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Science Forum Index » Medicine - Cancer Forum » GIST and Gleevec (or Glivec) (and CML)
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| J |
 Posted: Tue Nov 28, 2006 3:59 pm |
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http://www.gleevec.com/info/page/gist
GleevecŪ and GIST
Gastrointestinal Stromal Tumors (GIST)
On February 1, 2002 the FDA granted Novartis approval of Gleevec (imatinib
mesylate) for the treatment of patients with KIT (CD117) positive
unresectable and/or metastatic malignant Gastrointestinal Stromal Tumors
(GIST). The effectiveness of Gleevec is based on objective response rates.
There are no controlled trials demonstrating a clinical benefit, such as
improvement in disease-related symptoms or increased survival.
Gleevec, formerly known as STI571, has gone through a rapid development
process. Novartis Pharmaceuticals Corporation saw the potentially
significant patient benefits of Gleevec in early testing and took every
step to ensure that Gleevec was made available to as many patients as
possible and as quickly as possible. As a result, the overall time to make
Gleevec available for prescription was drastically reduced.
Federal regulations permit the Food and Drug Administration to accelerate
the approval of certain new drugs and biological products, for serious or
life-threatening illnesses, that may offer a significant improvement
compared to currently marketed products. Accelerated approval of Gleevec
was based on time to progression as the primary surrogate endpoint.
Approval under these regulations requires further adequate and
well-controlled studies to verify and describe clinical benefit.
Gleevec was first made available to patients with Chronic Myeloid Leukemia
(CML) in May of 2001. Gleevec is indicated for the treatment of newly
diagnosed adult patients with Philadelphia chromosome-positive (Ph+) CML
in chronic phase. Follow-up is limited. Gleevec is also indicated for the
treatment of patients with pH+ CML in blast crisis, accelerated phase, or
in chronic phase after failure of interferon-alpha therapy. Gleevec is
also indicated for the treatment of pediatric patients with pH+ chronic
phase CML whose disease has recurred after stem cell transplant or who are
resistant to interferon-alpha therapy. There are no controlled trials in
pediatric patients demonstrating a clinical benefit, such as improvement
in disease-related symptoms or increased survival. .
Due to our efforts in bringing Gleevec to patients as quickly as possible,
we will be working closely with the FDA to make detailed product
information available to you, as soon as possible.
http://www.ohsu.edu/news/2003/060203gist.html
June 2, 2003
LAB TESTS CAN REVEAL WHICH PATIENTS RESPOND TO GLEEVEC
Mutational analysis of gastrointestinal tumors gives clinicians new tool
to predict outcomes
PORTLAND, Ore. -- An international team of researchers has concluded that
lab testing can reveal ahead of time just how well patients with certain
gastrointestinal cancers will respond to therapy with the drug Gleevec,
according to study results presented at the annual meeting of the American
Society of Clinical Oncology.
Patients with a favorable lab result had an 84 percent chance of a partial
remission in response to Gleevec. Only 10 percent of patients with an
unfavorable lab result had a partial remission.
"These results demonstrate that the most important predictor of tumor
shrinkage during Gleevec therapy is not age or tumor size but rather the
specific type of mutation causing the tumor," said Michael Heinrich, M.D.,
member of the Oregon Health & Science University (OHSU) Cancer Institute,
associate professor of medicine at the Portland VA Medical Center, and
co-principal investigator of the study.
Gastrointestinal stromal tumors (GISTs), which occur in the stomach and
intestines, are diagnosed in up to 10,000 Americans annually. Surgery is
the treatment of choice for localized tumors, but in many patients the
tumor recurs and spreads elsewhere, particularly to the liver. Up until
two years ago, at this metastatic stage, the disease was invariably fatal
because chemotherapy, radiation and surgery are ineffective in advanced
cases. More recently, however, physicians have shown that metastatic GISTs
are responsive to Gleevec.
Gleevec, technically known as a tyrosine kinase inhibitor, was first
introduced for the treatment of chronic myelogenous leukemia (CML), the
growth of which is driven by a mutant tyrosine kinase enzyme called
BCR-ABL. Gleevec is a potent inhibitor of the BCR-ABL enzyme, effectively
shutting down the growth of leukemia cells with only relatively minor side
effects.
Gleevec also inhibits a related tyrosine kinase called KIT. The presence
of mutant KIT protein in GISTs led researchers to suspect that Gleevec
would be an effective treatment for this cancer.
"The majority of GI stromal tumors have a mutant form of KIT that acts
like a gas pedal stuck to the floor, providing a constant stimulus for
GIST cells to grow," Heinrich said.
A fast-tracked clinical trial proved this hypothesis, and the drug was
approved by the FDA in 2002 for patients with advanced GIST. This clinical
trial was performed at the OHSU Cancer Institute, Dana-Farber Cancer
Institute, Fox Chase Cancer Center and the University Hospital of Helsinki
(Finland).
"Treatment with Gleevec inhibited KIT activity much like turning off this
engine driving tumor cell growth," Heinrich said.
While the majority of the GIST patients treated in the Gleevec trial
benefited from the drug, a subset did not respond well, and the latest
research was designed to reveal why that was so. The researchers analyzed
DNA samples of the GIST tumors from 127 patients enrolled in the trial to
determine whether a KIT tyrosine kinase mutation was present and whether
the specific type of mutation had an impact on drug response.
The results revealed three distinct subsets of GIST. Those with "exon 11"
mutations of KIT responded well to Gleevec; 84 percent of patients with
such tumors had a partial remission (greater than 50 percent shrinkage of
their tumors), and half of the members of this group are still benefiting
from the drug after 22 months. GISTs that lacked a KIT mutation, however,
did not respond well to Gleevec. Only 10 percent of patients in this group
had a partial remission, and all had failed therapy in less than a year.
GIST with an "exon 9" mutation of KIT responded in an intermediate fashion
in the trial, with half of the patients failing treatment after 187 days.
"KIT mutation status not only predicted the likelihood of Gleevec
response, it was also the most important predictor of duration of response
and overall patient survival in the trial," Heinrich said.
Further studies by Heinrich and his colleagues also revealed a new wrinkle
in the GIST story. Among the tumors that lacked a KIT mutation, some had a
mutation in a different (but closely related) tyrosine kinase called
PDGFRA. While mutations in this kinase were found in only 4.7 percent of
GIST cases in the Gleevec clinical trial, the drug was effective against
some of these PDGFRA mutations.
"We are in the process of studying the PDGFRA mutations, but so far
preliminary data suggest that there are parallels with KIT - that is, if a
PDGFRA mutation is present, then Gleevec response can be predicted by the
exact type of mutation," Heinrich said.
The study results suggest that clinical testing for specific mutation type
may help clinicians treat patients with GIST. KIT mutational testing is
now available at OHSU and testing for the newly identified PDGFRA
mutations will be available soon.
"Mutational testing can be helpful in confirming the diagnosis of GIST and
in defining the prognosis for patients who need Gleevec therapy," said
Christopher Corless, M.D., associate professor of pathology in the OHSU
School of Medicine, and co-investigator in the GIST research.
"As Gleevec is used more and more in combination with surgery, we believe
that testing for mutations in GIST will be important in deciding whether
Gleevec therapy should be used before and/or after surgery for GIST,"
Heinrich said. |
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| J |
| Posted: Tue Nov 28, 2006 4:02 pm |
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J wrote:
Quote: Gastrointestinal Stromal Tumors (GIST)
http://www.cancerhelp.org.uk/help/default.asp?page=6161
GIST is a rare type of sarcoma that is found in the digestive system, most
often in the wall of the stomach. Some GISTS are benign (not cancerous) but
they can become cancerous if not treated. Generally speaking, the larger the
GIST, the more likely it is to be cancerous.
These tumours do have a rather complicated name. They are found in the
digestive system - the gastrointestinal tract. They develop from cells of
connective tissues that control the movements of the gut. The tissues that
support body organs are called the 'stroma', so that's where the stromal bit
comes from. Cancers of connective tissues are 'sarcomas'. So the full name
is gastrointestinal stromal sarcoma.
About 6 out of 10 of these tumours grow in the stomach, but they can crop up
anywhere in the digestive system, for example in the bowel or oesophagus.
Very rarely, they develop outside the gastrointestinal tract.
These tumours are most common occur in people between 50 and 70 years old. We
don't really know the cause but there is a condition called neurofibromatosis
(NF), which can increase the risk of developing it. Rarely, GIST can develop
in children, but there are only about 20 cases a year in the UK.
Symptoms of GIST
People with early stage GIST often do not have any symptoms. Most GISTs are
diagnosed in later stages of the disease. The symptoms are likely to include
* Pain or discomfort in the tummy (abdomen)
* A feeling of fullness
* Being sick
* Blood in stools or vomit
* Feeling very tired
* Low red blood cell count (anaemia)
Other diseases apart from GIST can cause these symptoms. If you have these
symptoms you should see your doctor. It may be nothing serious but it is
always best to check.
Treatment for GIST
The most common treatment option is surgery and this alone may be a cure for
people with small tumours. But larger tumours are less likely to be
completely removed. If the GIST has spread, it is sometimes possible to
remove these secondary tumours too. Chemotherapy and radiotherapy don't work
well for GIST, so researchers have been looking for other types of treatment.
Glivec, also called imatinib, is a relatively new drug used to treat GIST
since 2004. Glivec is not a chemotherapy drug. It is a type of drug called a
tyrosine kinase inhibitor. This means it blocks a chemical (an enzyme) that
the cancer needs in order to grow. It is used to treat GISTs that cannot be
completely removed with surgery.
Surgery is still the best way of curing GIST. If your GIST cannot be removed,
your specialist may suggest you have Glivec to try to shrink it so that it can
be removed.
In October 2004, NICE (the National Institute for Health and Clinical
Excellence) recommended that imatinib (Glivec) should be the first choice of
treatment for people with GIST that can't be completely removed with surgery.
Your surgeon will remove a sample of your tumour during your operation and
send it to the laboratory. A specialist will then test the cells to confirm
the diagnosis of GIST, and to see if the cells carry a receptor on their
surface called CD117. Your doctor may say that your GIST is 'CD117 positive'
or 'KIT positive'. The important thing is whether your tumour really is a
GIST or not. Even GISTs that are CD117 negative can respond to treatment with
Glivec.
NICE recommend that people have a dose of 400mg a day of imatinib (Glivec) for
12 weeks. After that, your specialist will arrange a CT scan to see if your
GIST has responded to the treatment. In some cases, the GIST will disappear
altogether. But to show a response to treatment, the GIST may not necessarily
have shrunk. It may have become less dense. Your doctor may say it has
'become cystic'. This means that there is fluid inside it, instead of solid
tumour. Improvement in your symptoms is another way of telling that the
treatment is working.
If the Glivec appears to be helping, you will carry on treatment for another
12 weeks. Then your specialist will check again to see how the GIST has
responded. You will carry on having treatment until your GIST comes back, or
shows signs of growing again.
If your GIST responds to treatment with Glivec, it may become possible for you
to have surgery to remove it. Sometimes it is even possible to remove GIST
tumours that have spread to another part of the body, such as the liver.
If your GIST has grown or your symptoms have got worse, your specialist will
know that Glivec is not helping in your case and may recommend stopping
treatment. NICE do not currently approve increasing the dose of Glivec, but
this has been investigated and there is some evidence that it may help.
Another drug, called sunitinib (or Sutent) was recently licensed in Europe to
treat GIST if Glivec does not work, or stops working. But until new
treatments such as this are looked at by NICE, they may not be available on
the NHS.
Side effects of Glivec
Glivec is a tablet. So you can have treatment at home. The commonest side
effects are
* Tiredness (fatigue)
* Feeling or being sick
* Fluid retention causing swelling of the hands and feet and around the
eyes
* Skin rash
Other less common side effects are headaches and diarrhoea. Glivec can
irritate your digestive system, so it is best to take it with food and drink a
glass of water to dilute it.
If you are looking for information elsewhere on the web, it may help to know
that in the UK we call imatinib 'Glivec' but in the US they call it 'Gleevec'.
Is GIST curable?
If GIST can be completely removed with surgery, then it may well be cured. As
with any cancer, there may be a chance that the tumour could come back.
Because of this risk, you will have regular check ups with your specialist for
some time after your surgery. It is best that you talk to your own specialist
about whether there is a risk of GIST returning, as the circumstances will be
different in each case.
Since the discovery of Glivec, people with GIST that cannot be completely
removed are doing much better. Unfortunately though, specialists don't think
it is a complete cure. How people respond to particular drugs will always
vary, depending on all their individual circumstances. But generally
speaking, Glivec stops GIST from growing for around 2 years. Even if the GIST
comes back, Glivec may still help to slow down the growth of the tumour and
may help to control it for another few years. As Glivec is a relatively new
treatment, we don't have the full picture as yet. According to our specialist
advisors, the longest survivors are approaching 6 years of Glivec treatment,
with no sign of their GIST returning. |
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