Breast Cancer

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					   Monitoring colorectal Cancer
          after resection
Relationship to operative curability

        Prof. Fatma M. Nasrat
     Prof. Of Clinical Immunology
    Department of Clinical Pathology
       National Cancer Institute
             Cairo / Egypt
Follow-up after management of colon cancer
with curative intent.
  Follow-up after definitive management has two primary goals.
First, patients with a history of colorectal cancer are at higher risk
than the general population for a second colon cancer primary. A
colonoscopic screening may be of benefit in the early detection of a
 second primary malignancy or detection of a benign polyp, which
can then be resected to potentially prevent the development of an
invasive cancer.

   Second, surveillance may increase the chance of identifying
locoregional or distant recurrence that is potentially curable by
surgery. It should be noted that it is this detection of potentially
curable recurrent or second primary disease that justifies routine
postoperative surveillance.
 Proportion disease - free   Time to Recurrence


Modified Kaplan - Meier plot of disease – free survival of all patients
  Proportion disease - free

Modified Kaplan - Meier plot of recurrence at particular anatomic sites.
 Guidelines for follow-Up care after primary treatment for
 colorectal cancer – American Society of Clinical Oncology

                        1st Year     2nd Year      3rd Year        4th Year
                                                                   And on
Physical Examination         Every three to six months         Every six months
                                  After resection
                                                                 Until 5 years
    Colonoscopy          Once                        Every three to five years

       CEA *                                             Every six months
                       Every two to three months           For 5 years

Proctosigmoidoscopy Every six to 12 months ( for patients with stage II or stage
                    III Rectal cancer who did not have pelvic radiation
                    treatment ).

* If they had stage II or III C.C. managed definitively.
Tests Not Recommended by ASCO for Regular
Follow-up Care

   Liver function tests.

   Fecal occult blood test.

   Computerized tomography ( CT ) scan.

   Pelvic imaging.

   Chest x-ray.

   Complete blood count ( CBC ).
 What is a “Tumor Marker” ?

         Biochemical indicators associated with the

presence or progress of malignancy.
       It is advisable to use the same CEA method consistently

for a given patient because different CEA test methods do not

give equivalent CEA test values for individual samples.

   Only 50% to 60% of patients with colon carcinoma showed

elevated blood CEA levels.

   In cancer localized to the mucosa and submucosa, without

invasion into the muscularis propria, the percentage of patients

with an elevated test result falls to between 30% and 40%.
          Levels higher than normal have also been found in

Heavy smokers and in persons with cirrhosis, pancreatitis,

Uremia, peptic ulcer, intestinal metaplasia of the stomach, as

well as ulcerative colitis. The antigen has been reported in

tissue of intestinal polyps: colonic inflammatory mucosa, and

normal intestinal mucosa of children. The antigen is detected

in about 50% of tumors of the breast, stomach, lung, and in

other solid tumors.
   The clinical usefulness of tumor markers

      can be assessed by determination of

    1 - Sensitivity.

    2 - Specificity.

    3 - Positive predictive value.

    4 – Negative predictive value.
       Sensitivity
   True Positives :   The number of patients in a population with a positive test

                        result for a tumor marker who actually have cancer.

    False Positives:   The number of patients in a population with a positive test

                       result for a tumor marker who do not have cancer.

    Cut-off value :    highest value obtained by the non- malignant groups

                       ( normal persons and those with a benign disease ).

    Sensitivity   =    True positives ( positivity in disease) the abitity of a

                        test to detect patients who actually have cancer.
Analytical vs Diagnostic Sensitivity.

                 Analytical sensitivity : minimum detectable concentration

  ( MDC) of an antigen that an immunoassay can reliably distinguish from

  “zero” concentration with 95% confidence.

     Diagnostic sensitivity : proportion of individuals with disease who

  yield a positive test for antigen )

  {I.e. TP / (TP + FN ) }. X 100

   True Negatives :   the number of patients in a population with a negative

                       test result for a tumor marker who

                       do not have cancer.

    False Negatives : the number of patients in a population with a negative

                       test result for a tumor marker who do have cancer.

    Specificity =      true negative ( negative in health ) the ability of a test

                       to distinguish those patients who do not have cancer

                       from those who do .
    Analytical vs Diagnostic Specificity

             Analytical specificity : ability of an immunoassay to measure

only the analyte of interest ( freedom from interferences); expressed typically

as % cross- reactivity

   Diagnostic specificity : Proportion of individuals without disease who

yield a negative test for antigen { I.e. TN/(TN + FP)} . X 100
Positive Predictive Value ( PPV) :

        It is the probability that a patient with a positive test result

actually has cancer.PPV,unlike NPV,markedly influenced by the

prevelance of disease in the population tested.

Negative Predictive Value (NPV) :

        It is the probabitity that a patient with a negative test

result does not have cancer
Ideal Tumor Marker for Cancer





    |     |      |      |       |      |     |      |      |      |      |      |
   0.0   1.0    2.0    3.0     4.0    5.0   6.0    7.0    8.0    9.0   10.0   100.0

         100% Specificity                     100% Sensitivity
Reality of Testing



 |     |     |         |        |     |     |        |         |     |      |      |
0.0   1.0   2.0       3.0      4.0   5.0   6.0      7.0       8.0   9.0   10.0   100.0
                     20%                            70%
                  FALSE NEG.                     FALSE POS.
Postoperative prognostic indicator
  Serial CEA in Monitoring Cancer therapy

              Assessment of the adequacy of Surgical Removal

   of primary tumor. If the preoperatively elevated CEA level

   fails to decrease to normal range of 2.5 ng / mL or less within

   4 to 8 weeks postoperatively, this strongly suggests persistent

   disease . Patients with a persistently elevated CEA level

   postoperatively may indicate an incomplete surgical resection

   or metastatic disease.

CEA appeared the most accurate to identify patients
     with cancer following curative surgery
            In this battery of tests, CEA was the first

indication of disease recurrence . The lead time to detection

of recurrence by serial CEA over all other diagnostic tests

was between l and 18 months with a median of 3 months.
Indicator of asymptomatic recurrence
             A persistent increase in the serum CEA concentration

 frequently indicate clinical evidence of recurrent disease . When an

 elevated CEA is detected in a patient in whom it was previously

 normal, the study should be repeated before a more extensive

 investigation . In one study in which 45 patients had false-positive

 values, 27 had an elevation in only one CEA value, which then

 returned to normal in the next several CEA determinations . Liver

 function test and renal function must be checked because

 abnormalities in either can elevate CEA level.
                CEA may become elevated ( false positive value )

 in patients undergoing adjuvant chemotherapy ( fluorouracil and

levamisole ) without evidence of cancer recurrence, most likely

because of the mild hepatic toxicity of these drugs.

   No studies show a benefit to providing chemotherapy for

an elevated CEA alone in the absence of measurable disease.
      Routine Monitoring after Treatment
            Evidence favoring routine monitoring. Advocates of CEA

monitoring point to evidence that resection of isolated metastases,

Particularly in the liver, increases survival compared with

unresected patients or those with chemotherapy alone .If surgical

intervention is potentially curative, any surveillance test that could

detect a recurrence when the tumor is still resectable would be useful.
        In a review of the patients who underwent surgical

resection at the Mayo Clinic, there was a significant increase in

survival for patients who had liver metastases detected because of

an elevated serum CEA level or surveillance imaging test, when

compared with those who had liver metastases detected by an

elevation in liver function test, physical examination, or symptoms.

In their multivariate analysis of factors affecting survival, CEA-

detected disease was one of the strongest predictors of survival .
          Therefore, the panel recommends serum CEA monitoring

every 2 to 3 months for 2 years, only for those patients who would

be willing and able to undergo a hepatic resection for recurrent

        Monitoring response to treatment

               for metastatic disease
           Another potential role for CEA would be to aid clinical

decision-making in patients with metastatic disease. Approximately

85 %of patients with metastatic colon cancer have an elevated

CEA level.Several studies show that a decrease in CEA level while on

chemotherapy, presumably indicating a tumor response, was associated

with a better survival compared with patients whose CEA level did not

        Therefore, a baseline value before treatment for metastatic

disease is recommended, serial monitoring is appropriate every 2

to 3 months on active treatment if no other simple test is available

to indicate a response. Two values above the baseline are

adequate to document progressive disease and prompt the

discontinuation of therapy, even in the absence of confirmatory

 radiologic testing .
Preoperative prognostic indicator

          A preoperative CEA value predicts a higher rate of

recurrence and colon cancer mortality compared with

patients with normal levels .
          In the National Surgical Adjuvant Breast Bowel Project

( NSABP) study of 945 patients, a preoperative CEA greater than

2.5 ng/mL increased the risk of recurrence by 1 to 2 fold in Dukes

B patients ; if the preoperative CEA value was greater than

10 ng /mL,the risk was increased by 3.25 fold.Wanebo et al

reported the time to recurrence was shorter if the CEA was

elevated .13 versus 23 months for a CEA level greater than 5

ng/mL or less than 5 ng/mL,respectively : survival was higher in

patients with CEA level less than 5 ng/mL.
         A normal preoperative CEA level does not assure that

CEA will remain normal.In a study by Zeng et al of 140 patients

with normal preoperative CEA ( < 5 ng/mL ),32 developed a

recurrence and 44% of these patients had a CEA level greater than

5 ng/mL at recurrence .
          TPA is a mixture of the low-molecular-weight epithelium

associated cytokeratins, primarily cytokeratins 8,18, and 19.

Released into the circulation during cell death (tumor necrosis ).

Because cytokeratins are more abundant in cells undergoing

mitosis and much less so in interphase cells, they are markers

for cell proliferation.

TPA is a sensitive but nonspecific markers for discriminating

between progressive disease and disease in complete remission.
Stool DNA
         Because of the utility of identification of mutations in

oncogenes and tumor-suppressor genes, it has been

suggested that this observation may have a demonstrable

advantage over occult blood determination .Some Studies

 have been reported which utilize purified DNA from stool

samples in individuals known to harbor colorectal cancer and

have detected these mutations .
Other markers

 Serum   protein hexose


        A rational postoperative surveillance program should include
CEA measurements evry 3 to 6 months and a yearly. CT scan for
the first 2 years. Colonoscopy can be performed every. 3 to 5 years
after the resection. At the time of CEA measurement, a physician
encounter should be scheduled in which the patients symptoms can
be discussed and a physical examination performed. If a rising
serum CEA level is detected on two consecutive measurements in
the absence of imageable disease by CT scan, an FDG-PET scan
can be considered .lesions found on colonoscopy should be
managed appropriately either with colonoscopic resection or
surgical management. These surveillance guidelines should allow
for the early detection of recurrence or second primary, lesions and
therefore provide the potential to impact patient to outcome.
     There is a tremendous literatures on cancer, but

 what we know for sure about it can be printed on

a calling card