Colorectal Cancer

							   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?