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Hislop J, Quayyum Z, Elders A, et al. Clinical Effectiveness and Cost-Effectiveness of Imatinib Dose Escalation for the Treatment of Unresectable and/or Metastatic Gastrointestinal Stromal Tumours that have Progressed on Treatment at a Dose of 400 Mg/Day: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Jun. (Health Technology Assessment, No. 15.25.)

Cover of Clinical Effectiveness and Cost-Effectiveness of Imatinib Dose Escalation for the Treatment of Unresectable and/or Metastatic Gastrointestinal Stromal Tumours that have Progressed on Treatment at a Dose of 400 Mg/Day: A Systematic Review and Economic Evaluation

Clinical Effectiveness and Cost-Effectiveness of Imatinib Dose Escalation for the Treatment of Unresectable and/or Metastatic Gastrointestinal Stromal Tumours that have Progressed on Treatment at a Dose of 400 Mg/Day: A Systematic Review and Economic Evaluation.

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1Background

Description of health problem

Introduction

Gastrointestinal stromal tumours (GISTs) are tumours of mesenchymal origin that arise in the gastrointestinal tract (GI tract). Historically, and based upon morphological appearance alone, GISTs were considered to be of smooth muscle origin and regarded as leiomyomas or leiomyosarcomas. Subsequently, electron microscopic and molecular analysis has demonstrated that GISTs are a distinct tumour type arising from the interstitial cells of Cajal, and characterised by the expression of receptor tyrosine kinase KIT (CD117) protein demonstrated by immunohistochemistry.1 CD117/KIT immunoreactivity now provides the diagnostic criteria for GISTs, although there is recognition that a small proportion of GISTs (4%) are KIT immunoreactive negative.2,3

Aetiology, pathology and prognosis

Recent investigation has provided clinically significant insights into the molecular pathogenesis of GISTs. This has allowed the rational development of systemic therapies (including imatinib and sunitinib), provided robust diagnostic criteria for GISTs, and demonstrated the ability of certain pathogenic gene mutations to predict clinical behaviour and response to therapy in GISTs, therefore having potential application as predictive biomarkers.

Activating mutations in the KIT proto-oncogene are an early and key event in the pathogenesis of GISTs, and present in up to 95% of cases.410 The protein product is a member of the receptor tyrosine kinase family and a transmembrane receptor for stem cell factor (SCF).11 Extracellular binding of SCF to the receptor results in dimerisation of KIT and subsequent activation of the intracellular KIT kinase domain,9 leading to activation of intracellular signalling cascades controlling cell proliferation, adhesion and differentiation. KIT mutation is necessary but not sufficient for the pathogenesis of GISTs; other mutations are essential, and KIT mutation is absent in a minority of cases (< 5%).12,13 In the majority of KIT mutation-negative cases, mutational activation of the closely related tyrosine kinase platelet-derived growth factor receptor alpha (PDGFRA) is the pathogenic event, and KIT and PDGFRA activation have similar biological effects.12,13

It has been demonstrated that KIT and PDGFRA gene mutations are mutually exclusive7,8,10,14 and GISTs with no KIT mutations have either PDGFRA-activating mutations or no identified kinase mutations.13 GISTs that lack KIT mutations may still have high KIT kinase activity and so may have KIT mutations that are not detected by conventional screening methods. Alternatively, KIT kinase activation may be due to non-mutational mechanisms.6

Diagnosis of GIST is made when morphological and clinical features of the tumour are consistent and the tumour has positive KIT/CD117 protein expression.15 However, as noted above, approximately 4% of GISTs have clinical and morphological features of GIST but have negative KIT immunoreactivity.2 These KIT-negative GISTs are more likely to contain PDGFRA mutations.2 It is important in these cases, when KIT/CD117 staining is negative, that other markers are investigated to confirm GIST diagnosis. Recent studies have shown that a novel protein DOG1 is highly expressed in both KIT and PDGFRA mutant GISTs,16,17 and immunostaining for DOG1 can be used in conjunction with CD117 staining, and diagnosis of GIST made on the basis of KIT and/or DOG1 immunoreactivity.15 PDGRFA immunohistochemistry should also be performed and positivity can assist with diagnosis. Mutational analysis also plays a role in the diagnosis of KIT/CD117-negative suspected GISTs, as with consistent morphological and clinical features, positive mutation analysis for either KIT or PDGFRA is diagnostic.15

Without treatment GISTs are progressive and will eventually metastasise to distant organs and so are invariably fatal without any intervention. GISTs are resistant to ‘conventional’ oncology treatments of cytotoxic chemotherapy and radiotherapy. Prognosis is highly dependent on the resectability of the tumour; however, only 50% of GIST patients have resectable disease at first presentation.18,19 Ten-year survival for resectable/non-metastatic tumours is 30–50%, and at least 50% will relapse within 5 years of surgery, but for unresectable tumours prognosis is very poor, with survival generally < 2 years without further treatment.18,19

Epidemiology and incidence

While GISTs are the most common mesenchymal tumour of the GI tract, overall they are a rare cancer, accounting for less than 1% of all cancers of the GI tract.20 GISTs can occur anywhere in the GI tract from the oesophagus to the rectum, but most arise in the stomach or small intestine.21 They are rare before the age of 40 years and very rare in children, with a median age at diagnosis of 50–60 years.22,23 Some data show a slight male predominance but this is not a consistent finding.22,24,25

Retrospective studies carried out using KIT immunoreactivity as a diagnostic criterion have shown that GISTs have been underdiagnosed in the past.26,27 These retrospective population-based reclassification studies provide the most reliable and accurate current estimate of an annual incidence of 15 cases per million, which would equate to 900 cases in the UK.15

Impact of health problem

The symptoms of GISTs depend on the size and location of the primary tumour and any metastatic deposits. While one-third of cases are asymptomatic and discovered incidentally during investigations or surgical procedures for unrelated disease, severe and debilitating symptoms occur in many patients and are invariable in those patients who have (or develop) metastatic disease.28

Gastrointestinal stromal tumours of < 2 cm in size with no metastatic disease are usually asymptomatic. Larger primary tumours and those of patients with metastatic disease are usually symptomatic and the most common symptom is GI tract bleeding, which occurs in 50% of patients, 25% of these patients presenting as emergencies with acute GI haemorrhage, either into the intestine or peritoneum.29 Abdominal discomfort is a feature of larger tumours.30 Oesophageal GISTs typically present with dysphagia, which represents the main symptomatic problem in these cases, and colorectal GISTs may cause bowel obstruction. In metastatic disease, debilitating systemic symptoms, such as fever, night sweats and weight loss, are common.

Current service provision

Management of disease

There is wide consensus that the management of GISTs should be undertaken in the context of discussion of individual cases by a multidisciplinary team.15,31

Management of resectable disease

Surgical resection is the primary treatment for GISTs and offers the only possibility of cure. Surgical resection is undertaken with the aim of achieving a complete microscopic resection (R0 resection). Evaluation of the suitability and possibility of a complete microscopic resection of a GIST is made after appropriate preoperative assessment to determine stage and also the fitness of the patient for the procedure required. Preoperative assessment for staging includes (as a minimum) a computerised tomography (CT) scan of the chest, abdomen and pelvis, and, in specific circumstances, there is a role for endoscopic ultrasound, laparoscopy and angiography.

After resection patients are followed up with protocols involving clinical examination and/or surveillance imaging, based upon relapse risk stratification by means of histopathological criteria of the resected tumour.15,32 Preliminary results from one randomised, placebo-controlled Phase III trial suggest that adjuvant therapy with imatinib (400 mg/day for 1 year) increases recurrence-free survival following resection, and it is therefore suggested that adjuvant imatinib may have an important role to play in the prevention of recurrence of GISTs after resection.33 The results of other similar adjuvant trials are awaited.15 At present imatinib is licensed for adjuvant treatment of patients who are at a significant risk of relapse,34 but although Scottish guidelines recommend adjuvant imatinib (400 mg/day) in patients considered to be of moderate or high risk of relapse, according to histopathological criteria,15 a National Institute for Health and Clinical Excellence (NICE) Technology Appraisal for this indication is still ongoing,35 and it is acknowledged that, until more data are available from ongoing adjuvant studies, there is still uncertainty regarding the optimal duration of treatment, and also the subgroups of patients who may or may not benefit from adjuvant therapy. The use of imatinib as an adjuvant therapy may have implications, for example with regard to the development of drug resistance, for the subsequent systemic treatment of GISTs upon recurrence.36

Studies are ongoing to determine the role of imatinib as preoperative therapy in resectable tumours.37 Nevertheless, the use of imatinib preoperatively to downstage tumours from unresectable to resectable is considered safe and clinically worthwhile.15 Similarly, preoperative imatinib has also been recommended to limit the extent and (accordingly) morbidity of resection in specific circumstances, for example to facilitate sphincter-sparing resection in rectal GISTs.

Management of unresectable and metastatic disease

Conventional cytotoxic chemotherapy and radiotherapy are ineffective in the treatment of advanced GISTs. Similarly, initial debulking surgery is not recommended unless there is an immediate clinical need, such as to remove an obstructing tumour.

Imatinib (Glivec®, Novartis Pharmaceuticals UK) is a rationally designed small molecule inhibitor of several tyrosine kinases, including KIT and PDGFRA, and has provided the first clinically effective systemic therapy for GISTs. The European licence for imatinib was based on a Phase II study of 147 patients who were randomised to receive imatinib at either 400 or 600 mg orally taken once daily.38 The treatment was well tolerated, objective response rate was the primary efficacy outcome and an overall partial response (PR) rate of 67% was demonstrated with no difference between treatment arms. Long-term results revealed median survival of 57 months for all patients.39 A concurrent study investigated dose escalation and established 800 mg daily as the maximum tolerated dose.40 Phase III trials performed both in Europe and Australasia [European Organisation for Research and Treatment of Cancer (EORTC) 62005 study], and in North America (S0033 Intergroup study), confirmed the efficacy of imatinib in a larger patient population, and established the starting dose of 400 mg orally per day.41,42

Primary resistance to imatinib is uncommon, but acquired resistance is highly likely, and manifest clinically by the observation of disease progression.4145 Guidelines suggest that patients should have a CT scan every 3 months while on therapy.15 Measurement of response by conventional criteria, such as Response Evaluation Criteria in Solid Tumors (RECIST), based on objectively measured changes in tumour size, may not occur, or may happen only after many months of treatment. This means that definitive evidence of patient response, and therefore clinical benefit, can be difficult to ascertain (at least initially). This has been addressed by the development of alternate methods of GIST response assessment, such as the ‘Choi criteria’ based upon tumour density as well as tumour size.46,47 Similarly, fluorodeoxyglucose-positron emission tomography (FDG-PET) has demonstrated some efficacy in predicting early response to imatinib therapy,48 although it should be noted that PET scanning is not widely available in the UK as very few NHS centres have access to this technology.

In addition, the assessment of progression of GISTs may be problematic if based on RECIST-based tumour size criteria, as tumour liquefaction (cystic degeneration) can occur, which may give the appearance of progressive disease (PD) although the tumour is actually responding.47 Accordingly, it is recognised that experienced radiologists should assess CT scans before confirming progression.

It has been demonstrated that interruption of treatment results in rapid disease progression in many patients with advanced GISTs.45 This includes patients with disease progression in whom a symptomatic worsening or ‘flare’ has been described.49 Therefore, continuation of imatinib in these patients has been common practice despite progression, as part of best supportive care (BSC).

Several studies have reported further disease control after progression on an initial imatinib dose of 400 mg orally per day with dose escalation of imatinib to 800 mg orally per day, and this has also become common practice.39,44 However, it should be noted that current NICE guidelines for imatinib do not actually recommend dose escalation for patients with unresectable and/or metastatic GISTs who progress on an initial dose of 400 mg/day.50

Recently, sunitinib (Sutent®, Pfizer UK), another molecular-based treatment for GIST, became available, and has been approved by NICE for patients with unresectable and/or metastatic GIST who have progressed on treatment with imatinib.51 The NICE advice follows a randomised, double-blind, placebo-controlled, multicentre Phase II trial in which 312 patients, who were resistant or intolerant to imatinib, received either sunitinib (50-mg starting dose in 6-week cycles; 4 weeks on and 2 weeks off treatment) or placebo;52 the trial was unblinded early when interim analysis showed a significantly longer time to tumour progression (the primary end point) with sunitinib.

To date, no randomised trial has been conducted comparing imatinib and sunitinib. One had been planned but was stopped owing to poor recruitment.53 As new options for management of patients with unresectable and/or metastatic GIST have developed since the initial 2004 publication of NICE guidance for GIST treatment with imatinib, a review of the evidence available on treatments currently used in clinical practice is required.

Current service cost and anticipated costs associated with the intervention

As GIST affects mostly the middle-aged and older age population, the loss of productivity from the middle-aged population suffering from GIST is of concern. The median age of the GIST patients was found to be between 50 and 60 years,22,23 and incidence of GIST was found to increase with increase in age.54 The cost of different treatment strategies needs thorough investigation in a robust economic evaluation.

Treatment with imatinib per patient within an NHS setting has been estimated at £18,896 and £24,368 annually for patients on 400 and 600 mg/day, respectively.55 Other associated annual costs of treatment (including the treatment of adverse events) were estimated at £2730 (price year not stated). Estimates from previous disease models suggest that in 2 years it would cost the NHS approximately £31,160 to treat a patient with imatinib, and for 10 years this figure would be £56,146 (2002 price year).54,55 Costs would differ when patients who fail to respond to imatinib are provided with higher doses or alternative treatments (e.g. sunitinib).50

The costs of treating patients with unresectable and/or metastatic GIST using imatinib were estimated at between £1557 and £3115 per month per patient, resulting in a cost to the NHS (England and Wales) of between approximately £5.6M and £11.2M per year (2002 price year).55 Another study estimates that the total costs over 10 years for managing GIST patients with molecularly targeted treatment would be between £47,521 and £56,146 per patient compared with a cost of between £4047 and £4230 per patient when managed with BSC (price year not stated).54

Variation in service and uncertainty about best practice

The treatment of GISTs after progression on imatinib is generally decided on a case-by-case basis by multidisciplinary teams, and the alternatives are dose escalation of imatinib, sunitinib at 50 mg/day (4 weeks out of 6 weeks) or, alternatively, BSC only (although due to the ‘symptomatic flare’ already mentioned this may include continuation of imatinib at 400 mg/day). Many clinicians advocate initial dose escalation of imatinib and then consider sunitinib on subsequent progression, but there will be variation in clinical practice depending on the specific needs of individual patients.

Relevant national guidelines

UK guidelines recommend the dose escalation of imatinib, and/or sunitinib following imatinib failure,15,56 but also suggest that clinical decisions are made on an individual case-by-case basis, reflecting uncertainty regarding optimal practice.

Description of technology under assessment

Summary of intervention

Imatinib

Imatinib (Glivec) is a rationally designed small molecule inhibitor of several oncogenic tyrosine kinases: c-Abl, PDGFRA and the KIT tyrosine kinases. Its therapeutic activity in GISTs relates to inhibition of KIT, although in cases with no KIT mutation the inhibition of PDGFRA is likely to be of therapeutic importance.2 Imatinib is a derivative of 2-phenylaminopyrimidine, and a competitive antagonist of adenosine triphospate (ATP) binding, which blocks the ability of KIT to transfer phosphate groups from ATP to tyrosine residues on substrate proteins. This interrupts KIT-mediated signal transduction, which is the key pathogenic driver for many GISTs. The inhibitory activity of imatinib on KIT is highly selective, and minimal inhibition of other kinases that are important in normal cell function occurs, thereby affording a good toxicity and safety profile.

Imatinib is licensed and approved for use in the UK NHS in KIT-immunoreactive positive advanced/unresectable GISTs.50,57

Sunitinib

Sunitinib malate (Sutent), is a tyrosine kinase inhibitor targeting KIT, PDGFRA, all three isoforms of vascular endothelial growth factor receptor (VEGFR), FMS-like tyrosine kinase 3 (FLT3) colony-stimulating factor 1 receptor (CSF-1R) and glial cell line-derived neurotrophic factor receptor.58 Sunitinib activity in GISTs may predominantly relate to inhibition of KIT and/or PDGFRA, and ex vivo investigation has shown that sunitinib can inhibit the kinase activity of KIT molecules harbouring secondary mutations conferring imatinib resistance.59 However, the potent antiangiogenic activity of sunitinib as a consequence of strong VEGFR inhibition may also be important for clinical activity in GISTs.

Best supportive care

Best supportive care is not well defined or standardised, and can also be referred to as ‘supportive care’ or ‘active symptom control’.55 It usually involves interventions to manage pain and treat fever, anaemia (due to GI haemorrhage) and GI obstruction,50 and can include palliative measures.60 A Cochrane review of supportive care for patients with GI cancer defined supportive care as ‘the multi-professional attention to the individual's overall physical, psychosocial, spiritual and cultural needs’.61 It was argued that this type of care should ethically be made available to all treatment groups, meaning that treatment with imatinib or sunitinib could not be provided without concomitant supportive care as well in clinical practice for patients with GIST, although it is possible that treatment with BSC could be provided without additional drug treatment with either imatinib or sunitinib. It should be noted that the amount of care required as part of BSC is likely to increase as the disease progresses and symptoms become worse.

Identification of important subgroups

The differential benefit from imatinib and sunitinib in subgroups of patients with GIST, whose tumours have different primary and secondary KIT mutations, has suggested possible benefits in personalising first- and second-line therapy.

Primary KIT mutations are those that are pathogenic and present before any systemic treatment, while secondary mutations are those that have been identified after imatinib treatment and confer resistance to imatinib. Identification of secondary mutations requires rebiopsy of tumours, and studies have suggested that the emergence of secondary (or acquired) imatinib resistance is polyclonal, so patients with GIST may acquire more than one secondary KIT mutation.62

A meta-analysis of 1640 patients revealed that patients with KIT exon 9 primary mutations have a better outcome if treated at the escalated dose of 800 mg daily.63 Similarly, objective response rates to imatinib 400 mg/day are higher in patients with exon 11 primary mutations than in those with exon 9 mutations, or those with no detectable KIT or PDGFR mutation.14,41 Therefore, advanced GIST patients with exon 9 mutations may benefit from immediate dose escalation of imatinib, and the benefit of dose escalation on progression may be more significant in this subgroup of patients and thereby have implications for therapeutic alternatives and choices on progression in different groups of patients defined by KIT mutations. Recent studies have indicated that plasma monitoring in GIST patients could assist clinicians' decision-making with regard to whether or not dose escalation of imatinib is required for particular patients, including those with mutations in KIT.6466

Secondary mutations in KIT exons 13, 14, 17 and 18 are associated with acquired resistance to imatinib.43 Sunitinib activity after progression on imatinib has been demonstrated in GIST patients with imatinib resistance conferring secondary KIT mutations.62 However, both the primary KIT mutation genotype and secondary KIT mutations may influence the clinical benefit effect of sunitinib in GIST patients who have progressed on imatinib.62 Interestingly, in contrast to imatinib, greater benefit from sunitinib (after imatinib failure) is seen in patients with primary exon 9 mutations or wild-type KIT as opposed to primary exon 11 mutations.62 However, it is not clear how dose-escalated imatinib (800 mg/day) compares with sunitinib in patients with primary exon 9 KIT mutations. While the polyclonal emergence of resistance is an investigational and clinical challenge, it appears that GIST patients with secondary KIT mutations associated with acquired imatinib resistance in exons 13 or 14 (which involve the KIT–ATP binding pocket) appear to gain greater clinical benefit from sunitinib after imatinib failure than those patients with exon 17 or 18 imatinib resistance secondary mutations (which involve the KIT activation loop).62

Changes in FDG (fluorodeoxyglucose) avidity of GISTs measured by FDG-PET occur earlier than anatomical changes in GISTs and so may also have a role as a predictive biomarker for imatinib response, and also for detecting early disease progression49 in the future as the technology becomes more widely available in NHS settings.

Current usage in the NHS

Current practice is to commence patients on imatinib 400 mg/day, and on confirmed disease progression the options are dose escalation of imatinib up to 800 mg/day or sunitinib, or BSC only. Practice is variable, and decided on a case-by-case basis. Some clinicians proceed with dose escalation of imatinib initially and then, on further progression, use sunitinib. Some guidelines and clinicians advocate returning to imatinib for symptomatic benefit, when there are no other therapeutic options, and the cessation of imatinib in the absence of alternative treatment options is not recommended owing to the tumour flare phenomenon, with rapid deterioration in symptoms observed in some patients.

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK99520

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