• National Institute for Clinical Excellence (NICE). Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. London (UK): National Institute for Clinical Excellence (NICE); 2004 Oct. 38 p. (Technology appraisal; no. 86).

This is the current release of the guideline.

Unresectable and/or metastatic gastro-intestinal stromal tumours (GISTs)

Assessment of Therapeutic Effectiveness
Treatment

Internal Medicine
Oncology

Advanced Practice Nurses
Physician Assistants
Physicians

To assess the clinical and cost-effectiveness of imatinib in the treatment of unresectable and/or metastatic, KIT positive, gastrointestinal stromal tumours (GISTs), relative to current standard treatments

Patients with unresectable and/or metastatic gastro-intestinal stromal tumours

Imatinib

• Clinical effectiveness:  The following outcomes were considered whenever available: Quality of life (most preferred), mortality (overall survival and median survival times), morbidity, and tumour response. (Tumour response could be measured using computed tomography [CT] scans, magnetic resonance imaging [MRI] scans, or positron emission tomography [PET] scans).
• Cost-effectiveness

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the West Midlands Health Technology Assessment Collaboration (see the "Companion Documents" field).

Search Strategy

The search strategy was divided into 6 parts and aimed to look for trials of imatinib (with or without standard treatment comparators), trials of alternative/experimental treatments, studies that had observed patient prognosis without treatment (to enable a comparison of disease progression should trials without comparators be available), and diagnostic papers in order to gain an insight into the uncertainty of gastro-intestinal stromal tumour (GIST) diagnosis and possible consequences of treating false positives. In addition ongoing trials were sought, as imatinib is a very recent drug. A search for economic evaluation of treatments for GIST was also conducted.

The searches were not restricted by language. Published and unpublished studies were sought. Databases were searched from inception. Searches (except for ongoing trials) were undertaken between 25 April and 15 May 2003.

See the section 2 of the assessment report for details of the electronic search.

Inclusion and Exclusion Criteria

A three stage sorting process was instigated to look through the yield of the search.

Stage 1 - Including or Excluding Studies

Two reviewers independently assessed papers for inclusion/exclusion using the title and where available the abstract. The following inclusion criteria were applied:

Inclusion Criteria

Study design: Relevant randomised controlled trials (RCTs), non-randomised controlled studies, cohort studies, and case series that reported effectiveness results of treatment with imatinib and/or other interventions in patients with GIST.

Population: Ideally patients diagnosed cKIT positive unresectable and/or metastatic GISTs (including primary or recurrent tumours). Not so ideal but still included were patients histologically diagnosed with GIST. In trials older than 1999 patients who were diagnosed with gastrointestinal leiomyosarcoma or soft tissue sarcoma that appeared to behave as GIST (e.g., tendency to metastasize in the liver), were included. Early terms for GIST4 could include oesophageal leiomyosarcoma; gastric leiomyoma; gastric leiomyoblastoma; small intestinal leiomyoma and leiomyosarcoma; colonic and rectal leiomyoma and leiomyosarcoma; gastrointestinal autonomic nerve tumour (GANT); leiomyoma and leiomyosarcoma of omentum and mesentery; retroperitoneal leiomyosarcoma.

Intervention: Imatinib. Oral dosage -- any dose. (Where imatinib = STI 571, Glivec, Gleevec, or CGP57148).

Comparators: The ideal comparator was the current standard treatment (symptom-relief and best supportive care), or placebo. If there were no trials with these comparators, data from trials that investigated experimental treatments in patients with GIST were sought, so that an indirect comparison could be made.

Outcomes: See the "Major Outcomes Considered" field in this summary.

Disagreements were resolved by discussion. Inclusion/exclusion decisions were made prior to detailed scrutiny of the results and study quality assessment. Foreign language publications were screened using English abstracts where available.

Stage 2 Consensus Meeting

Because the initial systematic search and sort at stage 1 had yielded in excess of 1000 papers using the above criteria, it was felt that tighter criteria were needed to eliminate papers that could not add substantial value to the review. In particular a large yield had come from prognosis/natural history papers and diagnostic papers. It was therefore agreed that the following inclusion criteria were to be applied:

Imatinib effectiveness - any patient with GIST (at any stage) who has been treated with imatinib. Ignore reviews and case studies of single patients published in abstract form only.

Other treatments -- any patient with GIST (at any stage) who has been treated with drugs other than imatinib, also include other procedures (e.g., surgery, radiotherapy, brachytherapy). Exclude papers that compare surgical laparoscopy vs. open surgery.

Prognosis -- papers describing primary research that involved the prognosis of 10 or more patients where clinical outcomes are described. Ignore reviews.

Diagnosis -- papers describing primary research that involved 10 or more patients with clinical outcomes reported. Major reviews on diagnostic accuracy or diagnostic criteria of GIST, especially those describing advanced disease were included.

Three reviewers applied the criteria on the papers selected at stage 1, and disagreements were resolved by discussion.

Stage 3

Full paper copies of studies identified in stage 2 were obtained for detailed examination. At this stage, additional papers were excluded as and when detailed study of the methods revealed that the paper did not meet the inclusion criteria. Usually this was because the wrong populations had been used; in particular some papers on examination had used patients with primary disease that was treatable with surgery and was not metastatic. Translations were also obtained on full papers where necessary or where possible. Translations were not obtained for 4 case studies included in the review, as it was not felt that a translation would add value to the review.

Data Extraction Strategy

Two reviewers independently extracted data using a pre-designed data extraction form (see Appendix 2 page 81 in the assessment report). Disagreements were resolved by discussion, consulting with a third party where necessary. Where there was missing information and time constraints allowed, the authors were contacted. Data from studies with multiple publications were reported as a single study but the source of the publications was noted.

Quality Assessment Strategy

Quality of studies was assessed using the York CRD criteria for experimental and observational studies (Appendix 11, page 128 in the assessment report). These criteria were tested and revised where necessary. The following quality issues were felt to be of paramount importance: study design, patient characteristics, (in terms of GIST diagnosis, disease severity, length of time with GIST), and any possible sources of biases in patient selection, treatment provided, and outcomes measured; where found these were reported.

Imatinib Treatment

Two uncontrolled trials and 8 single case studies that treated cKIT positive patients with unresectable and/or metastatic gastro-intestinal stromal tumours (GIST) with imatinib were published as full papers and were included from the systematic search. The main characteristics of these studies are shown in Table 2 of the assessment report, together with information on 4 trials and one case series published in abstract form only.

Alternative Treatments

Eleven published trials and 4 single case studies were identified from the systematic review. The characteristics of these studies are shown in Table 3 of the assessment report. None of the trials prospectively tested patients for cKIT s they commenced before the test was available. A retrospective analysis of patients for cKIT was undertaken in one report.

Expert Consensus

Not applicable

Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the West Midlands Health Technology Assessment Collaboration (see the "Companion Documents" field).

Methods of Analysis/Synthesis

A descriptive analysis of each individual included study was undertaken with the relevant evidence categorised and summarised in tables. Summary tables of survival, tumour response, adverse events, and quality of life were constructed. Where appropriate, results from individual studies were quantitatively pooled by meta-analysis. Identified research evidence was interpreted according to the assessment of methodological strengths and weaknesses and the possibility of potential biases.

Expert Consensus

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients, and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

No published cost-effectiveness analyses or quality-of-life studies for patients with advanced gastro-intestinal stromal tumours (GIST) were identified in the literature. The manufacturer submitted an economic model, and the Assessment Group re-analysed this model to overcome identified shortcomings. The Assessment Group also developed its own economic model, which was revised after discussion at the committee meeting to answer questions raised about some of the assumptions underpinning all the models. See Section 4.2 of the original guideline document for a detailed discussion and more information.

External Peer Review

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

• Imatinib treatment at 400 mg/day is recommended as first-line management of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic gastro-intestinal stromal tumours (GISTs).
• Continuation with imatinib therapy is recommended only if a response to initial treatment (as defined below) is achieved within 12 weeks.
• Responders should be assessed at intervals of approximately 12 weeks thereafter. Continuation of treatment is recommended at 400 mg/day until the tumour ceases to respond, as defined below.
• An increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding (see below).
• For the purpose of this guidance, response to imatinib treatment should be assessed on the basis of the results of diagnostic imaging to assess size and density of the tumour(s), patients' symptoms, and other factors, in accordance with the Southwest Oncology Group (SWOG) criteria detailed in Appendix D of the original guideline document. For the purpose of this guidance, response to therapy is defined as the SWOG classifications of complete response, partial response, or stable disease.
• The use of imatinib should be supervised by cancer specialists with experience in the management of people with unresectable and/or metastatic GISTs.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate use of imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours

The most commonly reported side effects of imatinib include nausea, diarrhoea, periorbital oedema, muscle cramps, fatigue, rash, and headache. The most common serious adverse events were unspecified haemorrhage and neutropenia, each event occurring in approximately 5% of patients.

This guidance represents the view of the Institute, which was arrived at after careful consideration of the available evidence. Health professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

Implementation and Audit

• All clinicians who treat people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic gastro-intestinal stromal tumour (GIST) should review their current policies and practice to take account of the guidance set out in Section 1 of the original guideline document (and the "Major Recommendations" field).
• Local guidelines or care pathways for the care of patients with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST should incorporate the guidance.
• To measure compliance locally with the guidance, the following criteria could be used. Further details on suggestions for audit are presented in Appendix C of the original guideline document.
  • For a person with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST, imatinib treatment at 400 mg/day is provided as first-line management for up to 12 weeks.
  • Imatinib therapy at 400 mg/day is continued beyond the first 12 weeks only if a person's GIST responds to treatment within 12 weeks. (Response to treatment is defined in Section 1.5 and Appendix D of the original guideline document.)
  • A person whose GIST has responded to imatinib therapy is assessed at intervals of approximately 12 weeks and imatinib therapy at 400 mg/day is continued until the GIST ceases to respond. (Response to treatment is defined in Section 1.5 and Appendix D of the original guideline document.)
  • If progressive disease develops in a person whose GIST initially responded to imatinib therapy, the dose of imatinib is not increased.
  • A cancer specialist with experience in the management of people with metastatic and/or unresectable GISTs supervises the use of imatinib.

Getting Better

Effectiveness
Patient-centeredness

• National Institute for Clinical Excellence (NICE). Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. London (UK): National Institute for Clinical Excellence (NICE); 2004 Oct. 38 p. (Technology appraisal; no. 86).

Not applicable: The guideline was not adapted from another source.

2004 Oct

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Dr Anthony Ades, MRC Senior Scientist, MRC Health Services Research Collaboration, University of Bristol; Dr Tom Aslan, General Practitioner, Stockwell, London; Professor David Barnett (Chair), Professor of Clinical Pharmacology, University of Leicester; Professor Sheila M Bird, MRC Biostatistics Unit, Cambridge; Professor Rosamund Bryar, Professor of Community and Primary Care Nursing, St Bartholomew's School of Nursing and Midwifery, London; Dr Rodney Burnham, Consultant Physician and Gastroenterologist, Oldchurch Hospital, Romford; Dr Gary Butler, Consultant Paediatrician/Endocrinologist, Leeds General Infirmary; Dr Karl Claxton, Health Economist, University of York; Dr Richard Cookson, Senior Lecturer, Health Economics, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich; Dr Christopher Eccleston, Director, Pain Management Unit, University of Bath; Professor Terry Feest, Clinical Director & Consultant Nephrologist, Richard Bright Renal Unit, & Chair of UK Renal Registry, Bristol; Ms Alison Forbes, Chief Executive, Hoffman de Visme Foundation, London; Professor Gary A Ford, Professor of Pharmacology of Old Age/Consultant Physician, Newcastle upon Tyne Hospitals NHS Trust; Ms Bethan George, Interface Liaison Pharmacist, Tower Hamlets PCT and Royal London Hospital, Whitechapel; Professor John Geddes, Professor of Epidemiological Psychiatry, University of Oxford; Dr Trevor Gibbs, Head, Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline; Mr John Goulston, Director of Finance, Bart's and the London NHS Trust; Mr Adrian Griffin, Health Outcomes Manager, Johnson & Johnson Medical Ltd; Dr Elizabeth Haxby, Lead Clinician in Clinical Risk Management, Royal Brompton Hospital, London; Professor Philip Home, Professor of Diabetes Medicine, University of Newcastle upon Tyne; Dr Catherine Jackson, Clinical Lecturer in Primary Care Medicine, Alyth Health Centre, Angus; Dr Terry John, General Practitioner, The Firs, London; Professor Robert Kerwin, Professor of Psychiatry and Clinical Pharmacology, Institute of Psychiatry, London; Mr Muntzer Mughal, Consultant Surgeon, Lancashire Teaching Hospitals NHS Trust, Chorley; Judith Paget, Chief Executive, Caerphilly Local Health Board, Wales; Dr Katherine Payne; Health Economist, Nowgen: The North West Genetics Knowledge Park, St Mary's Hospital, Manchester; Mr James Partridge, Chief Executive, Changing Faces; Mrs Kathryn Roberts, Nurse Practitioner, Hyde, Cheshire; Professor Philip Routledge, Professor of Clinical Pharmacology, College of Medicine, University of Wales, Cardiff; Ms Anne Smith, Trustee, Long-Term Medical Conditions Alliance; Dr Debbie Stephenson, Head of HTA Strategy, Eli Lilly and Company; Professor Andrew Stevens (Vice-Chair), Professor of Public Health, University of Birmingham; Dr Cathryn Thomas, General Practitioner, and Senior Lecturer, Department of Primary Care and General Practice, University of Birmingham; Dr Norman Vetter, Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff; Dr Paul Watson, Medical Director, Essex Strategic Health Authority; Dr David Winfield, Consultant Haematologist, Royal Hallamshire Hospital, Sheffield

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

This is the current release of the guideline.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.