There
is growing interest in tumour markers as aids for the diagnosis, staging and
management of cancer. Some are expected to succeed, after several years of
evaluation to trials and eventual clinical use. A large number, however, are
not likely to make it beyond development. On their part, physicians need to be
aware of both opportunities and limitations in the clinical use of tumour
markers.
Tumour
markers are substances (antigens, proteins, enzymes or hormones) which indicate
the presence of cancer or provide information about its likely course of
development. They are present in cancerous tissue as well as in the bodily
fluids of cancer patients.
Range
of applications
Tumour
markers have shown their potential for several applications. These range from
the differential diagnosis of benign and malignant conditions to prognostic
assessments, postoperative surveillance, the prediction of drug response or
resistance, and the monitoring of therapy in advanced disease.
The
key advantage of tumour markers in the above applications is convenience.
Inexpensive automated assays allow for fast processing of samples.
The
case for tumour markers
The
best known tumour markers include Her2/neu for breast cancer, which has an
established economic case. Her-2/neu is a target for trastuzumab, whose use as
an adjuvant has been shown to decrease cancer recurrence rates by 50%. However,
up to one in 20 trastuzumab recipients develop cardiac dysfunction. Given that
the cost of one year of therapy is close to 100,000 Euros, the need for
accurately and precisely assaying every tissue sample is evidently strong.
Work
in progress
Tumour
markers are, however, still a work in progress and expected to remain so. In
the US, the National Cancer Institute (NCI) states that “more than 20 tumour
markers are currently in use.” It however lists over 30. The European Group on
TumoUr Markers (EGTM) has a list of 16.
Despite
the number of tumour markers in development, only ‘traditional’ markers are
used in diagnosis, prognosis and monitoring. For example, at least six urine
tumour marker kits are approved by the US Food and Drug Administration for
bladder cancer. However, none are backed by data from clinical trials that
increased survival time, improved quality of life or decreased cost of
treatment.
Appropriate
use, caution urged
Many
experts urge caution with respect to tumour markers. Inappropriate use,
according to an article in the ‘British Medical Journal’, can cause patients
unnecessary anxiety and distress, and may also delay correct diagnosis and
treatment. The authors cite one hospital audit which found “that only about 10%
of requests for tumour markers were appropriate.”
The
European Group on Tumor Markers attributes part of this problem to the growing
availability of automated immunoassays. This makes tumour marker tests
available in routine rather than specialist laboratories. “Results are
consequently more readily available to non-specialist clinicians, who may be
less familiar with their interpretation.”
Challenges
of sensitivity and specificity
Only
some markers, known as tumour-specific markers, are produced exclusively by a
particular tumour As a result, most tumours cannot be detected by a single
test, and tests for multiple markers are often required.
Tests
are therefore often accompanied by the risk of both false positives and false
negatives. The Cancer Information & Support Network (CISN) sums up the picture:
False positives may occur because most tumour markers “can be made by normal
cells, as well as cancer cells,” and markers “can be associated with
noncancerous conditions.” On the other hand, the reason for false negatives is
that “tumour markers are not always present in early stage cancers” and because
“people with cancer may never have elevated tumour markers.”
For
example, the level of CA-125, a marker for ovarian cancer, is also elevated in
a variety of non-malignant disorders such as cirrhosis, pancreatitis,
endometriosis, and pelvic inflammatory disease. In addition, medications appear
to alter the results of a varied range of tests. So too do pregnancy,
menstruation, cigarette smoking and various benign disorders.
Biopsy
remains only definitive way for diagnosis
The
above lack of sensitivity and specificity has been a major limitation facing
the use of tumour markers in clinical practice. As with imaging, the use of
tumour markers has been limited to supporting the diagnostic process, and the
gold standard for diagnosis still remains a biopsy.
Although
difficult to access areas such as the brain are likely to result in more use of
tumour markers, a biopsy remains “the only definitive way” for diagnosis of a
tumour” even in the brain.
NACB
Guidelines
In
2008, the National Academy of Clinical Biochemistry (NACB) in the US released
updated Laboratory Medicine Practice Guidelines for the use of tumour markers.
The
guidelines made cross-referrals to efforts by numerous professional and
regulatory best-practices bodies, including the American Society of Clinical
Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), Britain’s
National Institute for Health and Clinical Excellence (NICE), the European
Group on Tumor Markers (EGTM), the International Federation of Gynecology and
Obstetrics (FIGO) and the Gynecologic Cancer Intergroup (GCIG).
The
NACB guidelines cover five cancer sites: testicular, prostate, colorectal,
breast, and ovarian.
Testicular
cancer
For
testicular cancer, α-fetoprotein (AFP), human chorionic gonadotropin and
lactate dehydrogenase are recommended for diagnosis, staging, prognosis
determination, recurrence detection and the monitoring of therapy. AFP is also
recommended for the differential diagnosis of tumours
Prostate
cancer
Prostate-specific
antigen (PSA) is considered to be potentially useful for detecting prostate
cancer recurrence and monitoring therapy. Free PSA is considered useful for
distinguishing malignant from benign prostatic disease.
Colorectal
cancer
In
colorectal cancer, carcinoembryonic antigen is recommended (with some caveats)
for prognosis determination, post-operative surveillance, and therapy
monitoring in advanced disease. Fecal occult blood testing is considered useful
for screening asymptomatic adults who are older than 50 years.
Breast
cancer
For
breast cancer, estrogen and progesterone receptors predict response to hormone
therapy, human epidermal growth factor receptor-2 predicts response to
trastuzumab, while urokinase plasminogen activator/ plasminogen activator
inhibitor 1 is used for determining prognosis in lymph node-negative patients.
CA15-3/BR27–29 or carcinoembryonic antigen can be used for therapy monitoring
in advanced disease.
Ovarian
cancer
CA125
is recommended (with transvaginal ultrasound) for early detection of ovarian
cancer in women at high risk for this disease. CA125 is also recommended for
differential diagnosis of suspicious pelvic masses in post-menopausal women, as
well as for detection of recurrence, monitoring of therapy, and determination
of prognosis in women with ovarian cancer.
Future
research to target higher specificity and sensitivity
In
the future, research is expected to focus on finding markers which are specific
of one pathology, have higher sensitivity with a low cut-off and deliver
results which correlate to tumour mass and growth potential. Ideal candidates
would also have a short life duration to permit efficient follow-up; in other
words, their presence should decrease during treatment and increase before a
relapse.
The
promise and challenges of screening
Given
that tumour markers can aid in assessing the response to cancer treatment and
making prognoses, many public health professionals have hoped they might also be
used for screening tests which would detect cancer before the presence of
symptoms.
Indeed,
many tests have both screening and diagnostic uses, with only the context of
use determining whether the test is one or the other. “A screening test is done
on asymptomatic individuals who receive the test principally because they are
of the age or sex at risk for the cancer. A diagnostic test is done on an
individual because of clinical suspicion of disease.”
However,
no tumour marker identified to date is sufficiently sensitive or specific to be
used on its own for screening, demonstrating a survival benefit in randomized
controlled trials in the general population.
One
of the best known examples is the prostate-specific antigen (PSA) test.
Although it is now accepted that most men with elevated PSA levels do not have
prostate cancer, the implications of this remain mired in controversy and also
illustrate the kind of limitations which other tumour biomarkers may face in the
future for use in screening.
PSA
screening has been the subject of two large randomized controlled trials in the
US and Europe in the 2000s. However, as the Mayo Clinic notes, in spite of the
size of the trials, there were “no clear conclusions.” This is because their
diversity of methodology allows for significant flexibility in interpretation.
As a result, “the decision of whether to screen or not screen - using PSA
testing or other means or both - is a decision best made between physicians and
their individual patients.”
The
two trials were PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening
Trial) conducted by the National Cancer Institute in the US, and the European
Randomized Study of Screening for Prostate Cancer (ERSPC), billed as “the
largest randomized trial of screening for prostate cancer” with 162,388
subjects.
In
2011, a US government task-force concluded that healthy men should not be
screened for prostate cancer. The finding, which “drastically changed the
standard of care for middle-age American men who had grown accustomed to annual
screenings,” was largely based on 10 years data from the two studies, which
found risk of over-diagnosis and over-treatment.
Problems
began when follow-on data from ERSPC two years later showed screening was
associated “with a 21% reduction in risk of prostate cancer mortality.”
However, this was accompanied by a still-sizeable risk of over-diagnosis and
over-treatment. As a result, the authors said that “population-based screening
could not yet be recommended.
In
April 2015, an article in ‘The Lancet’ re-confirmed “a substantial 21%
reduction” from PSA screening. However, due to access restrictions to the ERSPC
trial data, the authors called this figure into serious question.
The
controversy is unlikely to go away for some time. An Op Ed in The New York
Times called the PSA test “hardly more effective than a coin toss.” Although
the date of publication was 2010, the author of the commentary was Dr. Richard
Ablin, who discovered PSA in 1970.
Such
challenges are also likely to accompany screening for other conditions. For
instance, data from the PLCO trial show that screening for CA-125 (recommended
by the National Academy of Clinical Biochemistry for women with ovarian cancer,
along with transvaginal ultrasound), does not reduce ovarian cancer mortality.
Instead, false-positive screening test results have been associated with
complications.
I saw so many testimonies about Dr Itua a great HERBAL DOCTOR that can cure all kind of diseases and give you the rightful health to live a joyful life, i didn't believe it at first, but as the pain got worse and my life was at risk after visiting my therapist numeriuos times for combination of treatments. and no changes so i decided to take a try, I contacted him also and told him i want a cure for Vulvar cancer/ Testicular cancer and it was Stage IIIA, he gave me advice on what i must do and he delivered it to me in my state which i use according to his instruction, and today i must say I am so grateful to this man Dr Itua for curing me from Vulvar cancer/ Testicular cancer and for restoring me back to my normal health and a sound life,i am making this known to every one out there who have been living with cancers all his life or any sick person should not waist more time just contact him with his details below- WhatsApp- +2348149277967 Email drituaherbalcenter@gmail.com, believe me this man is a good man with Godly heart, this is the real secret we all have been searching for. Do not waste more time contact him today for you also to live a sound and happy life. he cure the following disease________Thyroid Cancer,Uterine cancer,Fibroid,Angiopathy, Ataxia,Arthritis,Amyotrophic Lateral Scoliosis,Brain Tumor,Fibromyalgia, Fluoroquinolone Toxicity Bladder cancer,Brain cancer,Hiv,Herpes,Esophageal cancer,Gallbladder cancer,Gestational trophoblastic disease,Head and neck cancer,Hodgkin lymphoma
ReplyDeleteIntestinal cancer,Kidney cancer,Hpv,Lung cancer,Melanoma,Mesothelioma,Multiple myeloma,Neuroendocrine tumors
Non-Hodgkin lymphoma,Oral cancer,Ovarian cancer,Sinus cancer,Hepatitis A,B/C,Skin cancer,Soft tissue sarcoma,Stroke,Lupus,Spinal cancer,Stomach cancer,Vaginal cancer,Vulvar cancer,
Testicular cancer,Tach Diseases,Pancreatic Cnacer,Leukemia,Liver cancer,Throat cancer,
Syndrome Fibrodysplasia Ossificans ProgresSclerosis,Alzheimer's disease,Chronic Diarrhea,Copd,Parkinson,Als,Adrenocortical carcinoma Infectious mononucleosis.