Insights on GI Malignancies and Hepatocellular Carcinoma Management

GI Malignancies SWOH Internal Medicine Update & Review Course 02/03/2018 Olugbenga Olowokure MD Associate Professor, Division Of Hematology-Oncology University Of Cincinnati

SITEMAN CANCER CENTER Estimated US GI Cancer Deaths - 2016 Men Women Lung & bronchus27% Prostate Colorectal Pancreas Liver/Cholangio 6% Leukemia Esophagus Urinary bladder 4% NHL Brain/CNS All other sites 25% 26% Lung & bronchus 14% Breast 8% Colorectal 7% Pancreas 5% Ovary 4% Uterine corpus 4% Leukemia 3% Liver/Cholangio 3% NHL 2% Brain/CNS 24% All other sites 8% 8% 7% 4% 4% 4% 3%

1) A 58-year-old female presents with a seven month history of intermittent bloody stools. She has no past medical history. Rectal exam reveals an anal mass . Anoscopy is performed and she has a 1.8 cm mass. CT C/A/P is negative with no pathologic appearing LAD. Biopsy of the anal mass reveals anal cancer at the margin. The pathologist says it is HPV+ and is well-differentiated, tumor is KRAS wild type. How do you manage her? A. Mitomycin/5-FU with Radiation B. Radiation only C. Mitomycin/5-FU plus cetuximab D. Surgery alone E. FOLFOX + Cetuximab

Question 1= D KRAS wild type anal cancer tumors are not treated with cetuximab at this time For Anal margin cancer (T1 well differentiated only): Surgery alone with clear margins For Anal canal cancer (T1-T4, or N+): Chemoradiation with Mitomycin/5-FU Ref: NCCN Anal cancer guidelines 2016

2) A 52-year-old woman is being followed for a 20-year history of hepatitis C, Child A liver function, with liver cirrhosis by imaging criteria. Serial AFP serum levels over the last 6 months have shown a significant increase from 10 to 100 mg/mL. She is asymptomatic and does not have any jaundice. An abdominal MRI reveals intrahepatic, multifocal (>10) scattered enhancing lesions in both lobes (largest 4.2 cm) as well as a non-occlusive portal vein thrombus. No extrahepatic disease is seen. An ultrasound-guided biopsy demonstrates moderately differentiated hepatocellular carcinoma. The patient now consults medical oncology for an opinion regarding the best management of her malignant disease.

Child-Pugh Score Measure 1 Point Each < 2.0 > 3.5 1.0-3.0 None None 2 Points Each 2.0-3.0 2.8-3.5 4.0-6.0 Slight I-II 3 Points Each > 3.0 < 2.8 > 6.0 Moderate III-IV Bilirubin (mg/dL) Albumin (g/dL) Prothrombin time (sec) Ascites Encephalopathy (grade) Grade A B C Total Points 5-6 7-9 10-15 Surgical Risk Good Moderate Poor Pugh RN, et al. Br J Surg. 1973;60:646-649.

Which of the following statements is correct with regard to the available treatment options? A. Transcatheter arterial chemoembolization (TACE) is contraindicated in a patient with non-occlusive portal vein thrombosis Tumor debulking by radiofrequency ablation of the dominating metastases would be useful to prolong the life expectancy of this patient Sorafenib has not been shown to be effective in patients with hepatitis C-derived hepatocellular carcinoma Sorafenib has been shown to prolong overall survival in patients with hepatocellular carcinoma and Child A liver dysfunction compared with best supportive care Doxorubicin is the standard first-line medical therapy for patients with unresectable HCC with normal bilirubin B. C. D. E.

Question 2 = D Sorafenib has been shown to prolong overall survival in patients with hepatocellular carcinoma and Child A liver dysfunction compared with best supportive care Based on SHARP trial, there is OS benefit for Sorafenib (Child Pugh score A). Sorafenib is a multikinase inhibitor of the VEGF pathway, RAF and PDGFR. The SHARP study was a Phase III, double-blind study that looked at over 600 patients with advanced, treatment na ve patients with HCC. Patients were randomized to either sorafenib or placebo. The median OS favored the sorafenib arm (10.7 months vs. 7.9 months; P<0.001). Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90

3. A 70-year-old man, complains about increased difficulty in swallowing solid foods. He has a long-standing history of gastroesophageal reflux, treated with a PPI. An EGD reveals a friable, mass in the stomach with biopsy confirming the presence of a moderately differentiated adenocarcinoma. Abdominal CT scan reveals three 2 cm lesions in the right lobe of the liver and enlarged celiac lymph nodes. Based on the limited options below What would be the most appropriate next step in order to plan treatment A. B. C. Test for KRAS in the tumor biopsies. Obtain a head MRI No further testing is needed to make a treatment decision Test for HER2 /Neu in the biopsy specimen Order a positron emission tomography (PET) Scan Biopsy one of the liver lesions to confirm metastatic disease D. E. F.

Question: - 3 = D HER2 overexpression has been found in approximately 25% to 30% of patients with gastric /GEJ adenocarcinomas. HER2-positive gastric cancers demonstrate significantly improved outcomes when trastuzumab, a monoclonal antibody against HER2, is added to chemotherapy Suggested Readings Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro- oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697. Epub 2010 Aug 19. PMID: 20728210

4. A 55-year-old man with a PMH of hypertension and DM, is diagnosed with a mass in the caecum. He has a good performance status and no other relevant comorbidities. He has no family history of colon cancer. He undergoes a right hemicolectomy without surgical complications. Pathology confirms the presence of an undifferentiated adenocarcinoma, pT3N0M0 (0/12 lymph nodes) without lymphovascular or invasion. Immunohistochemistry identifies loss of MSH2 protein expression. The patient wants to be very aggressive to reduce the risk of tumor recurrence. What would you suggest he gets as adjuvant therapy. A. No treatment B. 6 months of treatment with 5- fluorouracil/leucovorin C. 6 months of treatment with capecitabine D. 6 months of treatment with a fluoropyrimidine plus oxaliplatin[FOLFOX] E. 6 months of treatment with 5- FU/LV/irinotecan (FOLFIRI)

Question 4: - A The tumor characteristics (right-sided, undifferentiated histology, and stage II) suggested the presence of a defective mismatch repair enzyme phenotype (MMR-D or MSI-H), which was confirmed by demonstrating the loss of MSH2 protein expression. These tumors have an excellent prognosis and, in the absence of other clinical high- risk factors, do not require any further adjuvant therapy. Suggested Readings O Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937-3944. Epub 2010 Aug 2. PMID: 20679606. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219-3226. Epub 2010 May 24. PMID: 20498393.

5) A 60-year-old man presents with a 3 month history of abdominal discomfort with floating stools. MRI reveals a 3 cm mass at the pancreatic head. It is completely encases the celiac axis but does not involve the SMV, SMA, or Hepatic Artery. There are no enlarged lymph nodes. PET-CT confirms the above findings with no distant metastasis detected. What is the patient s TNM t score and what therapy should be considered? A. T4; Chemotherapy or chemoradiation B. T2; Whipple surgery C. T4; Whipple surgery D. T3; Whipple surgery E. T2; Chemoradiation F. T3; Chemotherapy or chemoradiation

Question 5: - A -T1 lesion limited to pancreas 2cm or less. -T2= more than 2 cm but limited to pancreas -T3= tumor extends beyond the pancreas but without involvement of celiac axis or SMA -T4 lesion connotes celiac axis or SMA involvement. -The patient has full encasement of the celiac axis; this makes his tumor unresectable as these areas cannot be reconstructed -T1, T2, T3 lesions are all possibly resectable. http://www.nccn.org/professionals/physician_gls/pdf/pancre atic.pdf

6) A 55-year-old female with a history of Stage III Colon cancer presents for a follow up. She was diagnosed with a Stage III (T3 N1) transverse colon adenocarcinoma 10 months ago and had this resected. She received 6 months of adjuvant chemotherapy with FOLFOX that was completed 2 month ago. In addition to a colonoscopy in 1 year, what do you recommend for surveillance? A. B. History/Physical q3-6 months, CEA q3-6 months History/Physical q3-6 months, CEA q3-6 months, yearly PET-CT History/Physical q3-6 months, CEA q3-6 months, PET- CT q6 months History/Physical q3-6 months, CEA q3-6 months, yearly CT C/A/P History/Physical q3-6 months, yearly colonoscopy, yearly CT C/A/P History/Physical q3-6 months, CEA q3-6 months, q 3 month CT History/Physical q3-6 months, q 3 yearly colonoscopy, CT as needed C. D. E. F. G.

Question 6 :D PET-CT imaging does not play a definitive role in the surveillance of colon cancer patients. The standard adjuvant therapy in patients with stage III colon cancer without any treatment-limiting contraindications is a combination of a fluoropyrimidine (either 5- FU/LV or capecitabine) and oxaliplatin (FOLFOX or XELOX). SuggestedReadingsAndr T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. PMID: 15175436. NCCN colon cancer guideline and MKSAP 17 hematology/oncology book Andr T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109-3116. Epub 2009 May 18. PMID: 19451431

7) A 66-year-old lady with chronic Hepatitis C induced cirrhosis presents to see you in your out patient clinic. She had been undergoing a screening protocol with AFP and USS every 6 months. Her AFP has consistently been < 10 ng/mL. However, a recent USS reveals a 1.8cm mass in the left hepatic lobe. A 3-phase CT reveals hyperenhancement on arterial phase and washes out during the venous phase. Which of the following is true to make a diagnosis? A. A.Order an FNA B. B. A 3-phase MRI should be ordered C. C.Repeat imaging in 3 months D. D. Order a core biopsy E. E. HCC is diagnosed F. F. HCC ruled out as AFP<200 ng/mL

Question: - 7 = D The bases for this is that metastatic lesions mainly derive its blood supply from the hepatic artery while the normal liver obtains its blood supply mainly from the portal vein If you see a liver mass > 1 cm AND 2 classic enhancements (arterial hyperenhancement and washes out on venous phase), HCC is diagnosed Bruix J et al. Management of hepatocellular carcinoma. Hepatology 2005; 42(5):1208-36

8) A 60-year-old lady undergoes screening colonoscopy and is found to have a rectal mass that is biopsy proven to be adenocarcinoma. A CT Chest/Abd/Pelvis with IV contrast reveals no distant disease. A EUS is done and the patient is felt to have T2 N0 rectal adenocarcinoma. She undergoes a transabdominal resection and the final pathologic analysis confirms a T2 N0 cancer but MSI is not reported. What adjuvant therapy do you offer her? A. 5-FU monotherapy B. Observation C. Capecitabine D. 5-FU/Radiation/FOLFOX E. FOLFOX F. Obtain MSI status then decide

Question: - 8 = B For rectal cancer patients that are T1-T2/N0, no adjuvant or neoadjuvant therapy is needed. T1 lesion: Invades the submucosa T2 lesion: Invades the muscularis propria T3 lesion: Invades through muscularis propria into the pericolorectal tissues T3 or higher or N1-2, offer adjuvant therapy (or neoadjuvant therapy) Suggested reading MK-SAP 17 http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf

9) 53 year old woman reports bloody stools and progressive abdominal pain over the last 3 months. She undergoes evaluation with an Abdominal CT scan demonstrating three liver metastases in the right lobe of the liver, with the largest one 2.9 cm in size and a mass in the caecum. Colonoscopy demonstrated a near-obstructing colon adenocarcinoma. She undergoes resection of the primary tumor, which demonstrates a T3N0 moderately differentiated adenocarcinoma. Post op CEA is 15ng/ml. After recovery from surgery, she was initiated on FOLFOX chemotherapy for three months. Repeat CT scans demonstrate stability of disease. She has no symptoms and is otherwise healthy. Review of her scans at a multidisciplinary tumor board suggests that the three liver lesions are considered resectable. Which of the following approaches to chemotherapy administration is recommended at this time? A. Change to FOLFIRI with or without additional monoclonal antibodies Continue FOLFOX to maximal radiographic response with CT every 3 months C) De-escalate to 5-FU maintenance therapy D) Referral for resection without further chemotherapy E) Check CEA and if still high continue chemotherapy B. C. D. E.

Hepatic Metastases From Colorectal Carcinoma Liver Metastases Location Resectable 20% to 25% Nonresectable 75% to 80% Number Size Downsizing Chemotherapy Survival Benefit 30% to 50% at 5 years 15% at 10 years Resectable 10% to 20% Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048

Question: - 9 = D The role of perioperative chemotherapy is based on a randomized study of surgery with or without pre- and post-resection chemotherapy with FOLFOX. The duration of neoadjuvant therapy should be limited to 3 to 4 months to prevent hepatotoxicity that may increase morbidity and mortality from liver surgery. Suggested Readings Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008, 371(9617):1007-1016. Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol 2010; 17(11):2870-2876

10) 65-year-old woman is seen in the ED with hematuria and undergoes an abdominal ultrasound for a presumed kidney stone. A kidney stone is found but Incidentally, the ultrasound identifies four intrahepatic lesions scattered throughout the liver with a maximum diameter of 2.5 cm. laboratory tests including renal function test and hepatic panel are normal. An MRI scan confirms these findings and also reveals a mass in the body of the pancreas of approximately 3 cm in diameter encasing the celiac artery. Fine needle aspiration biopsy of one of the liver lesions confirms a well-differentiated metastatic neuroendocrine tumor. The patient does not have diarrhea, flushes, or skin rash. She has an excellent performance status. Which of the following do you recommend? A. Evaluation by your best GI oncologic surgeon B. Referral to interventional radiology for liver chemoembolization C. No treatment pending re-evaluation with CT imaging after 3 months D. Gemcitabine plus Nab-paclitaxel (Abraxane) E. Chemotherapy with FOLFIRINOX F. Everolimus

Question: - 10 = C She has a metastatic pancreatic neuroendocrine tumor, which is apparently nonfunctional, meaning it does not produce any hormone-related clinical symptoms. The tumor is well differentiated and is commonly characterized by rather benign biology. In general no immediate treatment intervention is warranted in asymptomatic patients with relatively low tumor volume, as with this patient. Recently, new medical treatment options have been developed, with sunitinib and everolimus demonstrating efficacy in these cancers. Somatostatin, which is routinely used in carcinoid tumors, does not play a big role in nonfunctional PNETs. Conventional chemotherapy has shown to be of some activity, but regimens are based on streptozocin and fluoropyrimidines and temozolomide (temodar) and do not follow conventional regimens for advanced adenocarcinoma of the pancreas. Chemoembolization can be used to debulk the tumor volume in liver metastases, in particular in functional (hormonally active) PNETs. Suggested Readings Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519-523. PMID: 1310159.. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523. PMID: 21306238.