Colorectal Cancer Thorvardur R. Halfdanarson, MD Hematology/Oncology University of Iowa Hospitals and Clinics Iowa City VA Medical Center Outline • Epidemiology • Staging • Risk factors • Management of • Biology localized disease • Anatomy • Management of rectal • Screening cancer • Symptoms and signs • Management of metastatic disease • Diagnosis • Hereditary syndromes Epidemiology • Colorectal (CRC) cancer is a common disease • It is the third most common cancer diagnosed in the US and the third leading cause of death • In the US in 2008 there are estimated – 108,070 new cases of colon cancer – 40,740 new cases of rectal cancer – 49,960 deaths by colorectal cancer CA Cancer J Clin. 2008;58:71-96. Epidemiology • The incidence of CRC has decreased slightly over the last decade • Despite the relatively stable incidence of CRC overall, tumors in the right side of the colon seem to be rising in incidence • Some of this increase may be explained by improved diagnostic methods Epidemiology • Trends in death rates: – The death rate from CRC may be falling – Possible explanations for falling death rates may include earlier diagnosis and more effective and widespread use of adjuvant therapy for early cancers – Currently, about 60% of patients with colon cancer survive for 5 years or longer (all stages included) Epidemiology Abeloff’s Clinical Oncology, 4 th Edition, 2008 Risk Factors • Most cases of CRC are sporadic • Geographic variability – Migrant studies • Hereditary syndromes (see later) – Familial adenomatous polyposis – Lynch syndrome (HNPCC) • Personal or family history of CRC or colonic polyps Risk Factors • Inflammatory bowel disease – The risk may be as high as 30% in severe cases of colitis – The risk is 0.5 – 1% per year • Alcohol consumption – Especially heavy consumption – The effects of modest use are unknown • Smoking – Increases risk of adenomas and likely CRC – Up to 20% of CRC may be explained by smoking Risk Factors • Diabetes mellitus – The risk may be increased up to 30% – Poorer DM control may increase the risk • Physical activity – Activity may be protective – May be independent from obesity • Obesity – Also increases the risk of dying from CRC Risk Factors • Other potential risk factors – Tobacco smoking – Consumption of red meat and processed meat – High fat in the diet – Cholecystectomy – Previous radiation therapy Protective factors • Vitamin D and calcium intake • Fruit and vegetables? • Fiber intake (uncertain role) • Physical activity • Folic acid intake • Aspirin and other NSAIDs Biology Anatomy Screening • Goals of screening – To detect colorectal cancer – To prevent colorectal cancer by detecting and removing adenomas Screening • The guidelines for CRC screening have recently been updated (2008) • There are 2 major guidelines 1. American Cancer Society, the US Multi- Society Task Force on Colorectal Cancer, and the American College of Radiology 2. U.S. Preventive Services Task Force Screening • Screening should begin at the age of 50 for patients of average risk • The screening of high risk patients is different • High-risk patients are: – History of colonic polyps – History of colorectal cancer – Hereditary syndromes (FAP, HNPCC) Screening Tools • Stool Tests – FOBT (guaiac) – Tumor DNA • Structural Exams – Colonoscopy – CT colonography – Double contrast barium enema (DCBE) – Flexible sigmoidoscopy Screening Tools Comparison of recent guidelines updated 2008 Ann Intern Med. 2008;149:680-682 Symptoms and Signs • Patients may not have any symptoms • Some common symptoms are: – Change in bowel habits – Blood per rectum (hematochezia/melena) – Anemia (resulting in fatigue and dyspnea) – Abdominal pain – Weight loss – Abdominal mass Symptoms and Signs • Up to 25% present with metastatic disease • Unusual presentations – Bacteremia (S. bovis, clostridia) – Lymphadenopathy – Fistula formation – Paraneoplastic syndromes – Fever of unknown origin Diagnosis • Many patients are diagnosed at the time of colonoscopy for screening purposes • Colonoscopy is the procedure of choice for diagnosis • Some patients may have a near-occluding tumor where the scope can not be advanced • These patients need a full colonoscopy at the time of resection Diagnosis • Histological confirmation is crucial • Not all colonic tumors are adenocarcinomas – Low-grade neuroendocrine tumors (carcinoids) – High-grade neuroendocrine tumors – Sarcomas – Metastases (melanoma) – Benign tumors Pre-operative evaluation • Careful physical examination • Laboratory evaluation including CBC, renal and liver chemistries • Carcinoembryonic antigen (CEA) – This can be a helpful marker for follow-up – Should become normal after successful resection of the cancer – High pre-op CEA is an adverse prognostic factor • Other tests as indicated based on history and clinical findings Pre-operative evaluation • CT of the abdomen and pelvis – Should be done in most patients – Done to rule out distant metastases – Very good for ruling out liver metastases but less sensitive for peritoneal involvement • Chest radiograph – May do chest CT instead – CT more sensitive for lung metastases Pre-operative evaluation Pre-operative evaluation • MRI – Not routinely used for colon cancer – Can be very helpful in the staging of rectal cancer and in planning resection of liver metastases • PET – Not indicated for most patients – Can be valuable in looking for extrahepatic metastases in patients who are undergoing liver resection Pre-operative evaluation PET Pre-operative evaluation • Rectal cancer – The evaluation is a little different from colon cancer – It is crucial to do adequate imaging of the rectum, perirectal area and pelvis – Endoscopic ultrasound • Enables biopsies of suspicious lymph nodes – MRI with endorectal coil • Very accurate in evaluating the extent of the tumor T2 tumor Smooth outer margin of muscularis propria Staging • The current staging is according to the TNM staging system of the American Joint Committee on Cancer (AJCC) • Duke’s staging and Astler-Coller staging are not recommended • TNM Staging – T: Tumor – N: Lymph Nodes – M: Metastases (distant) Staging Staging O’Connell JB et al. J Natl Cancer Inst 2004;96:1420 –5 Management of localized disease • The only curative treatment is resection and it should be done by a surgeon experienced in cancer surgery • Adequate lymph node sampling is important for risk stratification • Some patients have large tumors that are borderline resectable and may benefit from pre-operative chemotherapy Management of localized disease • Patients with stage III cancers have a substantial risk of recurrence • 3-year disease-free survival in stage III CRC is 44% to 52% • That means about one-half will relapse and likely die of their disease • Not all patients with stage III are the same • Adjuvant! Online (adjuvantonline.com) Management of localized disease • Chemotherapy has been shown to improve the outcome in resected CRC • It is typically given for 6 months • Patients with higher risk (more advanced disease) benefit more than those with lower risk • The chemotherapy is not without risks – 12% get significant neuropathy (4% chronic) – Neutropenic fever and diarrhea – Deaths very uncommon Management of localized disease • The optimal chemotherapy is currently a combination of 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) • Other options are 5-fluorouracil and leucovorin (5FU/LV) without oxaliplatin or capecitabine • The more effective therapy (FOLFOX) is also more toxic (especially neuropathy) Management of localized disease MOSAIC Trial Andre T et al. N Engl J Med 2004;350:2343-51 Management of localized disease • What to do with stage II patients? • The benefits of chemotherapy are smaller than in stage III CRC • The risk of toxicity outweighs the benefits in many cases • Adjuvant therapy is currently not routinely recommended • Some patients with stage II CRC may benefit more than others (e.g. T4N0) Management of localized disease • Rectal cancer – This used to be easy – just send them to surgery… – Now, most patients with rectal cancer should be managed within a multidisciplinary group • Surgeons • Medical and Radiation Oncologists • Gastroenterologists • Radiologists • Pathologists Rectal Cancer • Management Old Model Adjuvant therapy Diagnosis Resection New Model Multidisciplinary Neo-adjuvant Adjuvant Diagnosis Resection Evaluation therapy therapy Rectal Cancer • Why do we give pre-operative therapy? – Less toxicity – Less risk of local recurrence – Better chance of preserving the sphincter (less likely to need colostomy) • This is debated • Pre-operative therapy does not change overall survival Management of metastatic disease • Up to 25% of patients have metastatic disease at the time of diagnosis • Many more (up to 50 – 60% of stage III) patients will develop metastases • The liver is the most common location of metastases followed by the lungs • Many patients have only liver metastases and never develop metastases to other organs or bones Management of metastatic disease • Liver-only metastases – Carefully selected patients can be resected – 5-year survival after liver resection is 25 – 30% – If the cancer recurs in the liver, some patients can undergo re-resection with good results – Chemotherapy given before or after liver resection may improve the outcome – Pre-operative PET is helpful Management of metastatic disease • Liver-only metastases – There are other modalities than surgery – Radiofrequency ablation (RFA) – Cryoablation – Stereotactic radiosurgery (Cyberknife) – Selective hepatic artery embolization using radioactive beads (SIR Spheres) Management of metastatic disease • Some patients with lung metastases can undergo resection • Radiation to painful bone metastases is very effective for palliation of pain but not curative • Solitary brain metastases can be resected or radiated • Multiple brain metastases may require whole brain radiation Management of metastatic disease • Chemotherapy has repeatedly been shown to prolong life • Chemotherapy also helps preserving quality of life and may in some instances improve it much • Until relatively recently, we had very few options regarding chemotherapy – (5-FU was all we had…) Management of metastatic disease • This used to be a uniformly fatal disease • Those with metastatic lesions live much longer now than they did two decades ago • Patients with unresectable disease now have a median survival of 2 years • Are we turning metastatic CRC into a chronic disease in some patients?? Metastatic Colorectal Cancer • Why are patients living longer? – More aggressive chemotherapy – Several new drugs • Oxaliplatin • Irinotecan • Bevacizumab • Cetuximab (and panitumumab) – Patients should expect to be on some sort of chemotherapy until all options are exhausted or side effects become intolerable Metastatic Colorectal Cancer Zuckerman DS, Clark JW. Cancer. 2008;112:1879-1891. Surveillance After Cancer Therapy • Patients with resected colorectal cancer have an increased risk of another colorectal cancer later on • They can also have a local recurrence • Early diagnosis of a recurrence or a metachronous cancer may markedly improve the prognosis Surveillance After Cancer Therapy • There are recent guidelines to help us • Patients need a full diagnostic colonoscopy before or shortly after resection • Another colonoscopy at 1 year and then after 3 years • If all is fine at 3 years, colonoscopy should be done every 5 years Surveillance After Cancer Therapy • CEA measurements – Rising CEA can herald cancer recurrence • CT – It is debatable if all patients should have CT – A common practice is to obtain a CT of the abdomen and pelvis (and sometimes chest) yearly for three years • PET – Not recommended Hereditary Colorectal Cancer • HNPCC (Lynch syndrome) – Defect in DNA mismatch repair – Autosomal dominant – Accounts for 2-3% of all colorectal cancer – Risk of other malignancies than colorectal cancer – Diagnosis • Amsterdam criteria • Bethesda criteria Annu Rev Med 2005;56:539–554 Lynch Syndrome J Med Genet 2007;44:353–362 Questions?
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