A Brief Overview of Screening and Management of Colorectal Cancer Gentry King MD Assistant Professor Hematology and Medical Oncology University of Colorado Disclosures Nothing to disclose Objectives Review the epidemiology of colorectal cancer Discuss screening, diagnosis, and work-up of colorectal cancer Discuss management of early-stage colorectal cancer Discuss the standard of care treatment options for advanced / metastatic colorectal cancer
Colorectal Cancer Epidemiology and Risk Factors Colorectal Cancer Fast Facts Colorectal cancer is the 3 rd most common cancer diagnosed in both men and women in the US. 2018 ACS estimates: 97,220 new cases of colon cancer 43,030 new case of rectal cancer *Source: American Cancer Society Risk Factors Overweight or Obesity Physical Inactivity Diet high in red meats, processed meats, and cooking meats at very high temperatures Smoking Heavy alcohol use Family History Inherited syndromes: FAP (1%), Lynch Syndrome 2-4% First degree relative
Colorectal Cancer Screening The Concept of Screening Screening is the presumptive identification of unrecognized disease with a feasible strategy that leads to a curative treatment Who should get screened and when? Depends on the RISK: Average risk vs Higher than average risk: A strong family history of colorectal cancer and polyposis A personal history of colorectal cancer or certain types of polyps A personal history of inflammatory bowel disease (ulcerative colitis or Crohn s disease) A known family history of a hereditary colorectal cancer syndrome such as familial adenomatous polyposis (FAP) or Lynch syndrome (also known as hereditary non-polyposis colon cancer or HNPCC) A personal history of radiation to the abdomen (belly) or pelvic area to treat a prior cancer
US Preventative Task Force Guidelines Population Adults aged 50-75 years Adults aged 76 to 85 years Recommendation Screen for colorectal cancer starting at age 50 years GRADE: A The decision to screen for colorectal cancer is an individual one GRADE: C US Preventative Task Force Guidelines Methods: Stool-based tests (gfobt, FIT, and FIT-DNA) Direct visualization tests Flexible sigmoidoscopy (alone or combined with FIT) Colonoscopy CT colonography Serology tests (SEPT9 DNA test) The USPSTF found no head-to-head studies demonstrating that any screening strategy is more effective than others USPSTF Screening for Colorectal Cancer. JAMA 2016;315(23):2564-2575. Incidence of colorectal cancer is decreasing Siegel et al. JNCI 2017 109(8).
But increasing in the younger population Siegel et al. JNCI 2017 109(8). The impact of young adult colorectal cancer: incidence and trends in Colorado Sheneman D, Lieu C, et al. Colorectal Cancer vol 6, no.2. Nov 2017 American Cancer Society 2018 Our finding that colorectal cancer risk for millennials has escalated back to the level of those born in the late 1800s is very sobering. People at average risk of colorectal cancer should start regular screening at age 45
Colorectal Cancer: Presentation, Work-up, Early-Stage Management History and Physical Examination Hematochezia 58% Abdominal Pain 52% Unexplained Iron Deficiency Anemia 57% Weight Loss 39% Altered Stools 25% Obstruction 4% Colon Cancer Diagnosis/Staging Labs CBC, CMP, CEA Procedures Colonoscopy with biopsy Flexible sigmoidoscopy with biopsy Radiology CT scan Chest/Abdomen/Pelvis (Chest is?) PET/CT (?) Liver MRI (?) http://www.uptodate.com/contents/image?imagekey=gast%2f83618&topickey=onc%2f2496&rank=1~150&source=see_link&search=colorectal+cancer&utdpopup=true
Rectal Cancer (Special Issues) Chest CT Venous drainage bypasses the liver Lung metastases Rigid sigmoidoscopy Transrectal ultrasound Pelvic MRI Colorectal Cancer Staging Localized (stage I and II) Regional (stage III) Distant (Stage IVB) Colorectal Cancer Survival by Stage Carncer.org
Colorectal Cancer: Management Strategies, localized disease Management of Localized (Early Stage I-II) Colon Cancer Surgery is the only curative treatment for colon cancer 5 yr survival rates: stage I colon cancer is about 92%. stage IIA colon cancer, the 5-year relative survival rate is about 87%. stage IIB cancer, the survival rate is about 65%. https://www.bcm.edu/healthcare/care-centers/general-surgery/procedures/colon-resection Cancer.org
Management of Localized (Early Stage I-II) Colon Cancer What about Adjuvant Chemotherapy? Goal is to eradicate microscopic metastasis to increase cure rate Many phase III trials and metanalyses demonstrate benefit in stage II disease, but absolute survival benefit is small ~3-4% vs observation Regimens used: 5-FU + Leucovorin 5-FU + Leucovorin + Oxaliplatin Capecitabine + Oxaliplatin Drugs not used: Irinotecan Biologic targeted therapy (panitumumab, bevacizumab) Popat et al J Clin Oncol. 2005;23(3):609. Management of Localized Colon Cancer Biomarkers and clinical features to predict benefit or non-benefit? dmmr/msi-h status: ~15-20% of early stage colon cancers A systematic review of 32 studies showed no benefit of adjuvant 5-FU based chemotherapy in stage II d/mmr/msi-h CRC, and a potential for harm (HR for death 1.24, 95% CI 0.722.14). BRAF V600E status: unclear Half of dmmr/msi-h CRCs have BRAF V600E, but similar 5yr OS MSS BRAF V600E tend to do worse Clinical High Risk features: T4,perforation, obstruction, high-grade, poorly differentiated (signet ring, mucinous), LVI, PNI, close margins, less than 13 LNs sampled, very high pre-operative CEA. Kim et al. J Clin Oncol 2007;25:767-772. Popat et al J Clin Oncol. 2005;23(3):609. Management of Localized Rectal Cancer Surgery is the only curative treatment for rectal cancer. Requirements: Negative margins Total mesorectal excision (TME): allows for a wide excision and resection of adjacent lymph nodes within the mesentery Transabdominal procedures: low anterior resection [LAR] abdominoperineal resection [APR]). Anatomical location of the tumor is problematic Surgery + Chemotherapy + Radiation Mery et al. Seminars in colon and rectal surgery, 2005
Sequencing of therapies Chemotherapy regimens are similar to colon cancer Chemo-RT: capecitabine often used (less toxic, more convenient) Neoadjuvant vs Adjuvant vs Total Neoadjuvant Therapy (TNT) Retrospective cohort analysis, 308 patients treated with TNT were compared with 320 patients treated with chemort with planned adjuvant chemotherapy Wang et al. Lancet, 2017 Patients in the TNT cohort received greater percentages of the planned systemic chemotherapy, had higher rates of complete response (pathologic and sustained clinical), and were more likely to have temporary ileostomy reversed within 15 weeks of proctectomy. Adjuvant Chemotherapy for stage III CRC Duration: IDEA trial, 3 vs 6 months of adjuvant chemotherapy Stage III Colon Cancer Patients R 12,834 patients 3 months FOLFOX * or CAPOX * 6 months Non-inferiority design: As agreed upon by patient advocates and oncologists, shorter duration of therapy should not sacrifice more than 12% of benefit of adjuvant therapy. In statistical terms: upper 95% confidence interval of Hazard Ratio (HR) of disease free survival (DFS) should not exceed 1.12 Adjuvant Chemotherapy for stage III CRC Negative study, overall statistically. But IDEA collaborators, ASCO 2017
DFS Comparison by Risk Group and Regimen LOW RISK Percent Without Event 100 Duration 100 Duration 90 3 Months 90 3 Months 6 Months 6 Months 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 3 m Rx: -1.6 (-3.8 to 0.6) 10 3 m Rx: +1.9 (-0.8 to 4.6) 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Percent Without Event T1-3, N1 CAPOX Years from Randomization 2311 2013 1642 1198 751 411 195 2308 2030 1669 1215 745 433 203 Years from Randomization 1433 1300 1154 736 313 116 16 141919 1306 1119 734 336 133 18 HIGH RISK Percent Without Event 100 90 80 70 60 50 40 30 20 10 Duration 100 Duration 3 Months 90 3 Months 6 Months 6 Months 80 70 60 50 40 30 20 3 m Rx: -3.2 (-6.6 to 0.2) 10 3 m Rx: 0.1 (-3.9 to 4.1) 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Percent Without Event T4 or N2 CAPOX Years from Randomization 1523 1189 900 612 360 216 94 1531 1242 937 648 396 228 103 Years from Randomization 1111 910 740 432 171 76 13 1091 909 718 446 190 73 7 Adjuvant Chemotherapy for stage III CRC CAPOX 3 mos if T1-3/N1, 6 mos if T4N2 If FOLFOX: 6 months IDEA collaborators, ASCO 2017 Colorectal Cancer: Management Strategies, metastatic disease
Management Principles of Metastatic Colorectal Cancer Still multi-disciplinary because of the possibility of cure Oligometastatic liver only disease Systemic therapy: 2018 vs 1980 Biologic / targeted therapy Immunotherapy Predictive biomarkers Mutations MSI sidedness Oligometastatic CRC Resectable Liver only: 60 study meta-analysis showed 5-year and 10-year survival rates ranging from 16% to 75% (median 38%) and 9% to 69% (median 26%), respectively. Ablatable/resectable lung metastasis: data not as strong Extrahepatic oligometastatic disease other than lung: limited, weak data 50% of CRC patients will develop liver mets 10% will have liver only 10-20% of CRC patients will develop lung mets 2-4% will have lung only Kanas GP et al. Clin Epidemiol. 2012;4(1):283-301 King, Lieu, Messersmith. AJHO. 2016;12(10):4-11 14 FDA Approved Drugs for Metastatic CRC Cytotoxics 1. 5-FU (pyrimidine analog) 2. Capecitabine (oral 5-FU prodrug) 3. TAS-102 (5-FU w/ metabolism inhibitor) 4. Oxaliplatin (3 rd generation platinum) 5. Irinotecan (topoisomerase inhibitor) Biologics / Targeted / Immunotherapy 6. Cetuximab (chimeric EGFR antibody) 7. Panitumumab (humanized EGFR antibody) 8. Bevacizumab (VEGF antibody) 9. Ziv-Aflibercept (VEGF trap) 10. Ramucirumab (VEGF small molecule inhibitor) 11. Regorafenib (multi-kinase inhibitor) 12. Pembrolizumab (anti-pd1 inhibitor) 13. Nivolumab (anti-pd1 inhibitor) 14. Ipilimumab (anti-ctla4 inhibitor)
Biomarkers Biomarker testing is necessary to tailor treatment and prevent harm Mutations KRAS NRAS BRAF MSI-H vs MSS Dudley et al, CCR, 2016 RAS mutations and anti-egfr therapy ~50% of CRCs HAVE RAS mutations (K/Nras) RAS mutations confer resistance PRIME trial Doulliard et al, NEJM, 2013 MSI-H Immunotherapy Pembrolizumab monotherapy for CRC MSI-H in CRC 1 2 5 1 0 0 M M R -p ro fic ie n t C R C M M R -deficient CRC Stage Prevalence Prognosis Compared to MSS II 15%-20% excellent III 8%-10% same IV 4%-5% same or worse Hypermutation=neoantigen probability The immune system has the potential eliminate MSI-H cancers and prevent spread % C h a n g e fro m B a s e lin e S L D 7 5 5 0 2 5 0-2 5-5 0-7 5-1 0 0-1 2 5 3 6 5 7 3 0 Dung T. Le et al. Science 2017;357:409-413 Le et al. NEJM 2015; 372:2509-20.
Sidedness: Right vs Left R>L have better prognosis, R CRC don t respond well to anti-egfr with 1 st line therapy King, Lieu, Messersmith. AJHO. 2016;12(10):4-11 Therapeutic Fulcrum Benefit Harm J Korean Med Assoc. 2010 Jul;53(7):582-591. Question 1 40 year old male presented with hematochezia and was found to have an ascending colon adenocarcinoma on colonoscopic evaluation. He underwent resection and was pathologically staged as pt3pn0 (0/18 LNs). His tumor was found to be MSI-H. There was no LVI, PNI or perforation. What is recommended after the resection? 1. Adjuvant chemotherapy with FOLFIRI x 6 mo 2. Adjuvant FOLFOX + bevacizumab x 6 mo 3. Adjuvant FOLFOX + pembrolizumab 4. Observation
Question 1 Answer is 4: observation This is a low risk stage IIA CRC that is MSI-H. Prognosis is excellent without further chemotherapy in the absence of high risk features. Irinotecan, bevacizumab and pemrbolizumab are not used in the adjuvant setting. Potential for harm with 5-FU based regimens in stage II CRCs that are MSI-H Question 1.2 The patient was then lost to follow-up (joined a cult and ultracleansed with durian fruit instead of colonoscopic surveillance and genetic counseling). He then presented back with anemia and weight loss and found to a 4cm splenic flexure colon mass with 2 liver hypodensities in segment 6. Biopsy of the liver met showed adenocarcinoma, MSI-H, RAS/RAF wild type. He has re-joined civilization and now wants therapy. What would you treat him with? 1. FOLFOX + erlotinib 2. Multi-disciplinary evaluation for resection of primary and liver mets 3. Ipilimumab and Nivolumab upfront 4. Probiotics The End Questions?