Until a few years ago, if surgery was not possible, or if GIST came back after surgery and was then inoperable , there was nothing more that could be done. Ordinary radio-therapy and chemo-therapy do not work on GIST.

GLIVEC (Spelt “GLEEVEC” in the USA)

However, a few years ago a drug was developed by Novartis (a Swiss-based international drug company) for the treatment of CML (a particular variant of leukaemia ) which proved to be extremely successful. Shortly after this, it was discovered that the mechanism on which this drug acted in the body was the same as the one in GISTs, and the drug was found to work on GIST.

The way Glivec (also sometimes known as "Imatinib") works is to stop the condition producing more tumour. It does not "cure" the underlying condition. The condition is sending out messages "make tumours" to the body and Glivec cripples the messengers. So, as long as the Glivec does its job, the production of tumours is inhibited; that is why one must take Glivec for life. It’s rather like wearing spectacles; your eyesight is not cured but you can continue with your life so long as you wear them.

Glivec can also sometimes be used to reduce ("debulk") the tumour to the point where surgery becomes feasible.

Trials are taking place to see whether Glivec will help to prevent recurrence after surgical removal of the tumour. It will be years before we know the answer!

Taking Glivec

Glivec is a local irritant and the reason for the instruction on the packs "Take with a large glass of water" is to minimise the irritant effect on your digestive system. So:

• Don’t let the stuff touch your digestive system in the initial concentrated form in the pills; take it with food so that it is surrounded when inside. .
  
  
• Glivec is very soluble in water so drink at least half a pint of water with each dose of pills. This way you can get it diluted as quickly as possible..
  
  
• Don’t lie down or slump on the sofa for an hour after taking it; if possible sit upright or, better, walk about a bit to shake it up and encourage it to dissolve and get into your bloodstream.

For most people the side-effects of Glivec are not serious and certainly nothing like the fierce effects of conventional chemotherapy. This is mainly because the drug is targeted at a particular chemical process in the body. Conventional chemotherapy acts by attacking all rapidly dividing cells in the body. Of course cancer cells are dividing rapidly, but then so are many other types of non-cancer cells. An example of this would be the cells providing hair growth, hence the familiar loss of hair during chemotherapy.

Possible side effects of Glivec

Glivec is a powerful drug and does have side effects, most of which seem to diminish with time (or maybe one just gets used to them):

• Everyone experiences some tiredness and fatigue at least at first; this was the top side-effect in a survey of about 200 GIST patients undertaken by the Life Raft Group
  This may well be delayed reaction to abdominal surgery in many patients as well as the effect of Glivec, hence the experience that it gets better with time. In any case a quick afternoon nap is no hardship for most people.
  
  
• Everyone seems to experience the odd side-effect of "puffy eyelids" and some eye-watering which is a weird effect, considering where the drug is targeted, but it does ease with time in most patients and is not exactly painful or crippling.
  
  
• It is quite common to get digestive upsets of various kinds, most commonly wind ("gas" in the US) and the associated discomfort. Some patients are affected by diarrhoea. These digestive upsets are most troublesome in patients who have had part (or all) of their stomach removed because of the position of the original GIST. Glivec does cause digestive upsets and some discomfort (hardly pain) which can be mitigated by taking the drug with food and a large glass of water.
  
  
• There are a variety of rather surprising effects associated with skin and body hair. Some patients experience rashes and skin roughening which is helped by skin creams and anti-itch prescriptions. Body hair seems to turn brittle and be easily rubbed off by clothing. Quite a few (mainly male) patients have reported that their head hair has darkened from grey and there are a few cases of hair re-growth on bald patches(!).
  
  
• There is a feeling that Glivec reduces high blood pressure so, if medication is being taken for hypertension, one must be aware of this and not lower the blood pressure too much by the combination.
  
  
• A few reports indicate that Glivec may be effective in reducing blood cholesterol levels.
  
  
• In August 2006 there was a report that in a very small number of patients Glivec may affect the heart. However the risks appear to be small, and for a patient with inoperable GIST there really is no choice. We do not currently know whether there are any similar side effects with Sutent.

The majority of patients seem to manage the side-effects very well and most are able to return to their normal lives with only a minority having to take specific measures to cope with the effects of taking Glivec.

Unfortunately, some patients have GISTs which do not respond to Glivec. Other patients have tumours which stop responding to Glivec after some time.

SUTENT (also known as "Sunitinib")

Patients in the US who are resistant to Glivec, or who cannot tolerate the drug, are being treated with a new drug (SU11248: Sutent from the Sugen company (now taken over by Pfizer). Some are treated with a combination of Glivec and SU11248 and some with the new drug alone. All these trials are looking good for GIST patients. In January 2006, Sutent was approved by the Food and Drug Administration in the US and since August 2006 has been available in the UK.

Sutent, which received a priority review and was approved in less than six months, is a tyrosine kinase inhibitor working through multiple targets to deprive the tumour cells of the blood and nutrients needed to grow.

Sutent was approved for the treatment of patients with GIST whose disease has progressed or who are unable to tolerate treatment with Glivec, the current treatment for GIST patients. While studying the treatment in patients, researchers conducted an early (interim) analysis of data that showed Sutent delayed the time it takes for tumours or new lesions to grow in patients with this rare type of stomach cancer.

FDA worked with the product sponsor to offer an expanded access program prior to approval, making the product available to patients not enrolled in a clinical trial. Currently, more than 1700 patients are being treated with Sutent through the expanded access program.

The most commonly reported Sutent-related side effects included diarrhoea, skin discoloration, mouth irritation, weakness, and altered taste. Patients treated with Sutent also experienced, fatigue, high blood pressure, bleeding, swelling, and taste disturbance. Hypothyroidism was also observed. A paper has been published in America on handling these side-effects, and although it is primarily aimed at health professionals, patients may also find it helpful. It appeared in the September's issue of Community Oncology and can be found at http://www.communityoncology.net/journal/articles/0309558.pdf

OTHER DRUGS

Novartis, as might be expected, are also showing new developments. Two new drugs are in the pipeline and trials are expected on RAD001 and on PKC-412 soon.

There are reports of an even newer drug BAY43-9006 by the Bayer company, but no information is available yet.

These new "targeted" drugs are a real breakthrough in cancer treatment ("Glivec electrified the cancer world": Wall Street Journal), and the drug companies are as anxious for new drugs as the patients are. We must rely on the biochemists to keep ahead of the cancers.

A SHORT UPDATE ON CLINICAL TRIALS

The Royal Marsden has just started a Phase II trial of Astra Zeneca's AZD2171 specifically for GIST which has proved resistant to imatinib and/or sunitinib.  Prof Judson thinks this is a "very interesting VEGF inhibitor".  He says it is probably the most effective of a whole crop of VEGF inhibitors which have been appearing over the last 18 months. VEGF provides the signalling in a tumour which helps it create a blood supply (angiogenisis). By turning it off the tumour becomes starved of blood and stops growing, or dies - at least that is the theory. Ian Judson hopes that because GIST is such a vascular tumour it may prove very effective. The biggest side effect is raised blood pressure and this means that it is not suitable for people with other problems such as heart disease. Newcastle is starting a trial of plitidepsin (trade name Aplidin from Pharmamar) for solid tumours including GIST. This is more like a traditional chemotherapy.  It is derived from a marine organism and has shown effect in thyroid cancer. Pharmamar has another product - trabectedin (Yondelis) - which is currently seeking licensing for use in soft tissue sarcoma where it creates stability if a much higher percentage of metastastic disease than anything else before it.

The pan-European adjuvant trial EORTC 62024 closed last month after recruiting 411 patients (target 400) in nine months (the aim was 400 in three years !!). It has received approval to re-open and imcrease recruitment to 750.  Patients with a complete resection (no marginal disease or mets) are randomised to 400mg imatinib for two years, or to no treatment (which is the standard).  The aim is to answer the question about whether imatinib has value giving long-term NED and survival.

We are awaiting publication of results for the first trials of Novartis’ new drug nilotinib. This is the 'son of imatinib' drug.  There should be some Phase II data coming in the next few months, possibly at ASCO in June.

Compilation of the data from the two big trials which compared 400mg and 800mg of imatinib is now underway and publication is anticipated sometime early next year.  It will follow an update of the S0033 trial (the US version of the 400/800 comparison) which according to Dr George Demetri includes valuable data about cross-over to 800mg.

Two trials are in preparation. The first is the inevitable comparison trial between imatinib and sunitinib on diagnosis with unresectable/metastatic disease.  Both Novartis and Pfizer will be funding this trial which I understand will be international. The second is a European trial of surgery following stability with imatinib for refractory disease. I am not yet sure of what the conditions will be but the aim is to see whether getting people back to NED with imatinib/surgery is valuable for quality of life and for longevity.

Roger WilsonSarcoma UK

Last updated November 2006