CEA Scan and Colorectal Cancer

  1. So what is CEA and where is comes from?
    1. CEA stands for carcinoembryonic antigen.   It comes from a family of related cell surface glycoproteins. There are up to 36 different types of type CEA glycoproteins to considered in this group.   CEA also has several types of epitopes on its surface and is therefore heterogeneous in nature.  
    2. During the embryonic stages of human development the fetus contains significant levels of CEA, which soon dissipate after birth, and in an adult the levels of CEA is relatively low, when disease is not present.  
    3. CEA assay, a clinical lab procedure, is used to determine the presence of colorectal cancer. It detects elevated levels of CEA which is indicative of tumor growth or reoccurrence of disease after surgery.   
    4. Whenever imaging a patient for colorectal cancer always check his/her CEA level as well as review the patient’s history. Has the CEA level going up?
  1. What are the normal values?  
    1. Depending on the situation a normal assay values will differ
    2. Radioimmunoassay or RIA, normal values are between 0 to 2.5 ngm/mL.   With   smokers that don’t have disease the normal value may be as high as 5.0 ngm/mL.  
    3. Enzyme Immuno Assay, or EIA, the more common lab procedure has slightly higher values, with normal values for non-smokers being as high as 4.0 ngm/mL.   Normal values in smokers can be as high as 10.0 ngm/ mL, however this is only in about 4% of the populations.   The important thing to note is that a smoker's CEA value may be elevated and and normal can be up to 10.0 ngm/ml.
    4. Another interesting point about CEA assay levels is that other types of cancer and diseases can cause the CEA level to rise.  
      1. Types of cancer and the percent that cause elevation from normal values are as follows:   45% for lung cancer, 55% for breast cancer, 50% for gastric cancers, 40% for pancreatic cancer, 25% for ovarian cancer, and finally 40% in uterine cancer.  
      2. In the non-cancerous diseases that cause increased levels of CEA include: hepatobiliary problems, inflammatory diseases, rectal polyps, benign breast disease, and ulcerative colitis.
  1. Correlation between the increased level of CEA and that of the different stages of colorectal cancer
    1. The most popular staging method is referred to as Dukes’ Classification of Colorectal Cancer.
    2. CEA levels to the first two stages of disease.  
      1. Stage A there is usually a 28% elevation
      2. Stage B, the CEA level can be somewhere in the range of 45% elevation.
    3.   The issue here is to comparing the biopsy/pathology/spread of disease (determining the extent of the disease), with the question being, how far has the cancer penetrated the bowel wall and to what degree is there lymph node involvement?
    4. Dukes’ Classification
      1. Stage A is when the cancer is found in the mucosa lining - 100 percent survival rate.
      2. Stage B occurs when the cancer invades the wall of the bowel - five year survival is 50 to 65%  
      3. Stage C involves the intestinal wall to include disease in four or less lymph node - five year survival rate drops to 40 %
      4. Stage D has greater than 5 lymph nodes containing disease - five year survival rate drops to ~25 %.  
      5. Stage E involves distal metastatic disease - five year survival rate drops to 5%.   Not very good odds, however, like any cancer; the sooner it can be diagnosed the greater the survival rate.

      Carcinoma sigmoid microscopic mucous secretion

    5. Well differentiated cells (cancer) found in the sigmoid - mucus secretion cells
  2. Use of diagnostic testing (other than nuclear medicine)
    1. In one study of 600 patients had elevated CEA levels and were monitored for recurrence of colon cancer, 16 percent had false positive tests where CEA level was elevated, yet there was no recurrence of cancer.  
    2. Likewise, on the other end of the spectrum false negative CEA levels can occur, specifically when the tumor reoccurs, but the tumor isn’t secreting the CEA antigen.  
    3. Despite these false negative and positive results CEA assay continues to play a significant role in predicting the presents of cancer as well as whether or not there is reoccurrence of cancer
    4. Elevated levels of CEA assay may result in the use of MRI or CT to diagnose the initial or reoccurrence of disease
      1. If CT or MRI finds a questionable lesion after tumor-ectomy, the question arises - Is it tumor, scar tissue or infection?
      2. If surgery is decided (from the above) the question becomes, is it really necessary?     The results can be unnecessary surgery are:   inappropriate patient care (unnecessary surgery was performed), morbidity, and/or unnecessary expenditure of health care dollars
      3. What are the predictive values of CT for colorectal cancer?
        1. Detection rate in the liver is between 70 and 73 percent, extrahepatic abdomen is 44 to 45 percent and the pelvis is 50 to 57 percent.   Some researchers have shown a negative predictive value of in the pelvis of only 20%
        2. Likewise, these values with CT show poor results in patients with postoperative situations.   After surgery, postoperative changes such as fluid, adhesions, and fibrotic changes are suspicious for tumor, but may not be.   This causes the patient to undergo exploratory surgery to identify what these suspicious abnormalities are, resulting in unnecessary discomfort to the patient
    1. Another interesting approach to identify disease is the use of sigmoid and colonoscopies.   Polyps found growing in the lining of the large intestine may become cancerous over time.   Therefore when a patient undergoes a colonoscopy, if polyp(s) is/are found that they are usually removed.   The relationship of polyps and the probability of them being cancerous to some degree relates to the size of the polyp.  
      1. Under sigmoidoscopy, when the polyp is under 1.5 cm (usually 90% are of this nature), biopsy shows that only 1 percent of these are cancerous.  
      2. While those polyps that are greater than 1.5 cm have a 10% chance of being cancerous
    2. Another indication of colorectal cancer is the finding of occult blood in the stool
    3. Hence, the primary screening techniques for colorectal cancer recommended by the American Gastroenterologic Association are as follows:  
      1. An annual digital rectal examination and fecal occult blood test starting at the age of 40
      2. Annual sigmoidoscopy with a barium enema or colonoscopy starting at the age of 50

The number of individuals that develop colorectal cancer is significant because it is the number three cancer killer in the US.  Statistically the CDC stated that, "135,260 people in the United States were diagnosed with colorectal cancer in 2011, including 70,099 men and 65,161 women."  Over 51,000 died from this disease. Currently as many as 600,000 people in the US are under care following surgery for colorectal cancer

  • The Nuclear Approach
    1. The first MoAb that was approved for routine use was OncoScint CR/OV satumomab pendetide, which is murine based and contains the entire IgG antibody B72.3 tagged to 111 In.   It tags to 83% of colorectal adenocarcinomas, 97% of epithelial ovarian carcinomas, as well as a variety of other cancers.  
      1. Disadvantages of this specific MoAb is that it applies the entire IgG antibody.   This larger MoAb causes significant delay time between injection and imaging.   Because of its size it takes time for the body to clear excess material resulting in high background levels when scanning.   Delayed imaging must be applied and can be done between 72 and 120-hour post injections.   In addition liver uptake is significant, which may result in missing tumors that are located in this area. Metastatic lesions may reside would be in the liver
      2. Finally, because we are dealing with the entire IgG molecule HAMA response can be significant even with just a single application of this agent.   In one study HAMA response was as high as 50%.  These patient's that had a positive HAMA response, their levels became negative in 4 to 12 months post administration (blood test).   Because of the high HAMA response serial imaging should not be attempted
    1. 99mTc Arcitumomab or CEA-Scan has also been approved for routine use in the United State, and appears to still be available in the US and made by mediLexicon.  This MoAb is a murine monoclonal antibody Fab fragment and is tagged to 99mTc.    The production of arcitumomab comes from the IMMU-4, a murine IgG1 monoclonal antibody produced in murine ascetic fluid
      1. Because it is a fragment the chances of a HAMA response is greatly reduced
      2. Likewise, it's smaller size result in improved renal clearance with significantly reduced liver uptake, clearing rapidly from the blood.   This improves target to background resulting in the better imaging agent for colorectal cancer  
      3. CEA-Scan clearance from the blood is significant and at: 1, 5, and 24 hours post infusion, the blood levels diminished at 63%, 23%, and 7% respectively
      4. From a physiological standpoint, CEA fragment transports to tumor cells that secrete CEA within 2 hours post administration and attaches itself to the tumor cells.   Most of the remaining agent is excreted from the kidneys.   In fact, in 24 hours post administration 28 % of the radiolabeled substance has been eliminated.  
      5. CEA-Scan is capable of imaging: metastatic disease in the liver, has less than 1% HAMA response in clinical trials, can be labeled with 99mTc (which means no special ordering of 111In), can be imaged between 2 to 5 hours post infusion and as long as 24 hours post.
    2. Imaging results with CEA Scan
      1. CEA-Scan to CT
        1. For extrahepatic abdomen area CEA-Scan was 55% and CT 32% accuracy
        2. Pelvis CEA Scan was 69% and 48% for CT
        3. And when both modalities are used together a positive predictive value improves
    1. CEA – Scan Procedure
      1. Patient preparation
        1. This study should not be done on patients with hypersensitive to mouse antigens
        2. Explain the study to the patient and identify any problem that might cause a HAMA response
        3. Identify CEA level and tell the patient not to have another CEA assay for at least one week.
        4. Have the patient void prior to imaging the pelvic area.
      2. Prepare 25 mCi of 99mTcCEA-Scan by diluting it in 30 ml of sterile saline and then administer IV over a 5 to 20 minute period
      3. Camera and computer setup
        1. Set the window at 140 keV with a 20% window.
        2. Planer matrix size 128 by 128 or greater
          1. Take anterior and posterior chest, abdomen, and pelvis views
          2. Imaging time should be set at 10 minutes per image
        3. Whole body images can be taken at a rate of 12 cm per minute or less
        4. SPECT imaging
          1. 64 by 64 matrix
          2. 64 stops
          3. 360 degrees
          4. 30 seconds per slice or greater
      4. Imaging can commence at 2 to 5 hours post administration of the radiopharmaceutical.
      5. If early images show a high level of background then wait for the 24 hours scan.   Should further delays be required, then additional acquisition time is recommended for any image acquired
    Case Studies - Were found at www.ceascan.com. This link no longer appears active, however, a copy of that site for your review can be found by clicking here

    1. The data presented above shows the difference between two types of MoAbs
      1. OncoScint
        1. Composed of the entire IgG
        2. Increased background
        3. Increased liver/spleen uptake
      2. CEA Scan
        1. Composed of a fragmented IgG
        2. Reduced background
        3. Less liver/spleen uptake

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