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Moderator Neil Love, MD

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Moderator Neil Love, MD

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  1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. Challenging Cases in Select Gastrointestinal Cancers Oncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited Faculty Saturday, May 3, 201412:00 PM – 1:30 PM Faculty Tanios Bekaii-Saab, MD Charles S Fuchs, MD, MPH Jessica Mitchell, RN, CNP, MPH Yahna T Smith, MSN, CNP ModeratorNeil Love, MD

  3. Oncology 6-Part Case Series: Key Themes • Mechanisms of action of novel agents and tissue assays to predict response • Side effects and toxicities of novel agents; dose adjustments • Assessment and management of adherence • Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease • Local and systemic complications of cancer: Fatigue, pain, CNS involvement • Care of older, frail patients and those with comorbidities

  4. Oncology 6-Part Case Series: Key Themes • Clinical trials as a means to access new treatments earlier • Management of anxiety and depression • Key determinants of patient satisfaction: What do people with cancer want and need? • Quality, value and cost: Investing resources optimally • End-of-life care and planning • Impact of the cancer experience on family and loved ones, including minor children • Impact of the oncology experience on oncology health professionals

  5. Agenda A Patient with Chronic Alcoholism and Metastatic Hepatocellular Carcinoma (HCC) • 48 yoman with stable disease on sorafenib whose adherence to treatments is challenged by his alcoholism (Ms Mitchell) Two Patients with Metastatic Gastroesophageal(GE) Cancer • 68 yo man with HER2-positive, metastatic gastric cancer (Ms Smith) • 38 yo mother of 3 young children diagnosed with recurrent metastatic disease 9 months after gastrectomy(Ms Mitchell)

  6. Agenda A Patient with Rectal Cancer and Metastases Confined to the Liver • A 55-year-old man diagnosed with Stage III adenocarcinoma of the rectum (Ms Smith) A Patient with Disease Progression on Multiple Lines of Therapy; A Patient Rendered Disease Free with Stereotactic Body Radiation Therapy • A 56-year-old woman with BRAF-mutant colon cancer metastatic to the liver (Ms Mitchell) • An 82-year-old woman with a history of congestive heart failure who presented with colon cancer that was surgically resected (Ms Smith)

  7. Case 1 (from the practice of Ms Mitchell) • A 48-year-old man with a history of alcohol-related cirrhosis (Child-Pugh A) was diagnosed in 2012 with extensive intrahepatic HCC and small metastases to the skin of the abdominal wall that were biopsy proven • The patient has received sorafenib intermittently • When a full dose was administered, he developed moderate hand-foot syndrome, anorexia and mucositis • With dose reduction the patient was better able to tolerate the drug and has experienced stable disease to date • The patient has been in and out of alcohol rehabilitation and continues to binge drink • Adherence to his oncologic medications has been problematic

  8. Post-sorafenib Stable disease Pre-sorafenib

  9. Clinical manifestations of HCC: Sites of metastases and biologic characteristics Discussion Point

  10. HCC-Related Symptoms • Pain • Fatigue • Weight loss • Ascites • Jaundice

  11. Diagnosis and interdisciplinary care of HCC; the challenge of coexisting liver disease Discussion Point

  12. Risk Factors for HCCA study of SEER-Medicare, 1994-2010 (≥68 years old) Welzel TM et al. Am J Gastroenterol 2013;108:1314-21.

  13. Local treatment of HCC for palliation and cure (organ transplant, TACE, radiofrequency ablation) Discussion Point

  14. Risks, benefits and approach to dosing of sorafenib Discussion Point

  15. N Engl J Med 2008;359:378-90.

  16. SHARP: Sorafenib in Advanced HCC (Child-Pugh A) Grade ≥3 Adverse Events Sorafenib Placebo Hand-foot syndrome 8% <1% Diarrhea 8% 2% Llovet JM et al. N Engl J Med 2008;359(4):378-90.

  17. Prevention and management of hand-foot syndrome Discussion Point

  18. Getting a Handle on Hand-Foot Syndrome Topicals Urea/Lactic acid Orals Pyridoxine Celecoxib Inflammation (Tenderness, edema, erythema) Topicals Urea 40% cream Salicylic acid cream Clobetasol 0.05% cream Hyperkeratosis (Thickening, peeling, cracking) Courtesy of M Lacouture.

  19. Ongoing Phase III trials in HCC Discussion Point

  20. Investigational Agents for HCC • Brivanib • Tivantinib (ARQ 197) • Lenvatinib (E7080) • Cabozantinib • Ramucirumab • Regorafenib

  21. REACH Phase III Study Design Ramucirumab + best supportive care (BSC) R (N = 565) Placebo + BSC Primary endpoint: Overall survival Estimated primary completion: March 2014 www.clinicaltrials.gov, Accessed March 12, 2014 (NCT01140347)

  22. RESORCE Phase III Study Design The study is ongoing and currently recruiting participants. Regorafenib + best supportive care (BSC) R 2:1 (N = 530) Placebo + BSC Primary endpoint: Overall survival Estimated primary completion: October 2015 www.clinicaltrials.gov, Accessed March 12, 2014 (NCT01774344)

  23. Two Patients with Metastatic Gastroesophageal (GE) Cancer • 68 yo man with HER2-positive, metastatic gastric cancer (Ms Smith) • 38 yo mother of 3 young children diagnosed with recurrent metastatic disease 9 months after gastrectomy (Ms Mitchell)

  24. Case 2 (from the practice of Ms Smith) • A 68-year-old man with HER2-positive metastatic gastric adenocarcinoma received first-line therapy with FOLFOX and trastuzumab, which resulted in a complete response • Treatment was then stopped for 6 months, at which time disease progression was documented • The patient was then restarted on treatment

  25. Pretreatment 2 months into treatment

  26. Comparison of HER2 testing in breast and gastric/GEJ cancers Discussion Point

  27. Bang YJ et al. Lancet 2010;376(9742):687-97.

  28. ToGA: Median Overall Survival Bang YJ et al. Lancet 2010;376(9742):687-97.

  29. ToGA: Cardiac Safety of Trastuzumab + Chemotherapy versus Chemotherapy Alone Bang YJ et al. Lancet 2010;376(9742):687-97.

  30. Ongoing Phase III Clinical Trials T = Trastuzumab www.clinicaltrials.gov, May 2014

  31. Case 3 (from the practice of Ms Mitchell) • A 38-year-old married woman and mother of 3 young children presented with metastatic gastric cancer in 2010 and received DCF followed by resection: • She developed significant mucositis in response to DCF and experienced a difficult postoperative course, including bacteremia and severe depression. • Nine months later she complained of persistent abdominal pain and was placed on FOLFOX, which she tolerated poorly. • Her pain, now diffuse, worsened and her disease ultimately progressed in the peritoneum and bone. • The patient worked as an ultrasound technician in the oncology clinic along with her husband who is an IT professional there. • They both struggled with her diagnosis and how to discuss her disease and the possibility of her death with their young children.

  32. 2010: Thickened GEJ and gastric wall at diagnosis

  33. Preferred Regimens for Metastatic or Locally Advanced Gastric Cancer Two-drug regimens preferred due to lower toxicity Three-drug regimens should be reserved for medically fit patients with good PS and access to frequent toxicity evaluation • Docetaxel, cisplatin, fluorouracil (DCF) • DCF modifications • Docetaxel, oxaliplatin, fluorouracil • Docetaxel, carboplatin, fluorouracil • Epirubicin, cisplatin, fluorouracil (ECF) • ECF modifications • Epirubicin, oxaliplatin, fluorouracil • Epirubicin, cisplatin, capecitabine • Epirubicin, oxaliplatin, capecitabine • Fluoropyrimidine and cisplatin • Fluoropyrimidine and oxaliplatin • Fluoropyrimidine and irinotecan NCCN Guidelines, Gastric Cancer, v2.2013.

  34. Ramucirumab: Mechanism of action and available research data as a single agent or in combination with chemotherapy Discussion Point

  35. Agents Targeting the VEGF Pathway Anti-VEGFantibody(bevacizumab) Anti-VEGFR2antibody(ramucirumab) VEGF-A Soluble VEGFreceptor(Ziv-aflibercept) VEGFR-1 VEGFR-2 VEGFR-3 P P P P P P P P P P P P Endothelial cell Small-molecule inhibitors of VEGFR (regorafenib, PTK-787, AZD2171, motesanib,sunitinib, sorafenib, pazopanib, axitinib, etc)

  36. REGARD Phase III Study in Gastric or GEJ Adenocarcinoma Ramucirumab 8 mg/kg q2wk + BSC (n = 238) R A N D O M I Z E Treatment until disease progression or intolerable toxicity Tumor assessment, survival, and safety follow-up 2:1 S C R E EN Placebo q2wk + BSC (n = 117) N = 355 BSC = best supportive care; GEJ = gastroesophageal junction Overall survival: 5.2 vs 3.8 months Progression-free survival: 2.1 vs 1.3 months All grade/Grade ≥3 hypertension: 16%/8% vs 8%/3% Fuchs CS et al. Lancet 2014;383(9911):31-9.

  37. RAINBOW: Phase III Study of Paclitaxel ± Ramucirumab in Second-Line Gastric Cancer 665 patients after failure of FU or platinum-based therapy R A N D O M I Z E Weekly Paclitaxel + Ramucirumab(n = 330) WeeklyPaclitaxel + Placebo(n = 335) Overall survival: 9.6 vs 7.4 months Progression-free survival: 4.4 vs 2.9 months Wilke H et al. Gastrointestinal Cancers Symposium 2014;Abstract LBA7.

  38. RAINBOW: Efficacy Summary Wilke H et al. Gastrointestinal Cancers Symposium 2014;Abstract LBA7.

  39. FDA News Release (April 21, 2014) The U.S. FDA approved ramucirumab to treat patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma. Single-agent ramucirumab is FDA approved for patients with unresectable or metastatic gastric or GEJ cancer after being treated with a fluoropyrimidine- or platinum-containing therapy. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394107.htm

  40. Possible Side Effects Associated with Ramucirumab Hypertension Fatigue Abdominal pain Anemia Decreased appetite Vomiting Bleeding or hemorrhage Dysphagia Dyspnea Fuchs CS et al. Lancet 2014;383(9911):31-9.

  41. Case 4 (from the practice of Ms Smith) • A 55-year-old man was diagnosed with Stage III adenocarcinoma of the rectum and received neoadjuvant chemoradiation therapy followed by surgical resection • He was noted on restaging images to have liver metastases • He received FOLFOX with bevacizumab and went on to surgical removal of the hepatic metastases • He is currently without evidence of disease a year and a half later

  42. November 2013: After resection of liver mets and RFA March 2012: Bilobular liver mets Postresection Post-radiofrequency ablation

  43. Discussion Point Clinical approach to patients with liver-only metastases; role of neoadjuvant and adjuvant systemic treatment

  44. Colorectal Liver Metastases • Hepatic metastases occur in approximately 50% of CRC patients and account for at least two thirds of all CRC deaths • 25% of CRC patients present with hepatic metastases • 30% to 60% of patients develop hepatic metastases Abdalla et al. Annals of Surgical Oncology 2006;13(10):1271-80; Donadon et al. Gastrointest Cancer Res 2007;1:20-7.

  45. Contraindications to Resection Donadon et al. Gastrointest Cancer Res 2007;1:20-7.

  46. Role of up-front systemic therapy for patients presenting with a primary tumor and simultaneous metastatic disease Discussion Point

  47. Phase III TRIBE Study Schema INDUCTION MAINTENANCE FOLFIRI + Bevacizumab (Up to 12 cycles) 5-FU/LV + Bev R (N = 508) FOLFOXIRI + Bevacizumab (Up to 12 cycles) 5-FU/LV + Bev Maintenance until disease progression PFS: 9.7 vs 12.1 mo OS: 25.8 vs 31.0 mo Response rate: 53% vs 65% R0 resection rate: 12% vs 15% Falcone A et al. Proc ASCO 2013;Abstract 3505.

  48. Possible Side Effects Associated with Bevacizumab Common Side Effects • Nosebleeds • Rhinitis • Headache • Hypertension • Proteinuria • Lacrimation disorder Serious Side Effects • Hemorrhage • Thromboembolism • GI perforation • Wound-healing complications • Reversible posterior leukoencephalopathy syndrome (RPLS)

  49. Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study Loprinzi CL et al. Proc ASCO 2013;Abstract 3501.

  50. Second-line treatment for patients with disease progression on first-line therapy with bevacizumab/chemotherapy Discussion Point

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