Colon Cancer Anthony F. Shields, M.D., Ph.D. Karmanos Cancer Institute Wayne State University Detroit Medical Center
US Mortality, 2007 Number of deaths % of all deaths Rank Cause of Death 1. Heart Diseases 616,067 25.4 2. Cancer 562,875 23.2 3. Cerebrovascular diseases 135,952 5.6 4. Chronic lower respiratory diseases 127,924 5.3 5. Accidents (Unintentional injuries) 123,706 5.1 6. Diabetes mellitus 71,382 2.9 7. Alzheimer’s disease 74,632 3.1 8. Influenza and Pneumonia 52,717 2.2 9. Nephritis 46,448 1.9 10. Septicemia 34,234 1.4 National Center for Heath Statistics
2011 Estimated US Cancer Deaths Source: American Cancer Society, 2011
Cancer Death Rates, for Men, US, 1930-2007 American Cancer Society
Cancer Death Rates for Women, US, 1930-2007 American Cancer Society
Colorectal Cancer Statistics - Incidence high in U.S. and other industrialized countries - 141,000 new cases in 2011 in the US - 49,000 deaths - Third leading cause of cancer death in men and women - Second most common cancer overall Michigan: about 4800 cases, 1700 deaths
Colon Polyp 2D View Virtual Colonoscopy Sigmoid Polyp Fenlon, NEJM 341:1496, 1999
Normal colon cell Increased cell growth Adenoma I Adenoma II Adenoma III Carcinoma Metastasis ras gene mutation p53 loss Chromosome 5q gene loss or mutation DCC loss Other genes lost or mutated Progression to Colon Cancer Normal Polyp Early Cancer Metastasis
Colorectal Cancer Signs and Symptoms - Depends on location - Many are silent - Symptoms include: pain anemia change in stools blood in the stool
Screening: Methods - Fecal Occult Blood Testing (FOBT) - Rectal Examination - Flexible Sigmoidoscopy - Total Colonic Examination Colonoscopy Barium enema (BE)
Effectiveness of Screening Effectiveness in general population of FOBT (fecal occult blood test): mortality 33-43% lower with screening Mandel JNCI 91:434, 1999; Winawer JNCI 83:243, 1991.
Factors AffectingFecal Occult Blood Test Avoid False rare red meat + turnips, horseradish + Aspirin, motrin + Vitamin C -
Colorectal Cancer Risk Factors - Diet high in saturated animal fats and meat - Diet low in fiber An average American diet - History of Colitis - Polyposis and other hereditary syndromes
Colorectal Cancer Screening: Average Risk: Age > 50 Fecal Occult Blood Test (FOBT) yearly Flexible Sigmoidoscopy 5 yr Sigmoidoscopy and FOBT Colonoscopy 10 yr CT Colonography 10 yr
Colorectal Cancer Screening: Moderate Risk: 1st degree relative colorectal cancer age <60 Two 1st degree relatives with colorectal ca or adenomatous polyps of any age Colonoscopy starting at age 40 or 10 yr before youngest case then every 5 yr
Colorectal Cancer Sporadic 65-85% Family History 10-30% Rare Syndromes <0.1% Polyposis 1% HNPCC 5%
Colorectal Cancer Screening: High Risk: Family history of familial adenomatous polyposis: Endoscopy starting at Puberty, consider genetic testing. If FAP confirmed consider colon removal or colonoscopy every 1 - 2 years.
Colorectal Cancer Screening: High Risk: Family history of Lynch Syndrome (HNPCC)- hereditary non-polyposis colon cancer: Colonoscopy starting at 21, consider genetic testing. Colonoscopy every 2 years until age 40, then every year.
Lynch Syndrome (HNPCC) Identification • Genetic testing may be of use for individuals with personal history of: • two Lynch-related cancers • colorectal or endometrial cancer diagnosed < 45 • colorectal cancer and 1st-degree relative with Lynch-associated tumor, one of which is diagnosed < 45 JNCI 1997;89:1758-62
Lynch-Hereditary Non-polyposis Colon Cancer • Colorectal Cancer • Endometrial • Less Commonly • Ovary • Stomach • Urinary tract • Small intestine • Biliary tract
Colorectal Cancer Screening: Blood In Stool or Anemia due to Iron Deficiency Colonoscopy and/or upper GI evaluation
Rectal Bleeding DO NOT ASSUME THE CAUSE IS BENIGN Patients with self-reported visual rectal bleeding screened with BE and sigmoidoscopy 24% Had serious disease including polyps inflammatory bowel disease cancer (6.5%) Helfand, JAMA 277:44, 1997
Colorectal Cancer Screening:Follow Up + Fecal Occult Blood (FOBT) 24,246 Medicare patients 9.3% positive findings Only 34% had recommended follow-up Lurie, JNCI 91:1641, 1999
Colorectal Cancer Screening:Follow Up + Fecal Occult Blood (FOBT) -1 of 3 cards positive is a positive test - Colonoscopy should be done
Fecal Occult Blood and GI Sources 248 pts. Guaiac+ upper endoscopy & colonoscopy Upper GI Causes:Lower GI Causes: Esophagitis 9.3% Adenoma 11.7% Ulcer 9.6 Cancer 5.2 Gastritis 4.8 Colitis 2.0 Cancer 1.6 Vascular 2.0 Other 3.3 Other 0.9 TOTAL 28.6 21.8 DC Rocky, NEJM 339:153, 1998
Colorectal Cancer Screening:Follow Up + Fecal Occult Blood (FOBT) 24,246 Medicare patients 9.3% positive findings 31% with polyps on testing 4% with cancer Lurie, JNCI 91:1641, 1999
Diagnostic Yield of Colonoscopy and Fecal Immunochemical Testing (FIT), According to the Intention-to-Screen Analysis. Quintero E et al. N Engl J Med 2012;366:697-706.
Rectal Bleeding inYounger Patients • DO NOT ASSUME THE CAUSE IS BENIGN • “Evaluation of the colon in persons 25 to 45 years of age … increases the life expectancy at a cost comparable to that of colon cancer screening.”JD Lewis, Ann Int Med 136:99, 2002 • Age <40 with bright red blood: • If obvious anal source treat symptomatically and if it recurs do flexible sigmoidoscopy. • Age <40 with burgundy blood marbled in stool: • Colonoscopy
Colorectal Cancer Screening: Don’t Screen Patients with limited life expectancy for example: metastatic cancer severe congestive heart failure severe obstructive lung disease
New Screening Approaches:CT Colonography • Abdominal helical computed tomography with virtual reality computer technology • other names include CT pneumocolon and virtual colonoscopy • Results in a two- or three-dimensional image of the inside of the colon • Images can be combined to create a complete view of the colon
CT Colonography DH Kim, NEJM ,2007
Colonography Issues • What (size) needs to be detected/removed? • Many more small polyps ( 1 cm) are seen with optical colonoscopy (2434 vs 561; in a study of over 3100 patients with each approach. DH Kim, NEJM, 2007). • Number with polyps > 1cm was the same (103 in each group) • 7.9% of patients who need CTC routine colonoscopy • The number of cancers and advanced lesions are similar for both optical and CT colonography • about 3% • Interval for screening (interval for small polyps)? • Cost effectiveness • Flat lesions • Impact on compliance • Logistics of same day colonoscopy • Bowel preparation • Extracolonic findings
Colonography Issues • Extracolonic Findings (DH Kim, NEJM 2007) • Normal variant 41.5% • Clinically unimportant (e.g. cysts) 47.7% • Probably unimportant, but require 8.5% further tests (e.g. renal lesions) • Potential important 2.2% • Covered in Michigan for incomplete colonoscopies • CMS declined to cover in Feb, 2009 due to reporting that completed studies did not apply to an older population
Predictions for 2011: What Won’t HappenJames Gorman, NY Times Nov 9, 2010. In 2011 human beings will not evolve, much. We will not find any good-size life in outer space. We will not find the ivory-billed woodpecker. Neanderthals will not be cloned. The virtual colonoscopy will not replace the old-fashioned really invasive one. The first human will not be conceived in space. No one will upload himself or herself (memories, personality, neuroses, creepy desires) into a computer. Atheism will not become a dominant world religion despite the efforts of some scientists. The largest living animal will not turn out to be a 76-meter (249-foot) octopus in the Mariana Trench.
Cumulative Mortality from Colorectal Cancer in the General Population, as Compared with the Adenoma and Nonadenoma Cohorts. Zauber AG et al. N Engl J Med 2012;366:687-696.
Prevention - A diet high in fruits and vegetables - Low fat diet - Exercise - Possible use of minerals and vitamin supplements
Folate -Data from nurses study of 88,000 with 442 colon cancer cases -Over 0.4 mg per day Folate decreased colon cancer by 31% -After 15 years decreased colon cancer by 75% Giovannucci, Ann Int Med 129:517 1998.
Folic Acid: Risk of Adenomas • Followed 1021 men and women with recent history of adenoma • Compared 1 mg/d folic acid supplement with placebo BF Cole, JAMA, 2007
Folate and Cancer: A Matter of Timing ? • By preventing DNA damage, folate may be effective in the primary prevention of colorectal neoplasia (this was a secondary prevention trial) • Effect on new, adenomas formation vs. progression from adenomas to carcinoma • Effects of folate on individuals with unresected polyps • Effect of folate on individuals with existing cancer
Calcium and Colorectal Cancer • - 930 patients with a history of polyps • - Randomized to Calcium 1200 mg per day or placebo. • Risk of polyps decreased by 24% • Other studies suggest that calcium supplements may increase prostate cancer in men. JA Baron, NEJM 340:101 1999
Aspirin & Colon Cancer Prevention American Cancer Society: 662,000 people surveyed in 1982 Those who used aspirin 16x/month 40% decrease in colon cancer (NEJM 325:1593, 1991) - Nurses study: After 20 years of use 44% reduction in colorectal cancer (NEJM 333:241, 1995)
Aspirin & Colon Cancer Prevention Physician’s Health Study: 22,071 male physicians randomized to one aspirin every other day or placebo. After 5 years: No change in colon cancer Was this too short for a response?? Sturmer, Ann Int Med 128:713, 1998
Trends in Colorectal Cancer Therapy 5-Fluorouracil (5FU) is the old standard treatment. Capecitabine (Xeloda) is an oral form of 5FU. It is just as effective and less toxic. Approved cytotoxic agents are available for clinical use: irinotecan (Camptosar, CPT11) and oxaliplatin (Eloxatin). New combination therapies with proven efficacy are available. Targeted therapy with bevacizumab, cetuximab, panitumumab is available.
Regimens Colorectal Cancer Therapy Single Agents: Capecitabine Irinotecan Cetuximab Panitumumab 5FU (with leucovorin) - rarely use Combinations: Oxaliplatin + 5FU (FOLFOX) Irinotecan + 5FU (FOLFIRI) Capecitabine + Oxp (CAPOX) All these combinations appear equally effective. Combinations with bevacizumab, panitumumab, and cetuximab
Enzymatic activation of Capecitabine (Xeloda) Intestine Liver XELODA XELODA tumor>normal tissue CE 5'-DFCR 5'-DFCR CyD CyD 5'-DFUR 5'-DFUR Thymidine phosphorylase (TP) 5-FU 5'-DFCR, 5'-deoxy-5-fluorocytidine; 5'-DFUR, 5'-deoxy-5-fluorouridine; CyD, cytidine deaminase; CE, carboxylesterase
Grade 3/4 treatment-relatedadverse events 25 20 15 10 5 0 capecitabine (n=596) 5-FU/LV (n=593) Patients (%) * * * * Hand-foot Stomatitis Diarrhea Vomiting Neutro- Neutropenic syndrome penia fever + sepsis *p<0.05
CapOx Phase II Trial Efficacy: Oxalipatin IV 130 /m2 on day 1 Capecitabine PO 1.5gm/m2/d x 14 days CR + PR 37% PFS (mo) 6.9 OS (mo) >16 Grade 3/4 Adverse Events (% of Patients) Diarrhea 20 Neutropenia 6 Neuropathy 11 Vomiting 11 Stomatitis 3 Hand-foot syndrome 3 Shields et al. Cancer, 2003
NO16966 Treatment Schedules: CAPOX and FOLFOX4 • CAPOX + bevacizumab • Bev (or placebo) 7.5 mg/kg i.v. over 30–90 min, day 1 • Oxaliplatin 130 mg/m2 i.v. over 2 hours, day 1 • Capecitabine 1000 mg/m2 orally, twice daily, days 1–14 • Schedule repeated every 21 days • FOLFOX 4 + bevacizumab • Bev (or placebo) 5 mg/kg i.v. over 30–90 min, day 1 • Oxaliplatin 85 mg/m2 i.v. over 2 hours, day 1 • Folinic acid 200 mg/m2 i.v. over 2 hours, days 1, 2 • Fluorouracil 400 mg/m2 i.v. bolus, days 1, 2 • Fluorouracil 600 mg/m2 i.v. inf over 22 hours, days 1, 2 • Schedule repeated every 14 days J Cassidy, #4030 ASCO; 2007
Randomize Arm A Arm B capecitabine capecitabine + irinotecan 1st line irinotecan capecitabine + oxaliplatin 2nd line capecitabine + oxaliplatin 3rd line CAIRO Dutch Study Study of Combination vs. Sequential Therapy in Advanced Colorectal Cancer C Punt, ASCO; 2007