 5

which includes pancreatoduodenectomy for definitive therapy. This is performed similar to surgery for pancreatic adenocarcinoma. Cancer of the Pancreas Cancer of the pancreas is a rare disease with around 44,000 new patients diagnosed with this disease each year in the United States. This roughly translates to 3 percent of all new cancer diagnoses per year. Unfortunately pancreatic cancer is the fourth leading cause of cancerrelated death in the United States among both men and women. The majority of these tumors (85 percent) are adenocarcinomas arising from the ductal epithelium. The disease is rare before the age of 45, but the incidence rises sharply thereafter. There are two main types of pancreatic cancer. Most often pancreatic cancer starts in the ducts that carry pancreatic juices. This type is called exocrine pancreatic cancer. In this report, we will discuss this type of pancreatic cancer. Much less often, pancreatic cancer begins in the cells that make hormones. This type may be called endocrine pancreatic cancer or islet cell cancer. This report does not cover information regarding that kind of cancer. Pancreatic adenocarcinoma arises from cells forming ducts. Roughly 70 percent of these ductal cancers arise in the head of the pancreas. They appear as hard, irregular, gritty masses that are yellow-gray and are usually poorly demarcated. At the time of diagnosis, they are usually larger than 3 cm in diameter, and both nodal and distant metastases are also frequently present. Those originating in the body or tail of the pancreas are often larger and more likely to have spread before their presence is discovered. Pancreatic cancers are insidious tumors that can be present for long periods and grow extensively before they produce symptoms. The symptoms, once they develop, are determined by the location of the tumor in the pancreas. Those in the head of the pancreas can cause bile duct, duodenal, or pancreatic duct obstruction. Symptoms include unexplained episodes of pancreatitis, painless jaundice, nausea, vomiting, steatorrhea (fatty, floating, runny, foul-smelling stool) and unexplained weight loss. With further spread beyond the pancreas, patients may note upper abdominal or back pain when peripancreatic nerve plexuses are involved and ascites when peritoneal carcinomatosis or portal vein occlusion develops. Patients with tumors arising in the neck, body, or tail of the pancreas usually do not develop jaundice or gastric outlet obstruction. Their symptoms may be limited to unexplained weight loss and vague upper abdominal pain until the tumor has grown extensively and spread beyond the pancreas. New-onset diabetes mellitus is occasionally the first symptom of an otherwise occult pancreatic cancer. Recent studies have suggested that this form of diabetes may be mediated by a factor released from the tumor that either inhibits insulin release from islets or induces peripheral insulin resistance. The physical findings in patients with pancreatic cancer are also dependent on the location, size, and extent of the tumor. Liver nodules indicative of metastases can sometimes be felt. Metastatic subumbilical ( Sister Mary Joseph node ) and pelvic peritoneal ( Blumer s shelf ) deposits, as well as left supraclavicular lymphadenopathy ( Virchow s node ), indicate the presence of distant metastases. Malignant ascites, caused by peritoneal carcinomatosis, may also be present. With portal, splenic, or superior mesenteric vein occlusion, mesenteric venous pressures may be increased, and collateral channels, including gastroesophageal varices and caput medusae, may develop. Distal common bile duct obstruction caused by the tumor often leads to bile duct and gallbladder distention. Thus, a palpable gallbladder in a patient with painless jaundice (i.e., Courvoisier s sign) suggests the presence of a periampullary neoplasm. There are some conditions that have been shown to predispose individuals to develop pancreatic cancer. One of the most important risk factors studied is cigarette smoking. People who smoke tobacco are more likely than nonsmokers to develop the disease. Another important factor that has been studied is diabetes, but it is not completely clear whether diabetes itself is a cause of the cancer or happens in correlation because of its ubiquity in today s society. Family history of pancreatic cancer increases the risk of developing the disease especially if a first-degree relative is affected (mother, father, sister or brother). 6 Miami Valley Hospital

Obesity has also emerged as one of the important risk factors for the disease. Inflammation of the pancreas or pancreatitis is another risk factor. There are different types of pancreatitis based upon whether it is hereditary or not, but both conditions are known to predispose individuals to developing pancreatic cancer. Finally, there have been many studies into other genetic conditions or abnormalities ( mutations ) that are considered risk factors for this disease; these include the breast/ovarian cancer genes BRCA1 and BRCA2 as well as the Peutz-Jeghers syndrome gene STK11, P16 and many others. Ataxia- Telangictasia is also associated with increased risk of pancreatic cancer. Diagnosis of pancreatic cancer is most often a multi-dimensional endeavor, falling under blood laboratory testing, radiologic imaging, and biopsy for tissue examination under the microscope. The usual work-up includes measuring levels of liver function enzymes, biliary excretions and tumor markers named carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA). Imaging modalities usually include a highquality CT scan using a focused pancreas protocol; this provides the clinician with local extension of the tumor and provides insight into the resectability of the tumor. Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans are sometimes performed as well; their usage is mostly dependent on clinical scenarios outside the scope of this report. Finally, there are real-time imaging procedures performed to obtain tissue diagnosis with cytology examination. These include CT-guided percutaneous biopsy, endoscopic ultrasound (EUS) combined with fine needle aspiration (FNA) or an endoscopic retrograde cholangiopancreatography (ERCP) with biliary brushing. Most often, however, final diagnosis occurs when tissue is removed during surgery and undergoes histologic examination by pathologists. Many surgeons believe that if a suspicious tumor is deemed resectable, negative biopsies are not sufficient to ensure a cancer does not exist. Surgical Treatment As noted earlier, tumors of the head and neck of the pancreas account for about 70 percent of pancreatic tumors. They are generally resected by a surgical procedure called pancreaticoduodenectomy (also known as the Whipple procedure). There are variations to the procedure but in essence the pancreas is resected at the neck and the surrounding structures including the duodenum, the gallbladder, and in many instances part of the stomach are resected and the small bowel is reattached to the bile duct from the liver, remaining pancreas and stomach outlet. Pancreatic body and tail tumors most often have already metastasized at time of diagnosis and extend locally to involve nodes, nerves or major vessels. Resection involves a distal pancreatectomy (removal of the end of the pancreas) either with or without splenectomy (removal of the spleen). The open end of the pancreas is then closed using different techniques. Most surgery is done with laparotomy, but advances continue to assess minimally invasive surgical approaches as they are feasible and appropriate. The technical aspects of surgery are beyond the scope of this discussion. A major part of both surgical procedures is extensive search for metastatic disease. Usually if metastatic disease is encountered in the operating room, palliative surgery could be performed to relieve the patient from obstructive or painful symptoms. In many cases a laparoscopy is done to assess this and spares patients from laparotomy if surgery is futile. Currently most patients with pancreatic adenocarcinoma are treated with chemotherapy or a combination of chemotherapy and radiation. The neoadjuvant and adjuvant approaches are discussed in the medical and radiation oncology sections. This underscores the need for a multidisciplinary evaluation of these complex cancer patients. Oncology Services Annual Report 7