Western GI Malignancies 2025 Student Version (PDF)

GI Malignancies Leonard Mankin, MD, FACP Associate Program Director Legacy Health, Portland, OR Associate Professor of Medicine Oregon Health & Science University Assistant Professor of Medicine Western COMP-NW [email protected] Objectives of this lecture T...

GI Malignancies Leonard Mankin, MD, FACP Associate Program Director Legacy Health, Portland, OR Associate Professor of Medicine Oregon Health & Science University Assistant Professor of Medicine Western COMP-NW [email protected] Objectives of this lecture The information provided in this lecture will allow students to recognize, evaluate, and treat patients with GI malignancies. Risk factors and prevention will be emphasized, and the role of the primary care physician will be highlighted.  Scope of Presentation Gastrointestinal Malignancies Esophagus Stomach Small bowel Colorectal Pancreas Liver Esophageal Cancer Esophageal Cancer In U.S. - ~16,000 deaths per year (81% men) - 7th leading cause of cancer death in men - Affects mostly men > 50 years - Lifetime risk 1:125 men; 1:417 women Two main subtypes: 1. Squamous cell carcinoma 2. Adenocarcinoma American Cancer Society: Key Statistics for Esophageal Cancer 2023 https://www.cancer.org/cancer/esophagus-cancer  Squamous Cell Carcinoma (ESCC) 90% of esophageal cancers worldwide, esp. in Asia, Africa and South America Affects mostly upper/middle esophagus Risk Factors: poor nutrition, smoking, alcohol, hot tea, radiation, nitrites, lye In US, alcohol/smoking/African American race are main risks N Engl J Med 2014;371:2499-2509 “The Asian esophageal cancer belt”  Adenocarcinoma (EAC) In 1960s, < 10% of esophageal cancers in US Rapidly increasing incidence over last 50 years; now the #1 cause of esophageal cancer in North America and Europe 75% occur in distal esophagus near LES Risk factors: GERD and obesity Barrett’s Esophagus often a precursor https://www.cancer.gov/types/esophageal/hp/esophageal-screening-pdq N Engl J Med 2014;371:2499-2509 Int J oncol 2012;41:414-424 Esophageal Adenocarcinoma Risk factors for Esophageal Cancers Can J Gastroenterol 2012;26:723-727 Esophageal Adenocarcinoma Esophageal Cancer - presentation Dysphagia of solids, odynophagia (pain), heartburn unresponsive to therapy, emesis and rapid weight loss Hoarseness may occur from laryngeal nerve involvement Cancer tends to spread to local structures (lymph nodes, lungs, pleura) rather than hematogenously  Barrett’s Esophagus Normal squamous epithelium gets replaced by specialized intestinal columnar epithelium (metaplasia) due to chronic exposure to acid  EAC Pathogenesis Normal squamous epithelium Chronic GERD Intestinal columnar epithelium (metaplasia) Low grade dysplasia High grade dysplasia Esophageal adenocarcinoma  Barrett’s Esophagus Risk Factors: - Chronic GERD symptoms (>5 years) - Advancing age (>50 years) - Male gender - Tobacco usage - Central obesity - Caucasian race - First degree relative with BE Am J Gastro 2016;1:30-50  Barrett’s Esophagus - caveats Presence of H pylori has an inverse association with BE – less acidic environment due to atrophic gastritis Alcohol consumption does not increase risk of BE. Wine drinking may be a protective factor Am J Gastro 2016;1:30-50 Int J oncol 2012;41:414-424 Should we screen for Barrett’s Esophagus? (controversial)  ACG Guidelines for Barrett’s Who gets screened? Consider screening in pts with chronic GERD (>5 years) and ≥ 3 additional risk factors (age >50, male sex, white race, obesity, smoking, 1st degree relative with BE) Evidence does not support screening women or the general population Am J Gastroenterol 2016;1:30-50 Am J Gastroenterol 2022;117:559-587  ACG Screening Guidelines How to screen and Rx: EGD is the preferred method of screening - If normal no further screening - BE without dysplasia Longterm PPI and repeat EGD q 3-5 years - BE with dysplasia Endoscopic ablative therapy Surveillance thereafter Am J Gastro 2016;1:30-50 Endoscopic ablation of BE or early-stage adenocarcinoma A B Adenocarcinoma Suction cup ablation C D Radiofrequency ablation Resolution at 3 mos Am J Gastro 2016;1:30-50  Shortcomings of Screening Only 5-15% of pts with chronic (>5 yrs) and frequent (≥weekly) GERD symptoms have BE Up to 50% of patients with BE or EAC do not report chronic reflux symptoms Majority with BE never develop EAC and die from other causes No randomized trials showing mortality benefit or cost effectiveness NCI recommends against screening Am J Gastroenterol 2016;1:30-50 https://www.cancer.gov/types/esophageal/hp/esophageal-screening-pdq#_71_toc Possible new direction for screening? RCT of cytosponge to collect esophageal mucosal cells without anesthesia in high-risk patients helped identify patients with Barrett’s esophagus with dysplasia and early esophageal cancer Lancet 2020;396:333-344 Esophageal Cancer - Prognosis Cures are uncommon unless detected very early (~20% 5-year survival) Canadian data: 13% 5-year survival American Cancer Society 2023 statistics - 21,560 new cases diagnosed (~80% ♂) - 16,120 deaths Can J Gastroenterol 2012;26:723-727 American Cancer Society: Cancer Facts and Figures 2022 Atlanta, Ga: American Cancer Society, 2022. Last accessed Jan 7, 2023 Esophageal Cancer - Staging Prognosis and treatment strategy dependent on: - Depth of tissue affected - Lymph node involvement - Distal metastases Goal of staging is to rule out distant metastasis  Staging endoscopic biopsy CT of chest and abdomen PET CT scan * endoscopic ultrasound * * If previous study did not show distant metastases N Engl J Med 2014;371:2499-2509 (muscularis mucosa/lamina propria) (submucosa) N Engl J Med 2014;371:2499-2509 Stomach Cancer 90-year-old man with early satiety and weight loss What abnormality do you see? N Engl J Med 2017;376:73  Stomach Cancer In US1: - 26,500 new cases/year (60% men) - 11,130 deaths/year - Average age at dx: 68 years - Lifetime risk 1:96 men; 1:152 women Worldwide2: - ~ 1 million new cases/year - 3rd leading cause of cancer death (782,000/yr) - The most common infection-related cancer! 1. American Cancer Society: Key Statistics for Stomach Cancer 2023 https://www.cancer.org/cancer/stomach-cancer 2. American Cancer Society: Global Cancer Facts and Figures, 4th edition, 2018.  Stomach Cancer It was the #1 cause of cancer death in the US until ~ 1930, now not in the top 10! Why did it decline so rapidly? - Refrigeration is felt to be a key factor, allowing for more fruit/vegetable consumption and less use of salting, smoking and brining of foods - Improved sanitation and higher use of antibiotics ® decline in rates of H. pylori American Cancer Society: Key Statistics for Stomach Cancer 2023 https://www.cancer.org/cancer/stomach-cancer  Stomach Cancer trends Gastric cancer in U.S. decreasing by 1.5% per year over the past decade https://www.cancer.org/cancer/stomach-cancer/about/key-statistics.html Gastric Cancer Incidence Gastric Ca Incidence by country Cancer Epidemiol Biomarkers Prev 2015; 25(1); 16–27  Gastric Cancer - types Adenocarcinoma most common (>90%) Lymphoma (~4%) Neuroendocrine tumors (carcinoid) (~3%) Stromal tumors make up the rest  Linitis plastica Rare type of adenocarcinoma marked by infiltration and thickening of the stomach lining (“Leather bottle” stomach) due to diffuse tumor invasion of stomach wall – very poor prognosis! Best seen with barium imaging or CT, not always apparent with EGD Stomach Cancer – risk factors Risk Factor Relative Risk H Pylori 2.97 Family hx of gastric cancer 2.82 High salt intake 2.05 Cigarette smoking 1.60 High fruit intake.61 High vegetable intake.75 Gastrointest Endosc 2016;84:18-28 H pylori and Gastric Ca Chronic infection Atrophic gastritis Intestinal metaplasia Gastric Cancer H pylori and Gastric Ca >90% of gastric cancer patients have had past or current H pylori infection Gastric cancer develops in 1-2% of individuals with H pylori over a lifetime Cancer development is dependent on bacterial virulence, genetics of host, and environmental factors N Engl J Med 2020;382:427-436 ACP J Club 2020;173(6):JC32-33 Gut 2020;69(12):epub ahead of print Can we prevent gastric cancer? H pylori eradication and Gastric Ca Meta-analysis of 7 randomized prevention trials in East Asia (n=8,323) Eradication of H pylori resulted in: - 46% reduction in gastric cancer - 39% reduction in gastric cancer mortality Controversial in US where incidence is low N Engl J Med 2020;382:427-436 N Engl J Med 2018;378:1085-1095 N Engl J Med 2018;378:1154-1156 Gut 2020;69(12):epub ahead of print  Gastric Cancer - Presentation History: - Weight Loss (early satiety, anorexia, nausea) - Abdominal Pain - Bloating - Dysphagia (proximal cancer) - Vomiting (distal stomach-outlet obstruction) - Melena Sx often occur late – most tumors are discovered in an advanced stage, beyond cure  Gastric Cancer - Presentation Physical Exam: - Left supraclavicular adenopathy (Virchow's node) - Left axillary nodes (Irish node) - Periumbilical nodes (Sister Mary Joseph’s node) - Enlarged ovary (Krugenberg’s tumor) - Ascites (peritoneal spread) Labs: - Stools positive for occult blood - Iron deficiency anemia  Sister Mary Joseph Node Assistant to Dr. William Mayo Palpable nodule in the umbilical region signifying an underlying GI malignancy Stanford Medicine 25; Feb 24, 2016  Stomach Cancer – Dx & Staging Dx: EGD with biopsy Staging: - CT scan - Endoscopic US - PET or PET CT - laparoscopy Purpose of work up is to accurately stage and decide if surgery +/- neoadjuvant therapy is indicated  Stomach Cancer - Prognosis Stage 5-year survival Localized 69% Regional 31% Distant 5% All stages combined 32% https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/survival-rates.html  Staging of Gastric Cancer with CT Scan Localized to stomach (A)--resectable Metastatic to liver and invading inferior vena cava (B) C Invasion into large vessels (C) A B Staging of gastric cancer Gastric Ca - Rx Early cancers endoscopic resection Non-early, operable tumors surgical resection + lymphadenectomy + adjuvant chemotherapy Non-operable cancers sequential chemotherapy (median survival < 1 year) Lancet 2020;396:635-648 Small Bowel Cancers  General information 11,790 new cases and 1,960 deaths/yr in US1 3% of GI cancers (yet small bowel makes up ~90% of surface area of GI tract)1 Histology2 - Carcinoid – 37% - Adenocarcinoma – 37% - Lymphomas – 17% - Sarcoma, usu. GI stromal tumors (GIST) – 8% www.cancer.org/cancer/small-intestine-cancer/about/what-is-key-statistics.html Ann Surg. 2009;249(1):63-71 Predisposing Factors Celiac Disease - Increased risk of GI lymphoma - Risk decreased with gluten-free diet Crohn’s Disease - Usually involving distal ileum Hereditary Syndromes - Lynch Syndrome (HNPCC) - Familial Adenomatous Polyposis (FAP) - Peutz-Jeghers  Small bowel CA - Dx Non-specific symptoms (abdominal pain, N/V, bloating, and cramping) often leads to a delay in dx and advanced stage at dx About ½ of cancers need emergent surgery at time of dx (obstruction, perforation, bleed) Dx often achieved through combination of radiographic (CT or MR enterography) and endoscopic (EGD, wireless capsule) studies Wireless capsule endoscopy  Carcinoid/NET Carcinoid = cancer of neuroendocrine cells, which have properties of nerves and endocrine cells Neuroendocrine tumor (NET) is preferred term Rare tumors of enterochromaffin cells Most common tumor affecting the small bowel Most often asymptomatic and found on EGD or colonoscopy as an incidental finding High overall 5-year survival rates (77-95%) unless distant mets (42%)  NET - Distribution NET most often found in the GI tract (55%) or lung (30%) GI tract distribution: - Small intestine 45% - Rectum 20% - Appendix 16% - Colon 11% - Stomach 7% Ann Surg. 2004;240(1):117-122  Carcinoid Syndrome Carcinoid syndrome - syndrome of cutaneous flushing and diarrhea caused by NET release of serotonin, usually from a tumor of small bowel origin If suspected, dx made by check of 24-hr urine 5-HIAA, the breakdown product of serotonin Colorectal Cancer  Colorectal Cancer (CRC) Stats - 2023 3rd most common cancer in U.S. Colon: 106,970 new cases/year Rectum: 46,050 new cases/year - 52,550 deaths/year – 2nd most common cause of cancer death (men + women) - Lifetime risk for colon cancer is ~ 4% - Median age at detection is 66 https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html  CRC Trends in past ~20 years Age > 65 – declining incidence (3.3%/yr) and mortality Age 50-65 – increasing incidence (1%/yr), although death rates are still declining Age < 50 – steadily increasing incidence (2%/yr) and death rate (1.3%/yr) 1. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html 2. CA Cancer J Clin 2020;70(3):145. Epub 2020 Mar 5 Why are CRC death rates decreasing in older adults (age > 65)? Removal of precancerous polyps during screening Discovery of cancers at earlier stages during screening More effective treatments have developed Why are CRC death rates increasing in younger adults (age < 50)? Increased sedentary lifestyle Dietary factors Obesity Other exposures?  CRC – Risk Factors Non-Modifiable Risks Age Race/Ethnicity Heredity IBD 1. www.cancer.org Colorectal Cancer Facts and Figures 2020-2022  CRC Incidence by Age www.cancer.org  CRC by Race/Ethnicity 50 45 40 35 Rate per 100,000 30 25 20 15 10 5 0 CRC Incidence CRC Death Black Native American Non-Hispanic White Hispanic/Latino Asian/Pacific Islander Source: Incidence – NAACCR, 2019. Mortality – NCHS, 2019  CRC – Family Hx Roughly 30% of patients with CRC have a family hx of CRC or adenomatous polyps www.cancer.org Colorectal Cancer Facts and Figures 2020-2022  CRC – Family Hx www.cancer.org Colorectal Cancer Facts and Figures 2020-2022 CRC – Hereditary Syndromes Lynch Syndrome (3% of CRC) Familial Adenomatous Polyposis (90% develop CRC by age 45! Rx: total colectomy  Familial Adenomatous Polyposis UpToDate 2020: Colorectal Cancer – Epidemiology, risk factors and protective factors Peutz-Jeghers syndrome (PJS) Rare autosomal dominant syndrome due to mutation in STK11 Est. incidence: 1 in 8,000 to 1 in 200,000 births 3 main manifestations: 1. Pigmented mucocutaneous macules 2. Hamartomatous polyps throughout the GI tract 3. GI and extraintestinal malignancies Peutz-Jeghers Syndrome (PJS) May present in teens/young adulthood with: - Iron deficiency anemia - Abdominal pains - Small bowel obstruction - Intussusception  Peutz-Jeghers Syndrome A. Mucocutaneous macules B. “Target sign” of jejunojejunal intussusception C. Jejunal resection with hamartomatous polyps and area of necrosis N Engl J Med 2019; 380:472  PJS and Malignancy Very high lifetime risk of cancer (37-93%) Median age of cancer = 42 Malignancies occur in virtually every part of the GI tract; CRC most common Breast, lung, ovarian, uterine, testicular, cervical cancer risks all increased Yearly physicals/labs, frequent endoscopies (EGD + video capsule + colonoscopy), and other cancer screens a must!  CRC and IBD People with IBD have roughly double the risk of developing CRC1 Cancer risk correlates with disease activity, percent of colon involved, and duration IBD patients with CRC have higher mortality than those without IBD2 IBD patients should undergo first screening colonoscopy 8 years after initial dx3 1. Inflamm Bowel Dis. 2013;19(4):789-799 2. Dig Dis Sci. 2017;62(8):2126-2132 3. Am J Gastroenterol 2010;105:2405-2411  CRC – Risk Factors Non-Modifiable Risks Age Race/Ethnicity Heredity IBD 1. www.cancer.org Colorectal Cancer Facts and Figures 2020-2022 CRC – Risk Factors Non-Modifiable Risks Modifiable Risks (55%) Age Diet Race/Ethnicity Lack of physical activity Heredity Alcohol IBD Smoking Obesity Low socioeconomic status2 - 40% higher incidence than highest earners (increased risk factors + decreased screening) 1. www.cancer.org Colorectal Cancer Facts and Figures 2020-2022 2. Cancer 2012;118(14):3636-3644  CRC and Diet May influence risk as a result of excess calories obesity May influence the gut microbiome, which modulates gut immune response and inflammation Difficult to pinpoint specific dietary triggers: - Inaccuracy of dietary self-reports in studies - Strong link to diet and other behaviors  CRC and Food Associations* Lower Risk Higher Risk Calcium from dairy source Processed meats Whole grains/fiber Red meat Fruits and vegetables Refined carbohydrates Vitamin D Processed sugar * Take this with a grain of salt, which may also be associated with increased risk of CRC www.cancer.org Colorectal Cancer Facts and Figures 2020-2022 Meat consumption and CRC risk The risk of CRC is increased by 18% for every 50g/d of processed meat consumed and by 12% for every 100g/d of red meat1 In 2015, the International Agency for Research on Cancer classified processed meats as “carcinogenic to humans”2 1. Ann Oncol 2017;28(8):1788-1802 2. Lancet Oncol 2015;16(16):1599-1600  CRC and Physical Activity The most physically active people have a 25% lower risk of CRC than the least active1-2 People who watch the most TV have a 25- 50% increased rate of CRC3 1. J Natl Cancer Inst 2012;104(20):1548-1561 2. Eur J Cancer Prev 2013;22(6):492-505 3. J Natl Cancer Inst 2014;106(7) CRC and Obesity Compared to normal weight individuals, obese men have a 50% increased likelihood of colon cancer, and obese women have a 10% increased risk European J Cancer Prev 2017;26(1):94-105  CRC - Tobacco 12% of CRC in US attributed to tobacco1 CRC risk is 50% higher in current smokers vs never smokers2 Survival rates are lower in CRC patients who smoke3-4 1. CA Cancer J Clin. 2018;68(1):31-54 2. N Engl J Med 2015;372:631-640 3. J Clin Oncol 2015;33(8):885-893 4. Ann Oncol 2018;29(2):472-483  CRC - Alcohol 13% of CRC in US attributed to alcohol1 CRC risk is 25-44% higher in individuals who consume heavy amounts of alcohol (>3 drinks/day)2-3 1. CA Cancer J Clin 2018;68(1):31-54 2. Int J Cancer 2020;146(3):861-873 3. Br J Cancer 2015;112(3):580-593  NSAIDs and CRC A substantial body of evidence links regular use of aspirin and other NSAIDs to a 20-40% risk reduction in colonic adenomas and CRC1-2 In a large cancer prevention trial (PLCO), aspirin use 3 days/week was associated with a 29% reduction in death from CRC3 1. Lancet 2011;377(9759):31-41 2. Lancet 2010;376(9754):1741-1750 3. JAMA Netw Open 2019;2(12):e1916729 Aspirin is not recommended as a preventive measure for colorectal cancer due to bleeding risks Screening for Colon Cancer  Keys to Appropriate Screening Important disease Common and well understood Detectable prior to late stages Suitable test to detect early disease - (accurate, readily available, easy to perform, acceptable to public, cost effective, low harms) Effective treatment widely available Treatment of disease in early stages reduces morbidity/mortality  CRC Scoreboard Important disease Common and well understood Detectable prior to late stages Suitable test to detect early disease - (accurate, readily available, easy to perform, acceptable to public, cost effective, low harms) Effective treatment widely available Treatment of disease in early stages reduces morbidity/mortality Guiding principles Adenomatous polyps are dysplastic and precursors to CRC There is a lag period of about 5-20 years for a polyp to transform into CRC Polyps can be resected endoscopically prior to becoming cancerous Screening can also detect CRC at earlier stages Colon cancer localized within a polyp Characteristics of Polyps Larger polyps (> 1 cm) more worrisome Flat, sessile, and serrated polyps more concerning than pedunculated Multiple polyps increase likelihood of subsequent cancer Adenomatous Polyps (dysplasia) 3 Main histologic types: 1. Tubular – most common type; low malignant potential 2. Tubulovillous – intermediate potential 3. Villous adenoma – highest rate of malignant transformation  Hyperplastic polyps (non- adenomatous) are quite common and appear to have no malignant potential  CRC – Distribution* BMJ 2016;354:i3590 *Roughly 2/3 of CRC occur beyond the splenic flexure Acceptable screening methods Colonoscopy (Gold Standard) Most Fecal immunochemical test (FIT) commonly used Fecal DNA test (Cologuard®) CT colonography Double-contrast barium enema Flexible sigmoidoscopy Fecal occult blood test (FOBT) Choosing screening tool for CRC No comparison trials between methods Offering patients screening choices increases overall adherence to screening, so all options are viable Form of test used is determined by availability, patient preferences, and cost  Colonoscopy (Most Common Method) Advantages Entire colon visualized Most sensitive test for polyp and cancer detection Can biopsy and remove polyps Can diagnose other conditions Repeat every 10 years if normal exam in low-risk patients  Colonoscopy (Most Common Method) Advantages Disadvantages Entire colon visualized Bowel preparation Most sensitive test for polyp Exam limited if bowel and cancer detection preparation is poor Can biopsy and remove Miss rates up to 6% polyps Usually requires sedation Can diagnose other Small risk involved (bleeding, conditions perforation, anesthesia)* Repeat every 10 years if Expensive normal exam in low-risk patients Must have ride home and missed day of work * 0.3-0.6% of patients examined Once you’ve had a colonoscopy, then what?  Surveillance/Screening Intervals N Engl J Med 2016; 374:1065-1075 ACP screening recommendations for asymptomatic average risk adults* 1. FIT or guaiac-FOBT every 2 years or 2. Colonoscopy every 10 years or 3. Flexible sigmoidoscopy every 10 years accompanied by FIT every 2 years * Average risk = no personal or family hx of CRC, IBD or genetic syndrome Ann Intern Med 2019;171:I-22 At what age should we begin screening for CRC?  When should we start CRC screening for average risk adults? USPSTF1 and ACG2 guidelines: - Start at age 50 (grade A), but consider starting age 45 for average risk individuals(grade B) ACP3 guidelines: - Start at age 50 1. uspreventiveservicestaskforce.org - May 2021 2. Am J gastroenterol 2022;117:57-69 3. Ann Intern Med 2023;176:1092-1100  Screening in patients with a family history of CRC Begin screening at age 40, or 10 years prior to the age at which the malignancy was discovered in their relative Screen using colonoscopy every 5 years Examples: - Patient’s mother diagnosed with CRC at age 45 screening colonoscopy q 5 years beginning at age 35 - Patient’s father with CRC at age 60 screening colonoscopy q 5 years beginning at age 40 When to stop CRC screening (USPSTF) Selectively offer screening for ages 76 - 85 Do not screen age ≥ 85 (risk>benefit) Do not screen adults with a life expectancy of 10 years or less! CRC Presentation  CRC – Symptoms 70-90% of patients present at an advanced stage, as symptoms develop late and are non-specific (abdominal pain, bloating, diarrhea, constipation) Hematochezia Fatigue (iron deficiency anemia) Anorexia/unexplained weight loss Change in stool caliber (“pencil-thin stools”) Bowel Obstruction due to Colon CA (Apple Core lesion) CRC - Physical Findings Uncommon until advanced disease Rectal mass – 10-25% of colorectal CA Blood in stool Abdominal mass Hepatomegaly CRC – Staging and Prognosis  Staging CRC – TNM classification T describes tumor penetration N describes nodes—location and number involved M describes distant metastasis—where liver is most common (lung occasionally with rectal cancer) Stage Penetration Nodes Mets 0 Mucosa No No I Submucosa No No IIA Muscularis propria No No IIB To Surface No No Peritoneum IIIA,B,C Varies, but can be Yes No to Peritoneum IV Varies Yes Yes CRC – 5-year survival (2009-2015) Stage Colon Rectum I 92% 87% IIA 87% 80% IIB 63% 49% IIIA 89% 84% IIIB 69% 71% IIIC 53% 58% IV 11% 12% Source: SEER Program, 2019 1. www.cancer.org Colorectal Cancer Facts and Figures 2020-2022 Work-up for Staging CT scan abdomen and pelvis CXR for colon cancer CT scan of chest for rectal cancer, as rectal drainage is via hemorrhoidal veins to IVC, bypassing liver and frequently metastasizing to the lungs CEA = Carcinoembryonic Antigen, a tumor marker in blood often seen with CRC  Tumor Markers - CEA Not helpful for dx (sens 46%, spec 89%) Pts with CEA > 5 at time of dx have worse prognosis across all stages CEA useful to determine success of surgery and for surveillance after treatment Treatment Localized Disease (80%) - Surgical resection for localized disease - Adjuvant chemotherapy to treat potential micro-metastases Metastatic disease (20%) - Resection of primary lesion and mets + chemotherapy (when only few mets found) - Palliative surgery to prevent obstruction or bleeding +/- chemoRx or XRT Pancreatic Cancer  Pancreatic Cancer Stats - 2023 64,050 new cases/yr (men≈women) 50,550 deaths/yr Highly Lethal! 11th most common cancer, but 3rd leading cause of cancer death in US Lifetime risk is about 1 in 64 (1.6%) Median age at dx = 71 https://www.cancer.org/cancer/pancreatic-cancer/about/key-statistics.html  Pancreatic CA - general 85% ductal adenocarcinoma (exocrine) - 60-70% located in head - 20-25% in body or tail >90% with mutations in KRAS gene Risk factors are primarily smoking and chronic pancreatitis; DM present in 50%, often of recent onset No accepted screening tool N Engl J Med 2014; 371:1039-1049 Anatomy  Pancreatic CA - presentation Most common sx are asthenia (severe fatigue & weakness), abdominal pain (often radiating to back), anorexia and weight loss Presentation dependent on location of tumor: - Tumors of head often cause obstructive “painless jaundice” with light stools, dark urine & pruritis - Body and tail cancers generally don’t cause sx due to their location until they are very advanced N Engl J Med 2014; 371:1039-1049 Pancreatic CA – Physical Exam Epigastric tenderness Jaundice Abdominal mass or palpable liver Ascites Non-tender palpable gallbladder (Courvoisier’s sign) Left supraclavicular nodes (Virchow’s) Sister Mary Joseph’s node (periumbilical) Thrombophlebitis (Trousseau’s sign) Blood Tests Anemia Elevated alkaline phosphatase, bilirubin, GGT if biliary obstruction present Elevated amylase & lipase (less likely) Elevated blood sugar Elevated tumor markers: - Not for dx, but may be useful for monitoring of treatment - CA 19-9 = 70 to 85% - CEA = 30 to 40%  Imaging CT scan of abdomen is gold standard - Sensitivity 100% with lesions > 2cm; only 75% if < 2cm - High predictive value for unresectability – need to assess local lymph nodes and vascular invasion MRI (magnetic resonance imaging) and MRCP (magnetic resonance cholangio-pancreatogram) may pick up lesions missed on CT Endoscopic ultrasound (ERCP) – usual method for obtaining biopsy; can provide info regarding spread PET scan – helpful to pick up smaller mets CT Scan - Pancreatic CA  Pancreatic CA - Rx >90% of patients with pancreatic cancer die of their disease Only chance for cure is surgery (Whipple’s procedure = pancreaticoduodenectomy) Resectability is determined by lack of involvement of local vasculature and absence of metastases. Only 15-20% of pts are eligible for surgery at time of dx N Engl J Med 2014; 371:1039-1049 Resectability of Pancreatic CA N Engl J Med 2014; 371:1039-1049  Pancreatic Cancer – Prognosis1 Overall: - 9% 5-year survival - 25% 1-year survival Pts who undergo Whipple’s surgery: - 30% 5-year survival if node negative (1/3 of pts) - 5% 5-year survival if node positive (2/3 of pts) - 800,000 new cases and >700,000 deaths per year Highest burden in SE Asia and sub-Saharan Africa HBV and HCV account for 70% of cases 1. www.cancer.org/cancer/liver-cancer/about/what-is-key-statistics.html 2. Nat Rev Gastroenterol Hepatol 2019;16(10):589-604  HCC Incidence N Engl J Med 2019; 380:1450-1462  HCC and cirrhosis HCC typically presents in people with cirrhosis or chronic liver disease Cirrhosis from any cause carries a 1-8% annual risk of HCC  HCC Trends HCC rates in the US have more than tripled since 1980 HCC death rates have increased by 43% between 2000 and 2016 A meteoric rise in obesity and DM is thought to be the likely etiology, leading to non-alcoholic fatty liver disease (NAFLD) 1. www.cancer.org/cancer/liver-cancer/about/what-is-key-statistics.html 2. N Engl J Med 2019;380:1450-1462  HCC risk factors Front Oncol;2020 doi: 10.3389/fonc.2020.601710 Hepatoma in the background of cirrhosis  HCC Risks – Viral Hepatitis Worldwide, HBV accounts for about 50% of cases, and HCV for another 20%1 HBV - HCC may occur in patients without cirrhosis - Increased risk with young age at acquisition, alcohol, tobacco, coinfection with HCV or Hep D, and ingestion of dietary aflatoxin B-1, a grain contaminant HCV - HCC only occurs with advanced fibrosis or cirrhosis - Increased risk with genotype 1B, alcohol, tobacco, and coinfection with HBV or HIV 1. Int J Cancer. 2018;142(12):2471  HCC Risks – Metabolic Disease MASLD is a rapidly increasing cause of cirrhosis and HCC in Western countries DM 2 and obesity are each independently associated with an approximate doubling of the risk of HCC  Surveillance for HCC HCC is a highly lethal disease, and does not typically cause symptoms prior to dx Surveillance is, in effect, a “screening” program in patients with chronic liver disease, hoping that earlier detection will improve survival Controversial – no RCTs, but indirect evidence suggests mortality benefit Method: Liver ultrasound q 6 months ± serum alpha fetoprotein (AFP), a tumor marker HCC on Ultrasound  HCC - Dx Often made by distinctive radiologic features in the setting of chronic liver disease, without need for biopsy HCC creates a blood supply via the hepatic artery, whereas benign liver nodules are supplied via portal vein Contrast CT will show tumor enhancement in arterial phase and washout in venous phase HCC Dx by Multiphase CT Scan HCC – Prognosis and Treatment  HCC - Prognosis 2nd most lethal common cancer 5-year survival of 18% Median survival is 6-20 months  HCC Rx - considerations Since most patients with HCC have underlying liver disease, benefits of therapy must be weighed against potential for harms and decompensation of chronic liver disease – hospice is a good option for many patients who are not candidates for liver transplant* Best candidates for cure have solitary tumor at an early stage with preserved liver function – up to 60% 5-yr survival, but up to 70% will have tumor recurrence N Engl J Med 2019; 380:1450-1462 * Personal opinion  HCC - Rx Resection – most are unresectable Ablation – radiation, microwave, percutaneous injection of ethanol or acetic acid Transplantation Chemoembolization – arterial catheter to tumor’s blood supply, inject chemo and then embolize the artery to prevent washout of the drug Systemic chemo or immunotherapy – more advanced disease Chemoembolization of HCC