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The Royal Marsden School

Imatinib for gastrointestinal stromal tumours

By Aoibhinn O’Reilly and YiWen Hon
Mon, 29/06/2020

Gastrointestinal stromal tumours (GISTs) are soft tissue sarcomas that arise from the interstitial cells of cajal within the gastrointestinal tract. Whilst soft tissue sarcomas are rare, gastrointestinal stromal tumours are their most prevalent form (Amelio et al, 2014). Currently within the United Kingdom, prevalence studies have not been published, although recent reports suggest that each year, 650 meaningful diagnoses are made with a total of 900 cases per year (Judson et al, 2017). Initially the biology of gastrointestinal stromal tumours was poorly understood. Surgery appeared to be the only curative option but this had a reoccurrence rate of 50% and conventional chemotherapy only had a response rate of less than 10% (Dematteo et al, 2002), this demonstrates that further research into more successful treatments is necessary. In 85-90% of GIST cases, oncogenic mutations are guided by the overexpression of KIT and CD117. The remainder are driven by platelet derived growth receptor alpha (PDGFRA) (Patel, 2013a). 

Imatinib Mesylate is a form of oral targeted therapy that inhibits the expression of tyrosine kinase (TK). TKs are essential in the signalling pathways for the development of cancer; they enable the growth, differentiation, metabolism and apoptosis (Somaiah, Gupta, & Patel, 2019). Imatinib obstructs the activity of ABL, BCR-ABL, PDGFRA, and c-KIT oncogenes by binding to an intracellular adenosine triphosphate (ATP) binding site within TKs (Schirmann et al, 2014). This supresses ATP binding and therefore inhibits phosphorylation, the activation of growth receptors in the downstream signal pathways (Balachandran & DeMatteo, 2014). The use of Imatinib for treatment of GIST in both the adjuvant and advanced metastatic setting has shown significant outcomes for patients.

Studies such as Milhem & Deutsch (2015) have shown that Imatinib is a highly efficacious first line treatment. It has been listed in guidelines such as Judson, et al (2017) and National Institute for Health and Clinical Care Excellence (2014) and has been approved for both neoadjuvant and adjuvant therapy in treatment against GISTs. Studies such as Blanke, et al (2008) and the Gastointestinal Stromal Tumour Meta-Analysis Group (2010) have identified that 400mg of Imatinib once a day is the optimal dose for the initial and long-term treatment of GISTs.  However, within the trial carried out by Blanke, et al (2008), it was also established that 800mg of Imatinib would be appropriate in those with disease progression on 400mg and in patients that have exon 9 mutations. Although, further research is needed to examine the importance of KIT and PDGFRA genotyping in GISTs when considering tailored treatment for patients (Heinrich, 2008). 

As a result of Imatinib being well tolerated by GIST patients with stable disease, long term administration has been proven as safe. The American College of Surgeons Oncology Group (ACOSOG) trial Z9001 identified that the risk of tumour recurrence during treatment was only 4%, however this increased to 8% once treatment was interrupted (Corless et al, 2014). In a study carried out by Lin et al (2017) patients were followed up that were treated with Imatinib over 1-3 years, 3-5 years and 5+ years. It was identified across all three groups that the longer the duration of treatment, the better the recurrence free survival and overall survival was for patients, particularly in those with high risk GISTs. The conclusion of this trial highlighted that treatment of Imatinib for a minimum of five years drastically improved patient outcomes. This was further supported by the PERSIST-5 trial (Raut et al, 2018) that followed patients through for five years of Imatinib treatment for GISTs that were considered high risk. Recurrence free survival was observed in 92% of patients that were followed up, representing the need for longer duration of treatment with Imatinib. However, the BFR14 study conducted by Blesius et al (2011) identified that a dose interruption after three years of 400mg Imatinib gave patients a 32% progression free survival of a year, compared to 92% of patients that remained on continuous Imatinib treatment. This study therefore demonstrated that Imatinib should be administered indefinitely until the point of disease progression. 

However, whilst it is important to consider the treatment duration with the best patient outcomes it is also necessary to discuss the main factors that can restrict long term treatment. Firstly patient compliance with treatment and follow up surveillance is vital, long term daily administration of Imatinib is necessary for effective disease control (Le Cesne, et al., 2010). Whilst close monitoring for any signs of disease progression using blood tests and CT scans every three months is fundamental in order to ensure that treatment is effective. Non-adherence to this has a direct impact on patient outcomes and can occur as a result of misunderstanding between professional and patient and also because of the side effects. This suggests that patient education is of great importance particularly in how to control and manage side effects such as nausea, diarrhoea or fatigue that may lead to treatment interruption (Patel, 2013b). Throughout the process of consenting patients for treatment it is important to discuss the potential outcomes and side effects with terminology that is understood by non-medical persons. During these conversations it is necessary to confirm from time to time that the patient understands what has been said and is able to adequately weigh up their decisions (Nursing and Midwifery Council, 2018a).  Secondary to this, providing patients with written information on both the treatment and its side effects is also beneficial as it they can take it home and read through it at their own pace (Ward, 2011). Furthermore, directing patients towards patient friendly websites for further information and support can enhance their understanding and allow them to feel more engaged in their care (Coulter, 2012).

Secondly, disease progression or recurrence will effect treatment duration. As discussed previously, once the point of progression occurs, second line treatment options must be considered.   At the first instance of progression on standard treatment of 400mg of Imatinib, a dose increase to 800mg once a day is recommended (Blay, et al., 2005). Following this, Sunitinib has been approved as second line treatment for GISTs, this could be used in place of an Imatinib dose increase due to similar patient outcomes (Hsu, et al., 2017). Due to metastatic GISTs eventually developing resistance to both first and second line therapies, Regorafenib was licensed for third line use in the UK in 2017 (National Institute for Health and Care Excellence, 2017).Patient centred care is pivotal within all treatment decisions as some patients evidently prefer their quality of life over quantity (NHS England, 2016a). This again, highlights the importance of effective counselling of patients on their treatment options and the adverse effects that may occur when undertaking a new regime. 

Considering the success of Imatinib for treatment of GISTs, patients are now living longer with cancer and with a better quality of life; with this in mind it is crucial to look at how we as professionals can support them. Clinical Nurse Specialists carry out holistic needs assessments (HNA’s) on individual patients to establish what their needs are and how they can be addressed at the earliest opportunity. By carrying out HNA’s, it opens a dialogue that will facilitate patient centred and tailored care. However, there is a lack of evidence identifying the impact that HNA’s have on patient centred care at present. As a result of this, a randomised controlled trial carried out by Snowden, et al (2015) attempted to highlight the benefits of HNA’s. The results of this study have yet to be published. Another supportive resource within the UK is the MacMillan Hotline (Macmillan Cancer Support, 2020). This 365 day a year service allows patients access to advice ranging from general the management of side effects to financial guidance. Providing supportive services such as the MacMillan Hotline is indispensable for ensuring improved patient outcomes (National Cancer Institute, 2019).  Similarly to the HNA, there is a lack of evidence demonstrating the benefits of the Macmillan hotline. Although in reports from both Enhanced Supportive Care (NHS England, 2016b) and the results of the National Cancer Patient Survey (NHS England, 2019) services such as the Macmillan hotline are warranted as patients found them beneficial. 

Currently within the NHS there is a lack of data available that measures the patient’s quality of life during and after their treatment (Haslam, Herrera-Perez, Gill, & Prasad, 2020). The long term side effects of treatment often arise during treatment itself and persist over a number of years but often; some side effects remain dormant and only occur after treatment has ended (Gegechkori, Haines, & Lin, 2017). In 2017 a pilot study was launched across eight NHS trusts, it required patients to complete questionnaires based on their experience with the aim of improving personalised care during and after treatment (NHS England, 2017).  The promising results so far from this pilot aim to have the Quality of Life Metric fully rolled out across the UK by 2020 (NHS England, 2018). It is important to consider that for cancer patients and their families, their quality of life at times can outweigh the clinicians need for better clinical outcomes. As a result of Imatinib being a daily long term treatment for GISTs, many patients experience side effects on a daily basis. The most commonly reported side effects of Imatinib treatment are fatigue, muscle cramping and nausea (Casali, et al., 2017). 

In a qualitative study carried out by Fauske et al (2019), patients identified that these side effects drastically effected their day to day lives and that although Imatinib is life prolonging, they felt that they needed to find a new normal and in particular instances were unable to carry out roles that they had prior to commencing treatment. Alongside the physical effects of Imatinib treatment, many patients identified psychosocial aspects that not only affected them but also their families. Due to the lack of curative treatment for GISTs patients were ultimately concerned with disease progression and how long they had left to live. Although the smaller sample size of this study may limit its generalizability, the nature of qualitative research allows further research to be carried out pertaining to the wider multidisciplinary team and what can be done to effectively support patients throughout treatment (Custers et al, 2015). As part of the multidisciplinary team, the nurse often has the best opportunity to develop excellent rapport with patients. By ensuring that nurses have the necessary knowledge and skills to adequately support and counsel patients, it allows for patients to better understand and manage their lives with and beyond cancer (Nursing and Midwifery Council, 2018b). 

Throughout the literature it is evident that the use of Imatinib has revolutionised the treatment of patients with GISTs. However due to continued disease progression even with the development of second and third line tyrosine kinase inhibitors it is indisputable that further research is needed into multi targeted tyrosine kinase inhibitors and genotype focused treatments. Better patient centred care is also important in order to improve patient outcomes. This can be achieved through educating and counselling patients prior to, during and after treatment to ensure that both their physical and emotional needs are met. The future of improved patient outcomes will be greatly benefitted by the implementation of the NHS England Quality of Life Metric in 2020, allowing for a greater understanding of what patients need to have a better quality of life whilst living with cancer. 


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