Digestive System: Gastric Cancer (PDF)

CBS II: BLOCK V, MODULE 1, CASE 4 DIGESTIVE SYSTEM patients who have a first-degree relative who has had DIFFERENT MALIGNANCIES THAT PRESENT WITH GIT MASS...

CBS II: BLOCK V, MODULE 1, CASE 4 DIGESTIVE SYSTEM patients who have a first-degree relative who has had DIFFERENT MALIGNANCIES THAT PRESENT WITH GIT MASS gastric cancer or who themselves have a prior history GASTRIC CANCER (TUMORS OF THE STOMACH) of an early-stage gastric cancer. ​ In addition to chronic inflammatory conditions, inherited cancer Reference: Harrison’s Principles of Internal Medicine (Ch. 80, pp 629) susceptibility genes increase the risk of gastric cancer. These EPIDEMIOLOGY/INCIDENCE/GEOGRAPHIC DISTRIBUTION include mutations of CDH1: Adenocarcinoma of the Stomach ○​ which encodes for the cell cohesion gene e-cadherin; ​ A century ago, gastric adenocarcinomas were among the most ○​ germline CDH1 mutations markedly increase the risk for the common of malignancies in the United States. Since the diffuse cell (signet cell) gastric cancer subtype (see below for 1920s, the incidence of gastric cancer has steadily decreased; discussion of histologic subtypes). while the reason for this has not been definitively identified, it ○​ Patients with an inherited deleterious CDH1 mutation are coincided with widespread use of refrigeration and a decreased considered for prophylactic gastrectomy. CDH1 mutations need for food preservatives. also increase the risk for lobular breast cancer. ​ In 2020, it is estimated that there will be 27,600 new cases of ○​ Germline mutations in the mismatch repair pathway gastric cancer diagnosed in the United States; while now seen (Lynch syndrome) slightly increase the risk for gastric much less frequently, it remains a lethal disease, with 11,010 cancer. deaths. Globally, gastric cancer is still very common, with an ○​ Other inherited cancer susceptibility genetic syndromes that overall global incidence of 1.03 million new cases per year and increase the risk of gastric cancer include: 780,000 deaths, making gastric cancer the third most common ​ familial adenomatous polyposis cause of cancer mortality. ​ juvenile polyposis ○​ High-incidence areas, as is the case for esophageal ​ Peutz-Jeghers syndrome. cancers, include large Asian countries such as China, Korea, ○​ Inherited cancer susceptibility genes such as BRCA and Japan; South American countries such as Chile; and mutations may not significantly increase risk for gastric Eastern European countries. cancer. Surveillance programs for the higher risk germline ​ While the number of new cases of body and distal gastric cancers cancer susceptibility genes should be employed. has decreased in Western, high-HDI countries, the incidence of ​ Gastric cancer stem cells originating in the bone marrow may play adenocarcinomas of the gastroesophageal junction has an important role in the development of gastric cancer. markedly increased in the same areas over the past several ○​ H. pylori may be an inciting factor for recruitment of such decades. bone marrow gastric stem cells. If this hypothesis is ​ The ingestion of high concentrations of nitrates found in dried, confirmed, it may have important implications for therapy of smoked, and salted foods may be a contributing factor. gastric cancers. ​ Bacteria such as Helicobacter pylori and ingestion of partially decayed bacterially contaminated food may lead to the CLINICAL FEATURES generation of carcinogenic nitrites from nitrate (80-4) Surveillance Strategies ​ As is the case for esophageal cancer, the overwhelming majority of Western patients with gastric cancer are symptomatic at the time of diagnosis. ​ Early detection programs, in Japan and Korea, where gastric cancer has been among the most common of malignancies (although its incidence has been decreasing), include upper endoscopy and, in Japan, upper endoscopy and serum pepsinogen; these programs have increased the number of patients found with early gastric cancer and decreased mortality rates. ​ This strategy has not been cost effective in populations in which the incidence of gastric cancer is much lower, such as in the United States. ​ In high-incidence areas, treatment of symptomatic H. pylori is a preventive measure. ​ Exceptions to routine surveillance in the United States are ○​ A causative factor is suspected to be chronic inflammation asymptomatic patients with CDH1 (and other cancer susceptibility due to reflux of gastric contents into the esophagus, gene) mutations who may be part of early detection programs and particularly in obese people. in whom prophylactic gastrectomy is a management option. ○​ Obesity alone is not the cause, as a substantial number of these patients are fit and not overweight. Presenting Symptoms ○​ Early-onset gastric cancers (gastric cancer occurring in ​ Presenting symptoms include vague upper abdominal patients under the age of 50), primarily proximal or discomfort, hematemesis or melena, anorexia and early gastroesophageal junction cancers, have also increased. satiety, and unexplained weight loss. ○​ A second cause of chronic inflammation, H. pylori infection, ​ For patients with esophagogastric junction cancers, dysphagia or is a known driver in many cases of gastric cancer. While H. odynophagia may be the presenting symptom. pylori is extremely common, occurring in approximately half ​ Anemia may be found due to occult bleeding. These symptoms of all humans, gastric cancer occurs in only a small subset of and signs lead to upper (and if site of bleeding is uncertain, lower) those infected. endoscopy and biopsy (endoscopy has long replaced barium ○​ Higher cancer risk has been associated with certain strains contrast radiography as an initial diagnostic step). of H. pylori; a specific human genetic predisposition has not ​ Occasionally, imaging using CT performed to evaluate abdominal yet been identified. symptoms may identify gastric thickening or a gastric mass ○​ Supportive evidence that H. pylori infection is a causative leading to upper endoscopy. factor in the development of gastric cancer includes ​ Physical examination can reveal left supraclavicular adenopathy prospective studies demonstrating that treatment of H. pylori (Virchow’s node), a periumbilical mass (Sister Mary Joseph infection decreases the overall risk of gastric cancer. nodule), a pelvic mass on rectal exam (Blumer’s shelf), ​ For example, patients with H. pylori infection who had ascites, or an ovarian mass (Krukenberg tumor). More at least one first-degree relative with a history of commonly, physical examination is unrevealing. gastric cancer (increasing their own risk of stomach ​ Upper endoscopy may reveal an ulcer or ulcerated mass, biopsy cancer) were randomly assigned to placebo or of which shows adenocarcinoma. treatment for H. pylori. ​ For the diffuse subtype of gastric cancer, a mass or ulceration may ​ The group receiving H. pylori eradication showed a not be seen, but rather, thickened gastric rugae may be noted. significant decrease in the incidence of gastric cancer ​ Initial biopsy may not reveal diffuse gastric cancer, which may (especially for those in whom H. pylori was track below the mucosal surface. In these patients, EUS may successfully eradicated) compared to the control guide biopsy. group. ​ Earlier studies had demonstrated that treatment of H. pylori in Korean patients who had a prior very-early-stage gastric cancer decreased the incidence of a second gastric cancer. ​ These data suggest that treatment of asymptomatic H. pylori gastric infection should be considered for 1  HISTOPATHOLOGY CLASSIFICATION OF PRIMARY GASTRIC elevated in a number of other gastrointestinal and other site CARCINOMAS cancers). ​ The large majority (~85%) of gastric malignancies are adenocarcinomas or subtypes of adenocarcinoma. ​ Other malignancies, discussed below, include neuroendocrine tumors (carcinoid tumors), primary gastric lymphomas, gastrointestinal stromal tumors (GISTs), and other rare malignancies. ​ Using the Lauren classification, pathologists classify adenocarcinomas on the basis of histopathology as intestinal (more common) or diffuse subtype (~20%). ​ As noted above, the diffuse subtype is associated with inherited CDH1 mutations; in addition, in the TCGA genomic analysis of gastric cancer, approximately a third of diffuse subtype cases had somatic CDH1 mutations. ​ The intestinal subtype is associated with H. pylori infection and atopic gastritis. Histologic grade also influences the clinical course. ​ Genomic analysis performed by several groups has resulted in molecular classifications of gastric cancer that may, in the future, inform staging systems, provide a better understanding of the driving factors in the development of gastric cancer, and provide important information on treatment options. ○​ For example, the TCGA group reported the results of a multiplatform analysis of 295 patients with previously untreated gastric cancer; both Western and Asian patients ​ Diagnostic CT scan of the chest, abdomen, and pelvis should be were included in the analysis. performed. ○​ Four subtypes of gastric cancer were identified: ○​ If metastatic disease is suspected on imaging, a biopsy of a ​ high Epstein-Barr virus burden metastatic site should be strongly considered to confirm ​ microsatellite unstable with hypermutation stage IV disease, which changes the goals of care from ​ genomically stable (associated with the diffuse potentially curative to palliative treatment. subtype) ○​ As is the case for esophageal cancer, FDG-PET/CT, which is ​ chromosomal unstable. more sensitive than diagnostic CT scan in identifying sites of ○​ The Asian Cancer Research Group (ACRG), studying metastatic disease, should be performed if the anatomic CT primary tumors from 300 Korean patients, analyzed gene is negative for metastatic disease. expression profiles and found four subtypes: ○​ Note, however, that FDG-PET may be noninformative (the ​ mesenchymal primary tumor may not be FDG-avid, particularly in ​ microsatellite unstable diffuse-type gastric cancer). ​ microsatellite stable with TP53 expressed ​ If imaging does not reveal metastatic disease, EUS should be ​ microsatellite unstable with TP53 mutated. strongly considered to determine depth of penetration of the ○​ Clinical outcome was correlated with genomic subtype in primary tumor and the presence or absence of regional both studies, with microsatellite unstable tumors having lymphadenopathy suspicious for metastasis. the best outcome and genomically stable (TCGA) and ○​ Lymph node biopsy and, on occasion, biopsy of left hepatic mesenchymal (ACRG) types the worst. parenchymal lesions found on EUS can be performed at the same setting. ​ Endoscopic biopsies usually provide enough tumor tissue for molecular diagnostic pathology testing for HER2, MSI/MMRP, and PD-L1 assessment; it may not provide enough tissue for genomic alteration analysis. ​ If neoadjuvant therapy is planned, laparoscopy should be considered to allow evaluation of the peritoneal cavity, with peritoneal washing for cytology if no peritoneal metastases are visible. ○​ The peritoneal cavity is a common site of metastases, especially from diffuse-type gastric cancer. ○​ The finding of peritoneal involvement either visibly or by positive cytology is staged as metastatic disease and diminishes the chance for curative resection. ​ The staging classification for gastric cancer is summarized in Table 80-5. Three staging classifications are provided: ​ In addition to histopathology, molecular diagnostics (including ○​ cTNM clinical staging (before any therapy has been given) NGS) are an important part of the pathology workup. The ○​ pTNM pathologic staging (for patients not undergoing molecular subtypes have therapeutic implications; for example, preoperative therapy) ~20% of gastric cancer or gastroesophageal junction cancer ○​ post-neoadjuvant therapy classification staging (ypTNM). patients’ tumors have overexpression or amplification of HER2, ​ The three components take into account current standard of care which would lead to the addition of agents such as trastuzumab as options for therapy in which the AJCC prognostic stage groups part of systemic treatment for metastatic disease. from clinical staging guide therapeutic decisions. ​ Immune modulation therapy may be used in patients with ○​ For example, after clinical evaluation, a large percentage of hypermutated tumors, found by NGS or by polymerase chain newly diagnosed patients will be found to have higher-stage reaction (PCR) for microsatellite instability (MSI). primary cancers (penetrating through the gastric wall [T3 or ​ An evaluation for overexpression or amplification of HER2, T4] or lymph node–positive tumors), in which case quantification of PD-L1 by immunohistochemistry, and assessment perioperative (neoadjuvant) systemic therapy may be of MSI by PCR or deficient mismatch repair protein (dMMRP) chosen. expression should be a routine part of the pathology workup of ○​ Pathologic examination of the resected specimen for patients with metastatic gastric cancer. prognostic stage classification must take into account ​ More controversial is whether these assays should also be exposure to preoperative therapies that may lead to routinely performed in patients with potentially operable gastric downstaging (thus, ypTNM staging). cancer because the addition of trastuzumab to neoadjuvant ​ Nomograms have been developed for predicting outcomes in chemotherapy has not yet been shown to change outcome. patients undergoing surgery as initial treatment. ​ In large-volume centers, NGS is routinely performed on pretreatment biopsies. Currently, the finding on pathologic assays of positive tumor Epstein-Barr virus (identified in 8–10% of gastric cancer patients) does not change therapeutic options. STAGING ​ Once a diagnosis of a primary gastric adenocarcinoma is made, algorithms for clinical evaluation of stage include physical examination and imaging studies. ​ Tumor-related biomarkers such as carcinoembryonic antigen (CEA) or CA19-9 may be elevated but are nonspecific (may be 2  ​ In the United States, a modified D2 (D1+)resection preserving the spleen and avoiding pancreatectomy is recommended but should be performed by experienced surgeons at high-volume centers. ○​ Japanese investigators and others have used very extensive lymph node dissections, but studies have not demonstrated an advantage for a D3 resection. ​ Both resection of the primary tumor and its regional lymph nodes can be performed laparoscopically in appropriate patients. ​ In the hands of experienced surgeons, operative mortality would be anticipated to be =2%. Neoadjuvant and Postoperative Adjuvant Therapy for Resectable Gastric Cancer ​ The large majority of potentially resectable Western gastric cancer patients have locally advanced tumors (cTNM stage IIA/B or III). ​ Multimodality therapy using systemic chemotherapy improves 5-year survival rates by 10–15% compared to surgery alone. ○​ A widely cited study, the MAGIC clinical trial, randomly assigned patients with potentially resectable disease to receive perioperative chemotherapy or to proceed directly to surgery. ○​ Five-year overall survival for patients undergoing surgery alone was 23%; for those receiving pre- and postoperative chemotherapy, it was 36%. ○​ On the basis of this and other clinical trials, for most medically fit patients with stage cTNM II and III resectable gastric cancers, preoperative systemic chemotherapy followed by resection and, if tolerable, postoperative chemotherapy is a standard of care. ​ Chemoradiation as given for esophageal cancers is usually used TREATMENT for gastroesophageal junction tumors. Potentially Curable Gastric Cancer: Surgery ○​ Preoperative chemoradiation or preoperative chemotherapy ​ Surgical removal of the primary tumor with negative followed by chemoradiation for gastric cancer, as opposed to microscopic margins (an R0 resection) and with resection of esophageal or gastroesophageal junction cancers, has been regional lymph nodes is currently the only curative therapy; studied but is still an investigational approach. with surgery alone, 5-year survival rates are approximately 25%. ​ For patients being treated with multimodality therapy, close ​ If tumor cells are found at the margin of resection (R1) or if visible interactions among the surgeon, medical oncologist, and radiation cancer is left at the time of surgical removal of the primary tumor oncologist are essential. (R2), surgery is palliative rather than curative. ​ Clinical trials have compared different cytotoxic chemotherapy ​ For patients with early-stage tumors (mostly clinical stage I), regimens, most of which include a platinum compound—either surgery without perioperative systemic therapy may be performed. cisplatin or oxaliplatin. ​ For patients with more locally advanced tumors (clinical stages IIA, ​ Currently, a platinum compound plus a fluorinated pyrimidine, such IIB, III), who compose approximately 70% of newly diagnosed as fluorouracil or capecitabine, given for three to four cycles operable patients, multimodality therapy (surgery and systemic before surgery is a standard of care option. chemotherapy) improves overall survival. ​ Drug combinations are favored; an example is the FOLFOX ​ Both neoadjuvant (preoperative) and postoperative systemic regimen, which includes fluorouracil, leucovorin, and oxaliplatin. therapy are accepted approaches. ​ For very fit patients, a combination of fluorouracil, oxaliplatin, and ​ If staging studies demonstrate a locally advanced cancer (T3/4 or docetaxel (FLOT) may be chosen. node positive), preoperative treatment is recommended in a ​ Addition of trastuzumab to chemotherapy has not improved medically fit patient. outcomes for patients with HER2-positive cancers. ​ If surgery is performed first and a locally advanced cancer is ○​ Careful monitoring of chemotherapy-related toxicities with found, postoperative chemotherapy or chemotherapy plus appropriate dose modifications is important. chemoradiation is recommended. ○​ Several clinical trials have included both preoperative and ​ For selected very-early-stage gastric cancers (primary tumors that postoperative systemic therapy; a substantial number of are =2 cm in diameter, are well to moderately differentiated, do patients will have a slow postoperative recovery and not not invade the deep submucosa, and do not show lymphovascular receive postoperative treatment. invasion or lymph node metastasis), which are not commonly ○​ Maximizing the ability to give preoperative chemotherapy is found in the United States, endoscopic mucosal resection (EMR) an important consideration. or endoscopic submucosal dissection (ESD) may be performed by ○​ For patients receiving preoperative systemic chemotherapy experienced gastroenterologists in place of surgical resection, with and undergoing a D2/D1+ dissection, postoperative favorable results in studies in high-incidence areas such as Japan. chemoradiation therapy has not improved outcome. ​ For patients in whom the primary tumor is in the distal stomach, a ​ For patients in whom the primary tumor has been resected and subtotal gastrectomy is the preferred surgical procedure. who did not receive preoperative chemotherapy, who are found to ​ For tumors of the proximal stomach, the options for resection have stage II or III cancers, or who have 80 ○​ Radiologic criteria are inadequate for iCCA diagnosis in cases per 100,000 inhabitants). cirrhotic patients. However, in noncirrhotic patients, ○​ The male-to-female ratio is 1.2. guidelines endorse a presumed diagnosis of iCCA (i.e., venous phase contrast enhancement on dynamic CT/MRI) if Molecular Classification and Drivers resection is considered. ​ No molecular classification of CCA has been established. ○​ Assessment of disease extent (venous or arterial invasion ​ Genomic studies have provided insight on two subclasses of and extrahepatic disease) and resectability is best iCCA: accomplished with CT and/or MRI studies. ○​ a proliferation subclass: characterized by activation of ○​ Doppler ultrasound is accurate in defining vascular invasion. oncogenic signaling pathways (including RAS and MET) ○​ Before surgery, PET scanning may be considered to rule out ○​ an inflammation subclass: characterized by activation of an occult primary or metastatic site. inflammatory pathways, overexpression of cytokines, and STAT3 activation. Staging System ​ Similarly, a molecular classification of eCCA has been proposed, ​ The staging system for iCCA resected cases is based on the dividing tumors into four categories (metabolic, proliferation, TNM staging as per the eighth edition of the AJCC/ International mesenchymal, and immune) based on molecular traits. Union Against Cancer (UICC) staging. ​ The hypothesis that the proliferation class with enrichment of ○​ T1 tumors are solitary without vascular invasion and can be ERBB2/3 mutations might respond to monoclonal antibodies divided into T1a or T1b if tumor size is =5 cm or >5 cm, against this receptor and the immune class might respond to respectively checkpoint inhibitors has not been tested or confirmed. ○​ T2 disease includes multiple tumors (e.g., multifocal ​ The iCCA mutation portrait is characterized by: disease, satellitosis, intrahepatic metastasis) or presence of ○​ ~50–60% of tumors having at least one targetable driver vascular invasion (microvascular or major vascular invasion); including FGFR2 fusion events (~25%); ○​ T3 tumors perforate the visceral peritoneum 5  ○​ T4 disease includes tumors involving local extrahepatic structures by direct invasion. ​ Regional lymph node metastasis in the hilar, periduodenal, and peripancreatic nodes is considered N1 disease, while distant spread is considered M1 disease. ​ TNM stages IA, IB, II, and IIIA overlap with T status, whereas stage IIIB includes T4N0 or N1M disease and stage IV includes M1 disease. TREATMENT ​ After adopting the TNM staging system, the International Liver Cancer Association (ILCA) guidelines for management of iCCA proposed a treatment algorithm (Fig. 82-9), adapted and updated with the new treatment modalities accepted. ​ Overall, most of the treatments endorsed have a modest level of evidence. ​ Surgical resection represents the sole curative treatment option in 30–40% of patients, with a median survival of 51 months in properly selected candidates. EXTRAHEPATIC CHOLANGIOCARCINOMA ​ In noncirrhotic individuals, the best candidates for resection are Perihilar and Distal Cholangiocarcinoma patients at TNM stage I–II, whereas in patients with cirrhosis, liver ​ The eighth edition AJCC/UICC TNM staging classification has function should be assessed as previously described for HCC. established pCCAs as tumors that arise between the ​ Preoperative disease assessment should discard vascular second-order bile ducts up to the insertion of the cystic duct, invasion, N1, and M1. whereas dCCAs arise from this point to the ampulla of Vater ​ Lymphadenectomy of regional nodes is recommended given its (Fig. 82-7). prognostic value. ​ Thus, dCCA can be difficult to distinguish from early pancreatic ​ The main predictors of recurrence (~50–60% at 3 years) and cancer. Both entities have a similar diagnostic approach. survival are identified at the pathologic examination, including ​ Acute onset of painless jaundice occurs in 90% of patients with presence of vascular invasion, lymph node metastases, and poor pCCA, and 10% present with cholangitis. differentiation. ​ Primary biliary cholangitis with a cutoff for CA 19-9 >129 U/mL is ​ A phase 3 trial (BILCAP trial) including all types of CCA in a suspicious for CCA. prespecified per-protocol analysis reported improved survival with ​ Imaging assessment starts with CT and MRI; they have a good adjuvant therapy (53 months vs 36 months; adjusted HR 0.75). sensitivity and specificity (>85%) for detecting the degree of bile Based on this trial, American Society of Clinical Oncology duct involvement and hepatic and portal vein invasion. guidelines recommend adjuvant capecitabine for a period of 6 ○​ MRI cholangiography is optimal for defining the extent of months. the bile duct lesion. ​ Other adjuvant regimens, such as gemcitabine monotherapy or a ○​ Ruling out IgG4 cholangiopathy by assessing serum IgG4 is combination of gemcitabine and oxaliplatin, did not improve OS. mandatory. ​ Liver transplantation remains controversial, and few studies have ○​ As a second step, endoscopic retrograde reported good outcomes for single tumors =2 cm. cholangiography with brushing to explore cytology and ​ Nonsurgical candidates have a dismal life expectancy fluorescence in situ hybridization (FISH) for exploring ​. Overall, patients at stage III might be considered for locoregional polysomy are recommended. FISH enhances the sensitivity therapies, such as chemoembolization or radioembolization, of cytology from 20 to ~40%. but the level of evidence is low and is mostly based on cohort ​ Diagnosis is based on pathology. The treatment algorithm for studies. pCCA indicates that in cases of a dominant stricture with positive ○​ A meta-analysis of 14 trials testing locoregional therapies cytology/ biopsy or polysomy, a lymph node biopsy via endoscopic reported median survival times of 15 months. ultrasound should be obtained. ○​ External-beam radiation therapy is not recommended as ​ pCCA with negative lymph node involvement is best treated by standard therapy. surgery, resection, or transplantation, the sole curative ○​ At more advanced stages (stage IV) in patients with an options. ECOG of 0–1, systemic chemotherapy with the combination ​ Staging laparoscopy is recommended to exclude metastatic of gemcitabine and cisplatin is considered the standard of disease before surgery; metastases occur in 15% of cases. practice, yielding median survival times of 11.7 months ​ Resection entails hepatic and bile duct removal and compared to 8 months for gemcitabine alone. Roux-en-Y-hepaticoje-junostomy with regional ○​ This recommendation for first-line treatment of advanced lymphadenectomy. tumors is based on a subgroup analysis of 80 iCCA patients ​ Bilobular involvement is considered a surgical contraindication. included in a large randomized phase III trial (n = 410, ​ Perioperative mortality is as high as 10%, mostly as a result of ABC-02 Trial) of patients with advanced biliary tract tumors. liver failure. In a few referral centers, unresectable single pCCA 432,000 deaths (seventh cause of cancer deaths). germline mutations could lead to specific and effective new ○​ Pancreatic cancer currently has the worst survival rate therapeutics for patients with these abnormalities in their tumors. of any cancer with an overall 5-year survival (regardless ​ The table below identifies the various germline mutations along of stage) of ~8.2%. with their familial cancer syndromes where an increased risk for ○​ However, that situation is changing. In particular, (1) pancreatic cancer is known. knowledge about specific molecular subsets of the disease has become crucial to provide the best possible care for patients, and (2) the application of treatment that improves survival for patients with advanced disease used either after surgery or even earlier in the disease has improved survival. EPIDEMIOLOGY ​ Pancreatic cancer accounts for 3.2% of all new cancer cases in the United States and for 7.8% of all deaths from cancer in the United States. ​ The lifetime risk of developing pancreatic cancer is ~1.7%. ​ The incidence of pancreatic cancer has been increasing about 1.03% per year. ​ Pancreatic cancer is more common with increasing age and more common in men than in women. ​ The 5-year survival rate for all stages has only increased from 3% ​ Knowing the patient has a BRCA2 or PALB2 germline mutation in 1975 to 9% in 2015. or any of the above mutations should lead one to not only refer the ​ The latest information from the U.S. Surveillance, Epidemiology, patient’s relatives to an early detection or high-risk individual clinic and End Results (SEER) database predicts that the 5-year survival but also realize that for patients with a BRCA2/PALB2 germline for patients with localized pancreatic cancer is about 37%, 12% for mutation consideration for treatment with a poly (ADP-ribose) those with regional disease, and 3.1% for patients with advanced polymerase (PARP) inhibitor should be considered (see below). metastatic disease. ​ Other germline mutations are under study to determine their ​ Pancreatic cancer is more common in developed countries increased risk of pancreatic cancer, including CFTR, PRSS2, (although generally it tracks with the prevalence of smoking). CDK4, FANCC, PALLD, APC, ATM, BMPR1A, BRCA1, EPCAM, ○​ The incidence is highest in Western Europe and North MEN1, MLH1, MSH2, MSH6, NF1, PMS2, SMAD4, TP53, TSC1, America followed by other areas in Europe, Australia, New TSC2, and VHL. Some of these mutations are associated with Zealand, and South-Central Asia. pancreatic neuroendocrine tumors. ○​ The population at greatest risk are women living in ​ In addition to the recognized genetic syndromes, other possible Scandinavian countries familial pancreatic cancer genes have not yet been discovered. ○​ While the lowest risk is seen for women living in middle ○​ For example, a family history of pancreatic cancer is Africa. associated with a 13-fold increase in the disease. ○​ If you have one first-degree relative, the risk is increased ETIOPATHOGENESIS/RISK FACTORS 4.6-fold, having two first-degree relatives increases the risk ​ Age is one of the greatest risk factors for pancreatic cancer 6.4-fold, and three or more first-degree relatives confers a with median age at diagnosis of 70 years (the disease is most 32-fold increased risk. frequently diagnosed in the 65–79 age group ○​ The risk is also increased if a relative developed pancreatic ○​ for men, 65–69 cancer at 30% in the first 3 years (along with a dramatic decrease in ○​ The pain is midepigastric (sometimes described as a their hemoglobin A1c and blood glucose). “boring-like” pain). ​ Physical inactivity also has been associated with an increased ○​ Often the pain is in the back (due to retro-peritoneal invasion risk in pancreatic cancer. of the splanchnic nerve plexus). ○​ The pain may be exacerbated by eating or lying flat. PATHOLOGY AND MOLECULAR CONSIDERATION ​ Other items of note in a history are light stool color from the Location absence of bile (steatorrhea also causes malodorous stools) and ​ The posterior location of the pancreas in the abdomen is likely the onset of diabetes in the prior year. one of the issues that leads to a late diagnosis (Fig. 83-1A). ​ Jaundice, first detectable with a bilirubin of 2.5–3.0 mg/dL, is usually associated with a tumor in the head of the pancreas. Pathology ​ In some instances, depression is noted (with a higher subsequent ​ Cancers of the pancreas can be divided into neoplasms of the number of suicides). endocrine pancrea and tumors of the exocrine pancreas. ​ Pruritus may be seen when the bilirubin reaches 6–8 mg/dL. ○​ The most common neoplasm of the exocrine pancreas and ​ Physical signs include: most deadly is pancreatic infiltrating ductal ○​ Jaundice adenocarcinoma. ○​ Signs of weight loss ​ These tumors arise in the head, body, or tail of the ○​ A palpable gallbladder (Courvoisier’s sign) pancreas and are characterized by infiltrating ○​ Hepatomegaly desmoplastic stromal reactions. ○​ An abdominal mass, and ○​ Other subtypes of non neuroendocrine pancreatic cancers ○​ Even an enlarged spleen (usually indicating a portal vein include acinar cell carcinoma (tumors of the exocrine thrombosis). enzyme producing cell), medullary carcinoma, ​ Migratory superficial thrombophlebitis can also be seen adenosquamous carcinoma, and other rare subtypes. (Trousseau’s syndrome). ○​ Each of these is different in behavior and in their molecular ​ Signs of late disease include a lymph node palpable in the characteristics and often requires other specific types of supraclavicular fossa (usually on the left where the thoracic duct treatment. enters the subclavian vein). ○​ This is clinically referred to as Virchow’s node. ​ Occasionally, one can palpate subcutaneous metastases in the periumbilical area referred to as a Sister Mary Joseph’s node—named after one of the scrub nurses on the Mayo Clinic Operative Team who noted that when she prepped that area and felt those nodules, the patient often had peritoneal metastases. ​ The history and symptoms noted above may lead a person to see a physician; often CT and MRI scanning detects the disease before advanced disease symptoms appear. DIAGNOSTIC WORKUP Imaging ​ Diagnostic imaging plays a major role in diagnosing pancreatic cancer and other intra abdominal diseases. ​ The best technique is the use of a dual-phase Molecular Characteristics. contrast-enhanced spiral CT using the pancreatic cancer ​ The molecular characteristics of pancreatic ductal protocol, which allows arterial phase enhancement and portal adenocarcinoma reveal four genes that are commonly mutated or venous phase enhancement. inactivated (sometimes referred to as the “four horsemen”). ○​ This special protocol can provide helpful prospective staging ○​ The most common is KRAS (usually in codon 12). and assessment of resectability. Figure 83-2 demonstrates ​ It is critical to determine the specific mutation in such a CT scan (with vascular involvement). KRAS because specific mutations may indicate specific therapies that should be considered. ​ KRAS mutations are seen in virtually 100% of pancreatic adenocarcinomas. ​ In fact, with the deep sequencing now available, if a KRAS mutation is not detected in the patient’s tumor, one should consider that the tumor is likely of a different origin (e.g., small bowel, gallbladder, or cholangiocarcinoma—all of which could require different treatments). ○​ p16/CDKN2A is also noted in >90% of invasive pancreatic ​ Figure 83-3 demonstrates the use of an 18F glucose positron adenocarcinomas. emission tomography (PET) scan. ○​ TP53 and DPC4/MADH4 are mutated in about half of these tumors. Histologic Diagnosis ○​ As a reference point, the BRCA2 gene noted in Table 83-1 is ​ A histologic (tissue) diagnosis is essential and should be obtained mutated in 7–10% of pancreatic adenocarcinomas. with a cutting biopsy needle (not a skinny needle with cytology). 8  ​ Misdiagnosis is more common based on only fine-needle aspirates. ​ Obtaining a tissue diagnosis allows not only for accuracy but also for molecular testing for KRAS mutations, microsatellite instability, and other important molecular abnormalities. ○​ Those molecular abnormalities and others will be increasingly important as more targeted therapies are developed for patients with pancreatic cancer. ​ The core needle (16–18 gauge) biopsy can be obtained via endoscopic ultrasound-guided techniques for a tumor localized to the pancreas or, if there are liver lesions or Virchow’s node, via percutaneous biopsy by interventional radiologists. Serum Markers ​ Before treatment, a serum sample should be obtained for levels of CA19-9, carcinoembryonic antigen (CEA), or if both are negative, for CA125 (can be positive when the CA19-9 is negative TREATMENT due to the patient not being a Lewis antigen secretor). These ​ Even for patients with resectable disease, the patient should be markers are not useful for staging but can be useful in following presented to a combined-modality conference. the course of pancreatic cancer. ​ Some clinicians feel the best approach for patients with resectable disease (as defined in Table 83-3) is surgery. IMPORTANT IMMEDIATE CONSIDERATIONS IN PATIENT CARE ○​ Only a small percentage of patients are in this category ​ While the patient is being evaluated and staged, one must be alert (10–20%). for biliary tract obstruction (and the attendant risk for sepsis from ​ Some clinicians feel neoadjuvant therapy(chemotherapy before the biliary tree). surgery) should be given before surgery (for controlling potential ○​ A stent can be placed (plastic if temporary or metal if needed micrometastatic disease and shrinking the primary tumor). longer) to relieve the jaundice and pruritus. ​ The surgery for patients with tumors in the head or uncinate body ​ If surgery is being contemplated, an early surgical consultation is of the pancreas is usually a pylorus-sparing in order as some surgeons may want to proceed to surgery without pancreaticoduodenectomy (a modified Whipple procedure). placement of a stent. ​ For tumors in the body or tail, a distal pancreatectomy is usually ○​ This immediate surgical approach is becoming less common performed. as many multidisciplinary teams want consideration of use of ​ Clinical and pathologic findings of the resection are defined as chemotherapy with or without radiation therapy (called either an R0 resection (no macroscopic or microscopic disease left neoadjuvant therapy) before a patient is taken to surgery. after surgery) or an R1 resection, which refers to residual disease ​ Patients with pancreatic cancer are often hypercoagulable and likely left behind. frequently have migratory thrombophlebitis (Trousseau’s sign) ​ Patients with smaller tumors and lymph node– negative disease as well as deep vein thrombosis with pulmonary emboli (a have a better survival (median of about 18–23 months with 5-year frequent cause of death). survival of about 20%). ○​ Appropriate examinations plus being alert to thromboses on ​ Two approaches are being explored to try to improve on this the routine workup are mandatory so appropriate ○​ 1. Postoperative adjuvant therapy. management can be put in place. ​ The standard of care is to use 24 weeks of adjuvant ​ Control of pain or of any symptoms should be pursued to help treatment with a modified folinic acid, patients be as comfortable as possible for their decision-making. 5-fluorouracil, irinotecan, and oxaliplatin Sometimes simple approaches like the use of a replacement (FOLFIRINOX) regimen. pancreatic enzyme (at good therapeutic doses) can relieve the ​ In the definitive clinical trial, the median survival was bloating, cramping, and diarrhea. Early involvement of a palliative 54 months for the combination of modified care team can improve a patient’s quality of life and sometimes FOLFIRINOX versus 35 months for gemcitabine even its length. alone (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48–0.86; p =.003). Toxicities were CLINICAL STAGING manageable. ​ The clinical staging of pancreatic cancer according to the ○​ 2. A newer approach is the use of neoadjuvant American Joint Commission on cancer staging is presented in chemotherapy (chemotherapy given before surgery) to try Table 83-2. to shrink the tumor and normalize the patient’s serum CA19-9 level. ​ Data suggest that patients who have borderline resectable/locally advanced disease can benefit from neoadjuvant therapy. Studies of neoadjuvant chemotherapy with or without radiation therapy are ongoing. Locally Advanced Disease (30% of Patients) ​ For patients with locally advanced disease, the median survival is also quite poor (6–10 months) because many of the patients die with local problems (e.g., portal vein thrombosis with bleeding varices, obstruction, sepsis). ​ The approach has been to try to reduce the bulk of the disease with use of radiation therapy plus chemotherapy or chemotherapy alone, with the goal that the disease could become resectable. ​ No standard therapy has been agreed upon, but experimental approaches are applying some of the treatments that show promise in advanced metastatic disease. Advanced Metastatic Disease (60% of Patients) ​ Only a few of the many phase 3 randomized trials in patients with ​ Table 83-3 presents another clinical way to express extent of advanced pancreatic cancer have led to meaningful increases in disease as well as therapeutic approaches (to be discussed later). survival. ​ For proper staging, some physicians believe that a laparoscopy ​ We have learned that a regimen needs to have at least a 50% either before or at the time of surgery is important. improvement in overall survival or 90% improvement in 1-year ​ If metastatic disease is found at laparoscopy, one can avoid survival in a pilot phase 2 trial to predict for any degree of success surgery that would not be helpful because disease is already in large randomized phase 3 trials. advanced. ​ Patients with the best chance of receiving a benefit from treatment have a good performance status (functioning up and around at least 70% of the day), have a reasonable albumin level (!3.0 g/dL), and a neutrophil/lymphocyte ratio of ≤5.0. ​ Single-agent gemcitabine achieves a median survival of 6 months and a 1-year survival rate of 18%. Table 83-4 details three combination regimens that have further improved survival modestly. Median overall survival still ranges from 6 to 11 months. ​ However, 1-year survival is now approaching 35% for these combination regimens with some long-term 4+ year survivors. 9  ​ Also of note in Table 83-4, liposomal irinotecan has U.S. Food and intrahepatic cholangiocarcinoma (iCCA; 10%), and other Drug Administration (FDA) approval in combination with malignancies accounting for 90% for early detection. ​ A 3-month interval does not enhance outcomes, and survival is lower with 12-month compared with 6-month intervals. ​ A shorter follow-up interval (every 3–4 months) is recommended when a nodule of 90% sustained virologic response (SVR) States. Public health policies encouraging the implementation of rates after 12 weeks of treatment. This effect has a direct such programs should lead to an increase in early tumor detection. implication in reducing HCC incidence in patients with cured chronic HCV infection. SCREENING TESTS ○​ Once cirrhosis is established, the incidence of HCC is lower Reference: Senior’s notes for patients with SVR than for those with active viral disease, Screening High-Risk Populations although they continue to have persistent HCC risk (>1% per ​ Screening has not been shown to save lives. year). ​ Prospective studies in high-risk populations showed that ​ Additional putative chemopreventive agents have been proposed ultrasound was more sensitive than AFP elevations. to reduce HCC incidence in at-risk populations. ​ An Italian study in patients with cirrhosis identified a yearly HCC ○​ Aspirin is associated with HCC cumulative incidence incidence of 3% but showed no increase in the rate of detection of reduction in large studies from 8% to 4%. potentially curable tumors with aggressive screening. ○​ Similarly, compelling cohort and case-control studies ​ Prevention strategies including universal vaccination against demonstrated a dose-dependent relationship between hepatitis are more likely to be effective than screening efforts. coffee consumption and reduced HCC incidence. As a ​ Despite absence of formal guidelines, most practitioners obtain result, coffee consumption is recommended as a 6-monthly AFP and CT (or ultrasound) when following high-risk chemoprevention strategy in patients with chronic liver patients (HBV carriers, HCV cirrhosis, family history of HCC). disease. ​ Current directions. Cost-benefit analysis is not yet convincing, even though screening is intuitively sound. However, studies from Surveillance areas of high HBV carrier rates have shown a survival benefit for ​ The aim of surveillance is to obtain a reduction in disease-related screening as a result of earlier stage at diagnosis. Gammaglutamyl mortality. transpeptidase appears useful for detecting small tumors. ​ This is usually achieved through early detection that enhances the applicability and cost-effectiveness of curative therapies. DIAGNOSTIC APPROACH TO THE PATIENT ​ U.S. and European guidelines recommend surveillance for patients at high risk for HCC on the basis of cost-effectiveness Reference: Harrison’s Principles of Internal Medicine (Ch. 82, pp 646) analyses. ​ HCC is generally diagnosed at early or intermediate stages in ​ As a general rule, high-risk populations are considered those Western countries but at advanced stages in most Asian (except presenting an incidence cutoff >1.5% for patients with cirrhosis Japan) and African countries. and 0.2% for patients with chronic hepatitis B. ​ A surveillance program yields early diagnosis in 70–80% of cases. ​ At these stages, the tumor is asymptomatic, and diagnosis can be made by noninvasive (radiologic) or invasive (biopsy) approaches. 13  ​ Without surveillance, HCC is discovered either as a radiologic ○​ This radiologic pattern captures the hypervascular nature finding or due to cancer-related symptoms. characteristic of HCC. ​ If symptoms are present, the disease is already at an advanced ○​ In these scenarios, the diagnostic specificity is ~95–100% stage with a median life expectancy 50% of ​ AFP is a serum tumor marker for HCC; however, it is only cases. increased in approximately one-half of U.S. patients. ​ The lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) Reference: Senior’s notes assay is thought to be more specific. ​ An ultrasound examination of the liver is an excellent ​ The other widely used assay is for des-γ-carboxy prothrombin screening tool. (DCP), a protein induced by vitamin K absence (PIVKA-2). ​ The two characteristic vascular abnormalities are ○​ This protein is increased in as many as 80% of HCC patients hypervascularity of the tumor mass (neovascularization or but may also be elevated in patients with vitamin K abnormal tumor-feeding arterial vessels) and thrombosis by tumor deficiency; it is always elevated after Coumadin use. invasion of otherwise normal portal veins. ○​ It may predict portal vein invasion. ​ To determine tumor size and extent and the presence of portal ○​ Both AFP-L3 and DCP are FDA-approved. vein invasion accurately, a helical/triphasic CT scan of the ​ Many other assays have been developed, such as glypican-3, but abdomen and pelvis, with fast-contrast bolus technique none have greater aggregate sensitivity and specificity. should be performed to detect the vascular lesions typical of HCC. ​ In a patient presenting with either a new hepatic mass or other ​ Portal vein invasion is normally detected as an obstruction and indications of recent hepatic decompensation, carcinoembryonic expansion of the vessel. antigen (CEA), vitamin B12, AFP, ferritin, PIVKA-2, and ​ A chest CT is used to exclude metastases. anti-mitochondrial Ab should be measured, and standard liver ​ MRI can also provide detailed information, especially with the function tests should be performed, including prothrombin time newer contrast agents. (PT), partial thromboplastin time (PTT), albumin, transaminases, ​ Ethiodol (Lipiodol) is an ethiodized oil emulsion retained by liver ã-glutamyl transpeptidase, and alkaline phosphatase. tumors that can be delivered by hepatic artery injection (5–15 mL) ​ Decreases in platelet count and white blood cell count may for CT imaging 1 week later. reflect portal hypertension and associated hypersplenism. ​ For small tumors, Ethiodol injection is very helpful before biopsy ​ Hepatitis A, B, and C serology should be measured. because the histological presence of the dye constitutes proof that ○​ If HBV or HCV serology is positive, quantitative the needle biopsied the mass under suspicion. measurements of HBV DNA or HCV RNA are needed. ​ A prospective comparison of triphasic CT, gadolinium-enhanced ​ New Directions. Newer biomarkers are being evaluated, MRI, ultrasound, and fluorodeoxyglucose positron emission especially tissue- and serum-based genomics profiling. tomography (FDG-PET) showed similar results for CT, MRI, and ultrasound; PET imaging was unsuccessful. Noninvasive (Radiologic) Diagnosis ​ New Directions. The altered tumor vascularity that is a Reference: Harrison’s Principles of Internal Medicine (Ch. 82, pp 646) consequence of molecularly targeted therapies is the basis for ​ Patients enrolled in a surveillance program are diagnosed by newer imaging techniques including contrast-enhanced ultrasound identification of a new liver nodule on abdominal ultrasound. (CEUS) and dynamic MRI. ​ Noninvasive diagnostic criteria can only be applied to cirrhotic patients and are based on imaging techniques obtained by Pathologic Diagnosis four-phase multidetector CT scan (four phases are unenhanced, Reference: Harrison’s Principles of Internal Medicine (Ch. 82, pp 646) arterial, venous, and delayed) or dynamic contrast-enhanced ​ Pathologic diagnosis is required in two scenarios: MRI. ○​ (1) in patients without cirrhosis and ​ A flowchart of diagnosis and recall policy recommended by U.S. ○​ (2) if imaging is not typical in at least one of two imaging and European guidelines is summarized in Fig. 82-2. techniques (CT and MRI). ○​ This occurs mainly with early-stage HCC lesions. ​ Biopsy has not been used as the gold standard in clinical practice because of variation introduced by sampling and complications. ○​ Nonetheless, with the advent of molecular therapies and precision oncology, some guidelines advocate obtaining tissue samples in the setting of all research studies in HCC, even if radiologic criteria are met. ○​ Sensitivity of liver biopsies ranges between 70 and 90% for all tumor sizes but decreases to 80% of patients have two diseases, HCC and cirrhosis, a clear measurement of liver dysfunction should be in place. 15 ​ The prognosis of chronic liver disease is commonly assessed antibody) plus bevacizumab showed superiority compared using the Child-Pugh score, which uses five clinical to sorafenib (median survival 19.2 months vs 13.4 months). measures—total bilirubin, serum albumin, prothrombin time, ○​ Three additional targeted therapies have shown improved ascites severity, and hepatic encephalopathy grade—to classify survival compared to placebo in patients with HCC patients into one of three groups (A–C) of predicted survival rates. progressing on sorafenib: regorafenib, cabozantinib, and ○​ In brief, Child-Pugh class A reflects well-preserved liver ramucirumab (only in patients with AFP >400 ng/mL). function, Child-Pugh class B indicates moderate liver ○​ Therefore, these treatments have been adopted by dysfunction with a median life expectancy of ~3 years, and guidelines and incorporated into the treatment algorithm. Child-Pugh class C indicates severe liver dysfunction with ​ Patients with end-stage disease (BCLC D) should be life expectancy of ~1 year. considered for nutritional and psychological support and proper ○​ At early BCLC stages, more granular criteria to define management of pain. patients with very-well-preserved liver function (Child-Pugh ​ Although the BCLC establishes validated stages and treatment hyper-A class; those patients with normal bilirubin and assignment according to evidence, clinical practice is not always without portal hypertension) need to be in place to select aligned with this classification. In large cohort studies and surveys, candidates for resection. only half of patients, or even less in Asia, are treated accordingly. ​ Modifications of Child-Pugh scoring or the Model for ​ Alternative staging or scoring systems have been proposed, but End-Stage Liver Disease (MELD) score have not been adopted none of them has acquired global consensus. for treatment allocation, except for prioritization on the waiting list ​ In contrast to BCLC, some proposed systems capture the standard for liver transplantation (MELD score). of practice in Asia, such as the Hong Kong classification or the ​ The ALBI score, which is based only on serum albumin and Japan Integrated Staging score. bilirubin levels, has been shown to accurately stratify patients with ○​ These systems capture extended indications for resection HCC, particularly those with less severe liver dysfunction. and TACE applied in clinical practice in Asia. ​ Performance status is assessed using the Eastern Cooperative ​ Finally, the tumor-node-metastasis (TNM) staging system is not Oncology Group (ECOG) performance scale (a 5-point system used in HCC since it does not incorporate the main prognostic where higher numbers indicate greater disability), and the variables related to liver function and performance status. presence of cancer-related symptoms (ECOG 1–2) is considered a ​ Due to the complexities of HCC diagnosis and management, it is sign of advanced stage. recommended that patients be sent to a referral center where all ​ Patients with severe liver dysfunction (Child-Pugh class C) or the armamentarium of therapies can be offered. performance status impairment (ECOG 3–4) are offered ​ In principle, patient management and outcome benefit from liver supportive care management. cancer multidisciplinary programs that include a hepatologist, ​ Considering all of these prognostic and predictive variables and oncologist, hepatobiliary and transplant surgeons, interventional evidence-based treatment efficacy, five BCLC stages have been and body imaging radiologist, hepatopathologist, and specialized defined (Fig. 82-4). nurses. ​ Patients with liver-only neoplastic disease, no symptoms (ECOG 0), and mild to moderate liver dysfunction (Child-Pugh A-B) can SURGICAL THERAPIES be classified as very early (stage 0) or early (stage A) or Resection intermediate (stage B) stages depending on tumor size and ​ Surgical resection is the first-line option for noncirrhotic patients number. with early-stage HCC (BCLC 0 or A) with solitary tumors (Fig. ○​ Very early HCC (BCLC 0) is defined by single tumors ≤2 cm 82-4). (if pathology is available, they should be well differentiated ​ In cirrhotic patients, ablation competes with resection for BCLC 0 with absence of microvascular invasion or satellites). tumors (2 cm (BCLC A), resection remains the ○​ Conversely, HCC is considered at advanced stages (BCLC mainstay of treatment in patients with Child-Pugh hyper-A class, C) when patients present with cancer-related symptoms i.e., those patients with normal bilirubin and absence of portal (ECOG 1–2) or tumors with macrovascular invasion (of any hypertension (portal hypertension is defined by hepatic venous type, including branch, hepatic, or portal vein), lymph node pressure gradient ≥10 mmHg). involvement, or extrahepatic spread. ​ Surrogate measures of portal hypertension are presence of ○​ Finally end-stage disease (BCLC D) is considered in cases esophageal varices or platelet count 15 ng/ mL per month. Chemoembolization ​ Several strategies have been proposed to overcome this ​ TACE is the most widely used primary treatment for unresectable limitation. HCC worldwide and the first-line indication for patients with ○​ First, apply neoadjuvant therapies in patients on the intermediate BCLC B stage (Fig. 82-4). waiting list. Neoadjuvant treatments such as TACE or RF ​ Conventional chemoembolization (c-TACE) consists of the local ablation have been assessed in the setting of cohort and hepatic artery administration of chemotherapy (either doxorubicin cost-effectiveness studies. 50 mg/m2 or cisplatin) mixed with an emulsion of lipiodol followed ​ In principle, the use of these therapies is by obstruction of the feeding artery with sponge particles. recommended when the waiting time exceeds 6 ​ c-TACE mainly benefits patients with liver-only disease, months, even though impact on long-term outcome is Child-Pugh A class or B class without ascites, good performance uncertain. status (ECOG 0), and absence of branch or trunk vascular ○​ Second, a priority policy has been established for invasion. patients enlisted. UNOS has implemented a scoring ​ Median survival is ~20 months (compared to 16 months for system based on the dropout risk. pooled control arms). ​ The Milan criteria are universally used as the basis for transplant ​ The best randomized phase 3 investigations have provided eligibility, and adherence to these criteria yields good median survivals for TACE of 20–30 months in properly selected posttransplant survival. populations. ○​ Modest expansion of Milan criteria applying the ​ Median objective response rates are 50–70%. “up-to-seven” criterion (i.e., those HCCs having the number ​ In randomized studies, the treatment is either performed at a 7 as the sum of the size of the largest tumor and the number regular schedule of 0, 2, and 6 months (median number of of tumors) in patients without microvascular invasion sessions: 3) or on demand according to tumor response. achieves competitive outcomes. ​ TACE procedures should be stopped upon tumor progression or ○​ These pathologically defined criteria are being used in any other contraindication. clinical practice to predict the expected outcome after ​ Exceptionally, occurrence of a new small untreated nodule as the transplantation. only progression feature can be considered for treatment. ○​ Similarly, downstaging to Milan criteria is currently defined ​ Around 50% of patients present with a limited postembolization as the reduction of HCC burden by locoregional treatments syndrome of fever and abdominal pain related to ischemic injury to achieve Milan staging before transplantation. and release of cytokines. ○​ This strategy leads to long-term 10-year survival rates of ​ Less than 5% of patients present with major complications (liver ~50%. abscess, ischemic cholecystitis, or liver failure), and in 10 cm). donors, and it is recommended as an alternative option in patients ​ Super-selective TACE minimize the ischemic insult to nontumor on a waiting list exceeding 6 months. The risks and benefits of tissue. this procedure should take into account both donor (death is ​ According to guidelines, treatment-stage migration allows estimated in 0.3%) and recipient, a concept known as double performing TACE on patients at early stages not suitable for equipoise. Due to the complexity of this treatment, it must be surgical or ablative therapies. restricted to centers of excellence in hepatobiliary surgery and ​ In selective studies, median survival times of 5 years have been transplantation reported in patients with single HCC treated by super-selective TACE. On the other hand, TACE performed beyond guidelines as LOCOREGIONAL THERAPIES a conventional practice in patients with advanced HCC yields poor Local Ablation outcomes. ​ RF ablation is recommended as the primary ablative technique ​ Drug-eluting bead chemoembolization (DEB-TACE) differs from (Fig. 82-4). c-TACE in the use of more standardized embolic spheres of ○​ The energy generated by RF ablation (heating of tissue at regular size embedded with chemotherapy. 80°–100°C) induces coagulative necrosis of the tumor, ○​ This strategy ensures drug release over a 1-week period, producing a safety ring in the peritumoral tissue, which might resulting in an enhancement of drug concentration within the eliminate small undetected satellites. tumor. ​ Treatment consists of one or two sessions performed using a ○​ DEB-TACE achieves similar antitumor activity (objective percutaneous approach, although in some instances, ablation with responses of ~60%) as c-TACE and is associated with laparoscopy is needed. significantly less systemic cytotoxic effects and better ​ RF ablation is more effective in response rate and time to tolerance, but with no clear differences in clinical outcomes. recurrence compared with the once-conventional percutaneous ○​ Phase 2 and 3 studies have compared DEB-TACE with the ethanol injection. combination of DEB-TACE plus sorafenib, orantinib, or ​ HCC patients treated by RF ablation have 5-year survival rates brivanib, which are VEGF receptor inhibitors. Median of ~60% (Table 82-2). survival in both arms of these international trials was 25–30 ​ In tumors 90% of cases with good long-term outcome and is competitive with resection in cost-effectiveness as first-line option. 17 Radioembolization and Other Intraarterial Therapies treatment of varices to mitigate the risk of bleeding ​ Radioembolization using beads coated with yttrium-90 associated with bevacizumab. (Y-90)—an isotope that emits short-range β radiation—is the most ○​ Thus, screening for varices is becoming standard before promising alternative to TACE. first-line therapy in HCC management. ​ Several phase II studies reported objective responses and overall ​ Alternatively, sorafenib and lenvatinib are indicated for HCC in outcome with a safe profile. patients with well-preserved liver function (Child-Pugh class A) and ​ Due to the lack of phase III trials, this treatment is currently not with advanced tumors either as first-line treatment in patients with recommended in guidelines. contraindications or with progression to the combination therapy ​ Radioembolization requires prevention of severe lung shunting (Fig. 82-5). and intestinal radiation before the procedure. ○​ A phase III study comparing sorafenib versus placebo ​ Around 20% of patients present with liver-related toxicity and 3% showed increased survival from 7.9 months to 10.7 months experience treatment-related death. (hazard ratio [HR] 0.69; 31% reduction in risk of death). ​ Due to the minimally embolic effect of Y-90 microspheres, ○​ Patients with HCV-related HCC achieve significantly better treatment can be safely used in patients with portal vein outcomes with sorafenib, with a median survival of 14 thrombosis, a setting where survival results in phase II were months. encouraging. ○​ No predictive biomarkers of responsiveness to sorafenib ​ However, three randomised controlled trials, including two have been identified. head-to-head trials against sorafenib and one trial combining ○​ The recommended daily dose of sorafenib is 800 mg. radioembolization plus sorafenib versus sorafenib alone, did not ○​ Median treatment duration is about 6 months. show OS endpoint superiority. Thus, these treatments are not ○​ Treatment is associated with adverse events, such as indicated in the advanced-stage scenario. diarrhea, hand-foot skin reactions, fatigue, and ​ TACE should be distinguished from other intraarterial therapies, hypertension. such as chemo-lipiodolization, which involves the delivery of an ○​ These toxicities lead to treatment discontinuation in 15% of emulsion of chemotherapy mixed with lipiodol; bland transcatheter patients and dose reduction in up to half. embolization, where no chemotherapeutic agent is delivered; and ○​ This therapy cannot be administered to around one-third of intraarterial chemotherapy, where no embolization is performed. the targeted patients due to primary intolerance, advanced None of these approaches is recommended due to the lack of age, or liver failure (ascites or encephalopathy). survival benefit. ○​ Active vascular disease, either coronary or peripheral, is considered a formal contraindication. SYSTEMIC THERAPIES ○​ The efficacy of sorafenib probably results from a balance ​ Conventional systemic chemotherapy and radiotherapy have not between targeting cancer cells and the microenvironment by produced survival advantages. Randomized studies also failed to blocking up to 40 kinases, including antiangiogenic (VEGF show benefit with antiestrogen therapies and vitamin D receptor [VEGFR], plateletderived growth factor receptor derivatives. [PDGFR]) and antiproliferative drivers ​ External beam liver-directed radiotherapy (stereotactic body (serine/threonine-protein kinase B-raf [BRAF] and mast/stem radiotherapy) efficacy is currently being tested with and without cell growth factor receptor [c-Kit]) (Fig. 82-6). sorafenib in phase III trials. ○​ Median time to progression on sorafenib is 4–5 months in ​ In 2007, a phase III trial demonstrated survival benefits for phase III trials. patients with advanced-stage disease treated with sorafenib, and lenvatinib showed similar effects to sorafenib in first-line treatment. ​ Recently, the combination of atezolizumab with bevacizumab demonstrated survival benefits in the advanced setting when compared to sorafenib and has now become the standard first-line treatment. ​ Three additional therapies, regorafenib, cabozantinib, and ramucirumab (only in patients with AFP >400 ng/mL), have been shown to benefit patients progressing on sorafenib. ​ Another alternative to sorafenib is the multikinase inhibitor lenvatinib; it was noninferior in a phase 3 investigation (13.6 months vs 12.3 months; HR 0.92) (Fig. 82-5). ○​ Lenvatinib induces objective responses in 24% of cases. ○​ The main side effects are hypertens