February 10, 2016 Tim Asmis, MD FRCPC Medical Oncologist Assistant Professor, University of Ottawa Objectives Colorectal Cancer in Canada 4th most common cancer in Canada 24,400 new cases in nd leading cause of cancer death after lung cancer 9,300 deaths 5 year survival 61% Colorectal cancer statistics 423 Canadians diagnosed with CRC every week 175 Canadians will die of CRC each week 1 in 14 men can expect to develop CRC during his lifetime 1 in 15 females can expect to develop CRC in their lifetime Risk Factors Associated with Colorectal Cancer Hereditary CRC Syndromes Personal or Family History of Sporadic CRCs HNPCC ( Hereditary nonpolyposis colorectal cancer) (Lynch Syndrome) 3-5% of all CRC Characterized by early age of onset, Right sided tumors Extra colonic cancers are very common including Endometrial, Gastric, Small bowel, Hepatobiliary system, Brain, Renal Pelvis or Ureter Familial Adenomatous Polyposis (FAP) Accounts for less than 1% of CRC In typical FAP numerous colonic adenomas appear during childhood Symptoms usually appear at 16 years Colonic cancers happen in 90 % of untreated individuals by age 45 Caused by germline mutations in the adenomatous polyposis coli (APC) gene which is located on chromosome 5 Risk Factors for CRC Inflammatory Bowel Disease Well documented association between Ulcerative Colitis and Colonic neoplasia Pancolitis confers a 5-15 fold increase in risk Risk of 0.5% per year in patients with a history of UC for years, then 1% per year after 20 years Less data for Crohns Routine surveillance is recommended Abdominal Radiation (survivors of childhood cancers) Screening recommended Age Clinical Presentation of Colorectal Cancer Can be asymptomatic, discovered at screening Symptoms include Abdominal Pain Change in bowel habits Hematochezia or melena Weakness Anemia Weight loss Staging of Colorectal Cancer Tumor, Node, Metastasis (TNM) staging Most recent version is 2010 AJCC/UICC Staging is completed by History and Physical Exam, colonoscopy CT scan Optional is a Liver MRI if questions raised on CT Pelvic MRI for Rectal cancer PET scans : dont appear to add significant information Final pathology of the resected cancer Prognosis of Colon Cancer Stage I (T1-2 N0) 93 percent Stage IIA (T3N0) 85 percent Stage IIB (T4N0) 72 percent Stage IIIA (T1-2 N1) 83 percent Stage IIIB (T3-4 N1) 64 percent Stage IIIC (N2 disease) 44 percent Adjuvant Systemic Therapy in Colorectal Cancer Definitions of Terms (NCI, Cancer.gov) Neoadjuvant : Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given Adjuvant : Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back Recurrence Free Survival (RFS) : amount of time from surgery to recurrence Overall Survival (OS) : amount of time from diagnosis to death Adjuvant Chemotherapy First large trial to show a survival benefit for adjuvant chemotherapy was NSABP C-01 5FU and levamisole was then shown to have survival benefit in the NCCTG trial (Moertel) Now Adjuvant Fluoropyrimidine based therapy is considered a standard option for patients with resected Stage II and III colorectal cancer Median F/U of 3 yrs FU/Levam 63% free of recurrence Obs 47% free of recurrence = 41% RRR, p50% of waking hours 4 Confined to bed or chair 31 Staging CT Chest 32 Staging CT abdomen 33 Initial treatment plan? a) Surgery of primary tumour --> chemo b) Systemic tx alone c) Radiation + Chemo 33 34 What is the best systemic tx for this patient? a) 5-FU / LV b) FOLFOX c) FOLFIRI + Bevacizumab d) Cetuximab 35 Treatment 20 years ago? 5 Fluorouracil based chemotherapy Usually given with leucovorin (folinic acid) which stabilizes the binding to thymidylate synthase and inhibits DNA synthesis. First approved by the US FDA in June, 1952 The only approved anti-neoplastic agent available in Canada until Sept (47 years) 36 Drug mechanisms Irinotecan : Irinotecan blocks certain enzymes needed for cell division and DNA repair, and it may kill cancer cells. It is a type of topoisomerase inhibitor and a type of camptothecin analog. Oxaliplatin : Oxaliplatin attaches to DNA in cells and may kill cancer cells. It is a type of platinum compound 37 5FU based chemotherapy with BSC vs. BSC BMJ Mar 20;306(6880): Small study only 40 patients Overall survival was 11 months (Chemo) vs 5 months (BSC) p=0.006 38 Adding Anti-VEGF in 1st line Bevacizumab : Bevacizumab binds to a protein called vascular endothelial growth factor (VEGF). This may prevent the growth of new blood vessels that tumors need to grow. Aflibercept : blocks the action of a protein called vascular endothelial growth factor (VEGF) and may prevent the growth of new blood vessels that tumors need to grow. It is a type of antiangiogenesis agent. 38 NCI Dictionary of Cancer Terms 39 Adding Bevacizumab to IFL improves OS in 1st line 39 mOS 20.3 vs 15.6 mos. 40 40 OS PFS 41 41 42 42 43 Adding Bevacizumab to FOLFOX / XELOX improves PFS, but not OS or RR in 1st line 43 PFS: 9.4 vs 8.0 mos mOS: 21.3 vs 19.9 mos. 44 44 PFS OS 45 FOLFOXIRI + Bev improves survival compared to FOLFIRI + BEV 45 46 Overall Survival 46 FOLFIRI + Bev vs FOLFOXIRI + Bev EGFR Inhibition in CRC Derek Jonker, MD FRCPC, Associate Professor GI Group Review December 4, 2015 EGFR Pathway and KRAS Gene EGFR signalling pathway is activated in response to ligand binding to cell-surface receptors: these ligands include TGF and EGF Activated signalling cascade is involved in regulating genes that control cell cycle progression Cell cycle progression gives rise to tumour survival, growth and proliferation, as well as metastasis and angiogenesis In the early part of the signalling cascade, the RAS protein regulates downstream proteins involved in these effects TGF = Transforming Growth Factor alpha; EGF = Epidermal Growth Factor; VEGF = Vascular Endothelial Growth Factor Adapted fromRAS Disruption of the Signalling Pathway TGF = Transforming Growth Factor alpha; EGF = Epidermal Growth Factor; VEGF = Vascular Endothelial Growth Factor Adapted fromAnti-EGFR antibodies block EGFR dimerization RAS EGFR Inhibitors Cetuximab : binds to a protein called epidermal growth factor receptor (EGFR), which is on the surface of some types of cancer cells. This may stop cancer cells from growing. Cetuximab is a type of monoclonal antibody Panitumumab : binds to the epidermal growth factor receptor (EGFR) and may block tumor cell growth. NCI Dictionary of Cancer Terms Anti-EGFR Monoclonal Antibodies: Cetuximab and Panitumumab 100% Mouse Protein34% Mouse Protein100% Human Protein Mouse Fully HumanChimeric cetuximab panitumumab mouse human NCIC CTG CO.17: Phase III trial in refractory CRC EGFR testing by IHC * Cetuximab 400 mg/m 2 IV week 1 then 250 mg/m 2 IV weekly Disease Progression or Unacceptable Toxicity REGREGIISSTTEERRREGREGIISSTTEERRISTER RANDOMRANDOMIIZZEERANDOMRANDOMIIZZEEIZE 1:1 Cetuximab* + BSCBSC alone Failed or intolerant to all recommended therapies, ECOG 0-2, No Prior EGFR directed therapy 1 o Endpoint: Overall Survival 2 o Endpoints:PFS ORR (RECIST criteria) Safety and QOL Only 7% crossover: Ideal biomarker trial Jonker NEJM 2007, Karapetis NEJM 2008 C0.17: Overall Survival and K-ras HR % CI (0.70,1.37) Log rank p-value: 0.89 Study arm MS (months) 95% CI Cetuximab + BSC 5.6 BSC alone 5.5 Mutant Wild type Study arm MS (months) 95% CI Cetuximab + BSC 10.3 BSC alone 5.5 CETUXIMAB + BSC BSC Jonker NEJM 2007, Karapetis NEJM 2008 HR % CI (0.41,0.74) Log rank p-value:
