For patients, policy makers and other non-medical professionals
This text was prepared by ESMO for the European Alliance for Personalised Medicine in March 2015 and updated in February 2017
Gastrointestinal stromal tumours (GISTs) are relatively rare and should be treated in specialist centres. They are also unusual since, unlike most forms of cancer, which are classified according to the organ in which they arise, GISTs can occur at many different sites throughout the gastrointestinal tract, which extends from the oesophagus to the rectum and includes the stomach, intestines and bowel.
This is because the cells that become malignant are part of the muscle wall that encourages the passage of food through the entire digestive system. GISTs are part of a larger group of cancers called soft tissue sarcomas which include tumours developing in fat, nerves and blood vessels, as well as muscle.
But GISTs are like other cancers in that their uncontrolled growth arises from genetic mutations that increase the sensitivity of cell surface receptors to growth factors or cause abnormalities in the way growth signals are transmitted from the receptors to the nucleus of the cell.
In the case of GIST, the most relevant mutations are in the KIT gene, involved in intracellular signalling, and in the receptor called PDGFRA (platelet-derived growth factor receptor alpha). Mutations can occur at several different sites in these gene sequences, so they have to be precisely identified. Our increased understanding of these mutations – which vary from one tumour to another – is helping doctors to personalise the selection of drug treatment, if this becomes necessary.
But the initial approach to managing a GIST requires assessment of how much risk the tumour represents to a particular patient. Central to this assessment is the size of the cancer, exactly where it is in the GI tract, and the extent of any spread.
Small GISTs which repeated scans show are not increasing in size may simply be left alone and regularly monitored. But this depends to some extent on where the cancers are. Those in the stomach, for example, are less likely to present future problems than GISTs in the small bowel or rectum. So the latter are likely to be surgically removed whatever their size. And GISTs that are 2 cm or greater are also likely to be operated on, wherever they are in the GI tract - although this decision may be influenced by analysis of a tissue sample taken from the cancer in a process called biopsy.
Examining the tissue under a microscope enables doctors to judge how abnormal the cells are, and so how aggressive the cancer is likely to be. One factor in their judgement will be the proportion of cells in the sample that are actively dividing, since this relates to the chances of tumour spread. They will also look for molecular markers on the cell surface that confirm the diagnosis and the presence of the specific mutations that predict drug sensitivity. These analyses should be carried out in expert laboratories.
Many patients who have had their GIST surgically removed experience no further problems. If doctors judge that someone is at relatively high risk of a recurrence, they may recommend several years’ treatment with a drug called imatinib which targets certain of the molecular abnormalities which cause GIST to develop and drive tumour growth. The frequency of follow-up scans will be tailored on a case-by-case basis to the risk of recurrence.
Imatinib can also be used before surgery to reduce the size of large tumours and so lessen the size of operation required.
But imatinib is not effective against all gene mutations responsible for the disease. Certain mutations of PDGFRA are resistant to imatinib, so the drug should not be used in these specific cases. And one particular KIT mutation (termed exon 9) may require a higher dose of the drug.
When the GIST is too large to be removed surgically or has spread to other parts of the body, imatinib is the standard treatment (providing that the tumour does not have one of the drug-resistance mutations). To continue to suppress tumour growth, the drug has to be given indefinitely. There may be value in removing as many as possible of the secondary cancers caused by tumour spread, but this decision has to be tailored to the circumstances of the individual patient.
More generally, we know it is helpful to monitor the tumour to see if imatinib is having the desired effect of shrinking or inactivating it. This can be done using magnetic resonance imaging (MRI), X-ray computed tomography (CT) or ultrasound. There is also a more advanced “positron emission tomography” (PET) technique that indicates how much glucose is being taken up by the cancer cells and therefore whether they are metabolically active.
If the tumour does not respond to imatinib, or becomes resistant after a period of response, treatment with another molecularly targeted drug can be tried. The usual choice of second-line drug is sunitinib, with the newer agent regorafenib held in reserve as a final option. These three agents are all inhibitors of tyrosine kinase enzymes which are involved in transmitting the abnormal growth signals within cancer cells that promote their uncontrolled division and spread.
As explained above, the great majority of GISTs in adult patients have mutations of either KIT or PDGFRA. But up to 15% of GISTs do not have these gene defects. Among them are tumours which lack the enzyme succinate dehydrogenase (SDH). This type of GIST occurs only in the stomach, and is found mostly in children and young adults.
SDH-deficient GISTs are generally slow-growing. If treatment is required, imatinib is not effective since the abnormal growth signalling that drives these tumours is different from that in most GISTS. Other small molecule tyrosine kinase inhibitors are therefore likely to be tried. Sunitinib is an option, and several new targeted drugs are being investigated in patients with SDH-deficient tumours.
The introduction of tyrosine kinase inhibitors has revolutionised the treatment of GISTs. Even so, much remains to be done before this form of cancer is fully controlled. People whose tumours are not responding adequately to existing drugs, or whose tumour have returned after treatment, may like to consider entering clinical trials of new agents. But there is no doubt that advances in our understanding of the mutations responsible for the disease is already greatly helping the personalisation of treatment in terms of the drug chosen, the dose used, and the duration of therapy.