Appraisal Consultation Document: Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE
Appraisal Consultation Document
Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours
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The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours (GISTs) and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of imatinib for the treatment of unresectable and/or metastatic GISTs. This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. The process the Institute will follow after the consultation period is summarised below. For further details, see the Guide to the Technology Appraisal Process (this document is available on the Institute's website, www.nice.org.uk).
The key dates for this appraisal are: Details of membership of the Appraisal Committee are given in Appendix A and a list of the sources of evidence used in the preparation of this document is given in Appendix B. |
| Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. |
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | 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). |
| 1.2 | Continuation with imatinib therapy is recommended only if a response to treatment is achieved within 12 weeks. Patients should be assessed for continuation of response at approximately 12 weekly intervals thereafter. |
| 1.3 | For the purpose of this guidance, a response is assessed by a computerised tomography (CT) scan or magnetic resonance imaging (MRI) and is classified as complete response, partial response or stable disease, as defined by the Southwest Oncology Group (SWOG) criteria detailed in Appendix D. |
| 1.4 | For treatment responders, imatinib therapy is recommended at 400 mg/day until the development of progressive disease (also defined by SWOG criteria detailed in Appendix D). |
| 1.5 | An increase in the dose of imatinib is not recommended for people unresponsive to treatment or for people receiving imatinib who develop progressive disease. In these cases, it is recommended that imatinib treatment should be continued only as part of prospective clinical trials. |
| 2 | Clinical need and practice |
| 2.1 | Gastro-intestinal stromal tumours (GISTs) are rare sarcomas thought to arise from the interstitial cells of Cajal. They represent less than 1% of the tumours arising in the gastro-intestinal (GI) tract. Although GISTs can occur along the length of the GI tract, the majority arise in the stomach (60-70%), small bowel (25-35%), the colon and rectum (5%) and, to a lesser extent, the oesophagus. Presenting features of these tumours depend on the size and location of the tumour and include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. However, many people with GISTs are asymptomatic during early stages of the disease until tumours reach a large size, at which time they rupture and bleed or obstruct the GI tract. |
| 2.2 | Most people with GISTs express the tyrosine kinase growth factor receptor c KIT, which is detected by immunostaining with the antibody for the cell surface marker CD117. Under normal conditions this receptor is activated by stem-cell factor, which stimulates signal transduction pathways such as cell growth, differentiation and apoptosis (cell death). Most GISTs express a form of the tyrosine kinase receptor that is permanently 'switched on' (constitutively activated), leading to unregulated cell proliferation. |
| 2.3 | Until recently, there has been no definitive test for the diagnosis of GIST. An immunohistochemical test for the presence of the cell surface marker CD117 (present in 80-100% of GISTs) is now considered to be the definitive diagnostic marker for the diagnosis of GIST. A diagnosis of GIST is made on the basis of histological characteristics of the tumour biopsy, clinical presentation and a positive test for the CD117 marker. |
| 2.4 | Estimates of the incidence of GIST vary widely, from 4 to 40 cases per million population, as a result of difficulties in the diagnosis of GIST. This corresponds to between 200 and 2000 new cases per year in England and Wales. Although GIST can occur at any age, the mean age of presentation is between 50 and 70 years. |
| 2.5 | The prognosis of people with GIST primarily depends on whether the tumour is resectable, although the size and location of the tumour, and the stage of tumour at initial diagnosis are also important prognostic indicators. A recent study suggested that the prognosis for unresectable and/or metastatic GIST is poor with few, if any, people surviving beyond 5 years. |
| 2.6 | Complete surgical resection is the treatment of choice for people presenting with GISTs amenable to surgery, but there is currently no effective treatment for people with unresectable and/or metastatic tumours. As GISTs are particularly resistant to conventional cytotoxic chemotherapy and radiotherapy, current treatment normally comprises symptom relief and best supportive care. This includes palliative care for the management of pain, fever, GI obstruction, and anaemia caused by GI haemorrhage. |
| 3 | The technology |
| 3.1 | Imatinib mesilate (Glivec, Novartis) is a signal-transduction inhibitor designed to selectively inhibit certain classes of tyrosine kinase that include the c KIT receptor expressed in GIST. Imatinib binds to activated c KIT receptors and blocks the cell signalling pathway to prevent uncontrolled cell proliferation. Imatinib was first licensed for the treatment of chronic myeloid leukaemia and has been approved by NICE for second-line use in the treatment of chronic myeloid leukaemia (NICE Technology Appraisal Guidance No. 50). |
| 3.2 | Imatinib received European marketing authorisation in May 2002 for the treatment of adult patients with KIT (CD117)-positive unresectable and/or metastatic malignant GIST. Licensing approval was based largely on a single, uncontrolled phase II study in 147 patients. |
| 3.3 | The manufacturer's summary of product characteristics recommends oral imatinib at a dose of 400 mg/day for the treatment of unresectable and/or metastatic GIST, to be taken with a large glass of water at meal times. The licence also states that there are limited data on the effect of dose increases from 400 mg/day to 600 mg/day in patients whose disease progresses at the lower dose. |
| 3.4 | Imatinib costs £12.98 per 100 mg (excluding VAT; British National Formulary [BNF] 47, March 2004). The approximate annual acquisition cost of imatinib is between £19,000 (400 mg/day) and £28,500 (600 mg/day). Costs may vary in different settings because of negotiated procurement discounts. |
| 4 | Evidence and interpretation |
| The Appraisal Committee considered evidence from a number of sources (see Appendix B). | |
| 4.1.1 | No randomised controlled trials (RCTs) were identified that compared imatinib treatment with best supportive care in patients with unresectable and/or metastatic GIST. In the absence of controlled studies, historical controls were identified to provide prognostic information on the natural history of advanced GIST. Many patients in these studies had received other treatments (such as chemotherapy or radiotherapy). These prognostic studies provide the most appropriate data for comparison with studies of imatinib treatment. |
| 4.1.2 | The Assessment Group identified 15 studies of imatinib treatment of c KIT positive GIST, which included six ongoing uncontrolled trials (four of which were only available in abstract form), eight single case studies and one case series. In the absence of any controlled trials, the Assessment Group also identified 14 uncontrolled 'prognostic studies', that is, comparator studies (one of which is currently unpublished). |
| 4.1.3 | Key study outcomes included: survival; tumour status (tumour mass measured by CT or magnetic resonance imaging [MRI], and classified by response evaluation criteria in solid tumours [RECIST] or Southwest Oncology Group [SWOG] criteria); and Eastern Cooperative Oncology Group (ECOG) performance status (which measures functional status in every-day tasks, and which are also reported in quality-of-life measurement scales). Positron emission tomography (PET) imaging, reported in one study, provided information on the effect of imatinib on tumour metabolism. |
| 4.1.4 | Imatinib treatment |
| 4.1.4.1 | Study CSTI571-B2222 is a published ongoing phase II uncontrolled trial of imatinib treatment in 147 patients (91% of which were c-KIT-positive) with unresectable and metastatic GIST, which formed the basis of the licence application. Patients were randomly assigned to receive a single dose of 400 mg (n = 73) or 600 mg (n = 74) of imatinib. Patients received imatinib treatment for a median of 21 months (range 7 to 783 days). The study was not powered to distinguish statistically significant differences in the efficacy of imatinib treatment between the two study arms (400 and 600 mg/day). The combined survival rate from the start of treatment was 88% at 1-year follow-up and 78% at 2-year follow-up. Median survival has yet to be reached in this study. |
| 4.1.4.2 | Tumour response (based on SWOG criteria, Appendix D) evaluated at 21 month follow-up showed 66% patients achieved a partial response, 17% stable disease and 12% progressive disease (with 5% of patients being unevaluable). No patients achieved a complete response. The manufacturer's submission reported resistance to imatinib in 16 patients; 3 patients exhibited primary resistance (no response to imatinib) and a further 13 exhibited secondary resistance to imatinib (loss of response to imatinib). |
| 4.1.4.3 | There were substantial improvements in patients' ECOG performance status. At the 4-month follow-up, the proportion of patients with normal functional status (grade 0) had increased from 42% at baseline to 64%, and the number of patients with impaired functional status of grade 2 (capable of self-care but unable to work) had decreased from 9% at baseline to 5%. These improvements were maintained in the 21% of patients followed up to 25 months. |
| 4.1.4.4 | The other published study was an ongoing phase I study, which evaluated imatinib treatment at licensed doses of 400 and 600 mg/day and unlicensed higher doses in 40 patients with advanced GIST (35 of whom were c KIT positive). After 9 to 12 months of follow up, survival from start of treatment was 90%. Tumour response was evaluated using RECIST criteria in the 35 patients who were c KIT positive: 51% achieved a partial response; 31% stable disease; and 8.5% progressive disease. Tumour function evaluated in 14 patients using PET imaging after 8 days of treatment demonstrated that eight patients had achieved a complete response, two patients a partial response and one patient no change. The remaining three patients showed disease progression after 28 days. |
| 4.1.4.5 | Of the four unpublished randomised trials, two were based on large patient samples and reported estimates of progression-free survival. An ongoing European study comparing 400 mg/day with (the unlicensed dose of) 800 mg/day in 946 patients, reported progression-free survival at 2 years to be approximately 40% (400 mg/day) and 55% (800 mg/day). A study based in the USA, comparing the same daily doses in 746 patients, reported progression-free survival at 6 months to be 80% (400 mg/day) and 82% (800 mg/day). |
| 4.1.4.6 | Study CSTI571-B2222 (registration study) reported that at least one adverse event had been experienced by all 147 patients by 21 months' follow-up. Of these, 37% were 'severe and undesirable' (grade 3) and 15% were 'life threatening and disabling' (grade 4). A total of 15 (10%) patients withdrew from the study because of adverse events; one third of these events were classed as drug-related. 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. Overall, imatinib was well tolerated. |
| 4.1.4.7 | Patient group submissions commented on the dramatic effect of imatinib, with the majority of patients experiencing improvements in disease-related symptoms such as abdominal distension and pain, improved appetite, and a feeling of well-being. Some patients were able to resume normal daily activities, which included a return to full-time employment. |
| 4.1.4.8 | Expert testimony at the committee meeting provided evidence on the issue of resistance to imatinib. The clinical expert informed the Committee that, although data from the clinical trials are too premature to give definitive answers regarding resistance, early results suggest that approximately 40% of patients may become resistant to imatinib. |
| 4.1.5 | Prognostic studies |
| 4.1.5.1 | Fourteen primary studies of alternative treatments (surgical resection, chemotherapy, radiotherapy and chemoembolisation) for patients with advanced GIST provided information on the natural history of disease. |
| 4.1.5.2 | Median survival reported in 12 papers (983 patients) ranged from 2 to 39 months, with survival rates of 37% to 80% at 1-year follow-up, 6% to 45% at 3-year follow-up, and 0% to 45% at 5-year follow-up. However, 12 out of 14 studies did not have the GIST diagnosis confirmed by c KIT testing. |
| 4.1.5.3 | Data from an unpublished prognostic study were used to represent the natural history of patients with GIST. A total of 143 c KIT positive patients (132 patients with recurrent or metastatic GIST) were included in the retrospective analysis. Of these, 91% had previously undergone surgical resection of the tumour, and all patients had received chemotherapy for a median duration of 55 weeks. Patients surviving to the time when imatinib treatment became available were transferred to the treatment (n = 67). Survival outcomes were presented for all patients (irrespective of whether they received imatinib) and for patients who never received imatinib. |
| 4.2 | Cost effectiveness |
| 4.2.1 | No published cost-effectiveness analyses or quality-of-life studies for patients with advanced 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. |
| 4.2.2 | The manufacturer's model estimated the incremental cost effectiveness of imatinib treatment compared with best supportive care. Patients in the control arm were assumed to start in a state of progressive disease, where they remained until death, on the basis of survival estimates extrapolated from the prognostic study (using selected patients who never received imatinib only). All patients in the imatinib treatment arm were assumed to respond to imatinib treatment immediately. The probability of developing progressive disease after initial response was based upon the results of the CSTI571-B2222 study. Both the trial and prognostic data were extrapolated to 10 years using exponential curves. Estimates of health-related utility were derived by using clinical judgement to map ECOG performance status to a generic measure of health status (the EuroQol EQ-5D). The results of the model showed the incremental cost-effectiveness ratio (ICER) estimates to be £59,000 at 2 years, £24,000 at 5 years, and £14,000 at 10 years. |
| 4.2.3 | The Assessment Group modified the manufacturer's model to overcome some concerns that the Group considered would overestimate the cost-effectiveness of imatinib. The first of two key amendments was to the model structure; it sought to rectify the overestimation of benefit of imatinib by using both the survival and time-to-treatment-failure curves from the registration study to estimate the proportion of patients in the imatinib health state. The second key change was to estimate survival with progressive disease from the whole cohort in the prognostic study, including those who later went on to receive imatinib. The ICER estimates following all the modifications were £41,000 at 2 years and £30,000 at 10 years. |
| 4.2.4 | At the instruction of the Appraisal Committee, the Assessment Group, in conjunction with the NICE Decision Support Unit (DSU), was commissioned to develop its own economic model. Additional data from the prognostic study (survival estimates, censored at the time imatinib became available) were sourced to improve the estimates of survival with progressive disease. One of the key differences between the DSU model and the other economic models was that the DSU model was structured so that all patients started in the same health state of progressive disease. Also, all the relevant censored data from the prognostic study were used to estimate survival following progressive disease, that is, not just patients dying before they could be prescribed imatinib, but also survivors up to the point at which they were transferred to imatinib treatment. Another key difference was that the extrapolations of both the trial data and the censored prognostic data were based upon all the data available and did not assume a constant hazard ratio. The estimates of utility were the same as those included in the manufacturer's economic model. The model was also structured to estimate the cost effectiveness of different policies regarding dose escalation. |
| 4.2.5 | The results of the DSU model suggest that the incremental cost per additional quality-adjusted life year (QALY) is approximately £32,000 for patients on 400 mg/day estimated over 10 years. The incremental cost effectiveness of a policy allowing dose escalation to 600 mg/day after failure of 400 mg/day was estimated to be approximately £39,000 at 10 years compared with a policy of no dose escalation. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Committee reviewed the evidence available on the clinical and cost effectiveness of imatinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed by users on the benefits of imatinib from people with GIST, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources. |
| 4.3.2 | The Committee heard evidence from experts on the current treatment of patients with GIST, and it was aware that imatinib is the only effective treatment for GIST. Experts advised that about half of all patients with GIST have unresectable and/or metastatic disease at presentation. Experts also advised that tumour response is most commonly assessed by CT or MRI scan. Although PET assessment of tumour metabolism at 1 week post-treatment can provide early information on patients' responses to imatinib treatment, this is not widely available. The Committee therefore considered that assessment of tumour response should be based on SWOG criteria because this classification of tumour response was reported in the published clinical study, and it formed the basis of all of the economic models. The committee also concluded that further research into the use of PET for assessing tumour response would be beneficial. |
| 4.3.3 | The Committee heard evidence that mutational analysis to determine whether patients have a mutation in exon 9 (these patients are not thought to respond as well to imatinib treatment) or exon 11 (these patients are thought to respond well to imatinib treatment) may enable clinicians to predict the patients who are most likely to respond to imatinib treatment. Although this test is not widely available in the UK, the Committee believed that it would be useful for the test to be carried out in people with GIST in order to determine whether a response to imatinib therapy is likely. |
| 4.3.4 | The Committee carefully considered the duration for which patients should receive imatinib treatment. Experts advised that patients are usually evaluated (by an assessment of diagnostic imaging and clinical symptoms) by 12 weeks, at which stage, the disease is classified as complete response, partial response, stable disease or progressive disease. On the basis of the economic models, the committee concluded that continuing to treat patients who show no response to imatinib treatment would not be a cost-effective use of resources. The Committee concluded that patients should initially receive imatinib treatment for up to 12 weeks before tumour response is evaluated. Only patients responding to treatment (defined as partial response, complete response or stable disease) should continue to be treated with imatinib until there is evidence of disease progression. |
| 4.3.5 | The Committee considered the views of the experts regarding dose escalation in patients with progressive disease following initial treatment. The Committee concluded that there is currently no robust evidence to suggest that continued treatment with imatinib (including dose escalation) in patients with progressive disease is clinically or cost effective. |
| 4.3.6 | The Committee heard evidence that the management of patients on imatinib treatment has changed since early studies were initiated. Originally, tumour assessments (by SWOG or RECIST criteria) were interpreted such that imatinib treatment would be withdrawn in patients with progressive disease. This included patients with multiple lesions if they experienced growth in one lesion only. Experts commented that current practice often includes the continuation of imatinib treatment in patients with progressive disease (as assessed by CT/MRI) providing they maintain a symptomatic response, or if some lesions continue to respond to treatment. However, the Committee considered that, because there is a lack of robust evidence on the effectiveness of extended treatment in these patients, the use of imatinib in this context should be undertaken only within prospective clinical trials. |
| 4.3.7 | The Committee carefully considered the most appropriate estimates of survival for a control group for imatinib treatment in the cost effectiveness modelling. All the models used data from the same unpublished historical control study to represent the natural history of GIST, but differed in the selection of patients and whether the data were censored for when imatinib treatment became available. The survival curve for patients that never received imatinib treatment was considered to underestimate the survival of these patients. However, the use of all-patient data (including data from patients who went on to receive imatinib treatment), as presented in the Assessment Group model, was considered to overestimate the survival of control patients. The Committee considered the use of data on the survival of the control group, censored for when imatinib became available, to be the best estimate of the likely prognosis of untreated GIST. |
| 4.3.8 | The Committee considered the different methods of extrapolating the trial and prognostic data to a 10 year time horizon in the cost effectiveness models. The DSU model, which did not assume constant hazard and used all of the available data for both the treatment and control groups, was considered to be the most appropriate method of extrapolation. The Committee concluded that the cost-effectiveness estimates based on a 10-year time horizon were the most appropriate, because this time horizon was likely to encompass the key costs and benefits. |
| 4.3.9 | The Committee considered that the assumption that all patients would respond to imatinib immediately (as presented in the manufacturer's and Assessment Group model) was unlikely. The Committee concluded that the estimates of cost effectiveness based upon the DSU model (in which all patients begin in the progressive phase) used the most appropriate available data and assumptions. |
| 4.3.10 | The Committee heard evidence from experts regarding likely tumour response rate in the event of dose escalation. The DSU model assumed patients who are escalated to 600 mg/day after disease progression on 400 mg/day have the same response as when they initially responded to the lower dose. The experts advised that the tumour response rate on the escalated dose is likely to be substantially lower than an initial response at 400 mg/day. The Committee considered that this assumption (of an equivalent response following dose escalation) would underestimate the ICERs for imatinib in scenarios that included dose escalation. This conclusion supported their view of the appropriateness of dose escalation in progressive disease as in section 4.3.5. |
| 4.3.11 | The Committee heard testimony from the patient and clinical experts about the dramatic improvement in health-related quality of life associated with successful imatinib treatment. The Committee discussed the method of estimating utility values by mapping from the ECOG performance status to the EQ-5D, which was used in all of the economic models. It concluded that the utility values derived in this way may underestimate the reduction in health-related quality of life experienced by people with GIST in the presence of progressive disease. Consequently the ICER values calculated by the models reviewed in the appraisal may be less favourable. |
| 4.3.12 | The Committee considered advice from the clinical expert that, in a minority of patients, imatinib treatment may be given until unresectable tumours shrink to a size at which they can be surgically resected. The expected survival of these patients is better than the expected survival of patients whose tumours remain unresectable. The Committee concluded that, although only a small number of patients become suitable for resection following imatinib treatment, if the benefits associated with resection had been taken into account in the economic models, the cost per QALY estimates for imatinib would be more favourable. |
| 4.3.13 | The Committee was concerned that in the absence of imatinib treatment, some patients may receive inappropriate surgical resection, or chemotherapy with little effect on prognosis. As the costs and likely decrement in utility associated with these treatments have not been incorporated in the control arm of the models, these exclusions could lead to an underestimate of the cost effectiveness of imatinib treatment. |
| 4.3.14 | For the reasons listed in Sections 4.3.11 to 4.3.13, the Committee considered that the ICERs for imatinib treatment may have been overestimated. Therefore, the Committee concluded that the cost effectiveness of imatinib for the treatment of GIST, administered according to the recommendations set out in this guidance, was acceptable. |
| 5 | Proposed recommendations for further research |
| 5.1 | A national register of all patients receiving imatinib treatment for GIST should be maintained. Details could include patient characteristics, dose and duration of treatment, mutational analysis, tumour response rates and survival both with and after discontinuation of imatinib treatment. The response rates of patients who have received escalated doses of imatinib treatment in the context of clinical trials could also be included. |
| 5.2 | A number of trials on the use of imatinib for GIST are still in progress. Data collection is ongoing for the dose-randomisation studies, including the study comparing 400 mg/day with 600 mg/day (study CSTI571-B2222) and the two large studies comparing imatinib 400 mg/day with 800 mg/day (unlicensed dose). |
| 5.3 | The Institute recommends that further trials be undertaken to evaluate the benefit of maintenance therapy at 400 mg/day for patients with progressive disease, and the response rate of patients after switching to higher doses of imatinib treatment. The effectiveness of dose escalation should be evaluated for patients who do not respond to imatinib treatment at 400 mg/day, and for patients who initially respond to the lower dose but later develop progressive disease. These trials should incorporate measures of health-related quality of life. Information on survival following withdrawal of imatinib treatment should also be collected. |
| 5.4 |
The Institute considered that studies should be conducted to assess:
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| 6 | Preliminary views on the resource impact for the NHS |
| This section outlines the Appraisal Committee's preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore, the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible. | |
| 6.1 | The cost impact of this guidance will depend on: the number of patients with unresectable and/or metastatic GIST; the proportion of patients who receive imatinib; the proportion of patients who respond to imatinib treatment; the duration of treatment; the price of imatinib; and the number of patients already prescribed imatinib for GIST. |
| 6.2 | Estimates of the annual incidence of GIST vary considerably. The manufacturer of imatinib estimated the number of new cases of unresectable and/or metastatic GIST to be between 80 and 240 people each year. It has also been suggested that current estimates of GIST are underestimates, and these figures may increase as more patients become c KIT tested. The annual drug cost of imatinib is just under £19,000. Assuming that there will be 240 new patients eligible for imatinib treatment for GIST and that patients will be monitored by an average of four CT scans per year, the total cost of treating new patients in accordance with the guidance will be approximately £4.7 million in the first year. Assuming that the incidence rate does not change and that patients remain on imatinib treatment for an average of 1.44 years (as predicted by the DSU economic model), the total cost of treating patients with imatinib for GIST will be approximately £6.8 million when the number of patients receiving imatinib has reached a steady state. |
| 6.3 | The resource impact of this guidance on the NHS will depend on the number currently receiving NHS prescriptions for imatinib for the treatment of GIST. Using the assumptions set out in Section 6.2, if 25% of eligible patients currently receive NHS prescriptions for imatinib for GIST, the additional cost of implementing this guidance will be approximately £5.1 million. If 75% of eligible patients are currently being treated with imatinib, the impact of the guidance will be less, at about £1.7 million. These estimates are based on a number of assumptions and could be much less if switching to higher doses of imatinib is reduced. The estimates may also be reduced further if GIST patients receive imatinib treatment as a result of the guidance rather than inappropriate surgery or chemotherapy treatment. |
| 7 | Proposals for implementation and audit |
| This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in Section 1. | |
| 7.1 | All clinicians who treat people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST should review their current policies and practice to take account of the guidance set out in Section 1. |
| 7.2 | 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. |
| 7.3 | To measure compliance locally with the guidance, the following criteria could be used. Further details on suggestions for audit are presented in Appendix C. |
| 7.3.1 | For an individual 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. |
| 7.3.2 | Imatinib therapy at 400 mg/day is continued beyond the first 12 weeks only if an individual's GIST responds to treatment within 12 weeks and only until the development of progressive disease. (Response and progressive disease are defined by the criteria set out in Section 1 and Appendix D). |
| 7.3.3 | If an individual's GIST does not respond to treatment, or more progressive disease develops, imatinib may be continued only as part of a prospective clinical trial. |
| 8 | Related guidance |
| National Institute for Clinical Excellence (2002) Guidance on the use of imatinib for chronic myeloid leukaemia. NICE Technology Appraisal Guidance no. 50. London: National Institute for Clinical Excellence. |
| 9 | Proposed date for review of guidance |
| 9.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. |
| 9.2 | It is proposed that the guidance on this technology is reviewed in September 2007. |
| David Barnett |
| Chair, Appraisal Committee |
| May 2004 |
| Appendix A. Appraisal Committee members and NICE project team |
| NOTE The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into three branches, with the chair, vice-chair and a number of other members attending meetings of all branches. Each branch considers its own list of technologies and ongoing topics are not moved between the branches. |
| 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. |
| The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. |
| 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 |
| Dr Sheila Bird MRC Biostatistics Unit, Cambridge |
| Professor Rosamund Bryar Professor of Community & Primary Care Nursing, St Bartholomew's School of Nursing & Midwifery, London |
| Dr Rodney Burnham Consultant Physician & 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 Health Policy and Practice, University of East Anglia, Norwich |
| Dr Christopher Eccleston Director Pain Management Unit, University of Bath |
| 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 & Pharmacovigilance, GlaxoSmithKline, Greenford |
| Mr John Goulston Director of Finance, Barts and the London NHS Trust |
| Mr Adrian Griffin Health Outcomes Manager, Johnson & Johnson Medical Ltd, Ascot |
| 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 |
| Mr Muntzer Mughal Consultant Surgeon, Lancashire Teaching Hospitals NHS Trust, Chorley |
| Judith Paget Chief Executive, Caerphilly Local Health Board, Wales |
| Dr Katherine Payne Health Economics, Nowgen: The North West Genetics Knowledge Park, Manchester |
| Mr James Partridge Lay Representative; Chief Executive, Changing Faces, London |
| Mrs Kathryn Roberts Nurse Practitioner, Hyde, Cheshire |
| Professor Philip Routledge Professor of Clinical Pharmacology, College of Medicine, University of Wales, Cardiff |
| Ms Anne Smith Lay Representative; Trustee, Long-Term Medical Conditions Alliance |
| Dr Debbie Stephenson Head of HTA Strategy, Eli Lilly and Company, Hampshire |
| Professor Andrew Stevens (Vice-Chair) Professor of Public Health, University of Birmingham |
| Dr Cathryn Thomas General Practitioner, & Senior Lecturer, Department of Primary Care & 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 |
| B. NICE Project Team |
| Each appraisal of a technology is assigned to one or more Health Technology Analyst(s) and a Technology Appraisal Project Manager within the Institute. |
| Eleanor Donegan and Louise Longworth Technical Leads, NICE project team |
| Kathleen Dalby Project Manager, NICE project team |
| Appendix B. Sources of evidence considered by the Committee | |
| A |
The Assessment Report for this appraisal was prepared by the West Midlands Health Technology Collaboration. Wilson J, Connock M, Song F, Yao G, et al. Imatinib for gastro-intestinal tumours. October 2003. |
| B | The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and Assessment Report. They are also invited to comment on the Appraisal Consultation Document (ACD) and consultee organisations are provided with the opportunity to appeal against the Final Appraisal Determination (FAD). |
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I Manufacturer/sponsors:
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II Professional/specialist and patient/carer groups:
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III Commentator organisations (without the right of appeal):
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C The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on imatinib for the treatment of GIST by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.
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| Appendix C. Detail on criteria for audit of the use of imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours | |||
| Possible objectives for an audit | |||
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An audit on the appropriateness and effectiveness of use of unresectable and/or metastatic GIST could be carried out to ensure the following.
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| Possible patients to be included in the audit | |||
| An audit could be carried out on patients diagnosed with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST over a reasonable time period for audit. In view of the small number of patients who may be eligible for inclusion in the audit, all patients should be included in the audit and it may be desirable to collect data for the audit concurrent with treatment | |||
| Measures that could be used as a basis for an audit | |||
| The measures that could be used in an audit on the use of imatinib for the treatment of unresectable and/or metastatic GISTs are as follows. |
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Criterion
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Standard
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Exception
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Definition of Terms
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1. For an individual with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST, imatinib treatment is provided as first line management as follows: a. at 400 mg/day and b. for up to 12 weeks |
100% of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST | None | 'Tumour response' is assessed by a CT scan or MRI and is classified as complete response, partial response or stable disease as defined by the SWOG criteria (see Appendix D). |
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2. Imatinib therapy at 400 mg/day is continued beyond the first 12 weeks only in the following circumstances: a. the individual's GIST has responded to treatment in the first 12 weeks, and b. progressive disease has not yet developed |
100% of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib | A. The individual is participating in a prospective clinical trial | See above for definition of tumour response. |
| Calculation of compliance with the measure | ||
| Compliance (%) with each measure described in the table above is calculated as follows. | ||
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Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed |
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X 100 | |
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Number of patients to whom the measure applies |
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| Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved. | ||
| Appendix D. Southwest Oncology Group (SWOG) criteria for assessing tumour response | |
| SWOG criteria | Definition |
| Complete response (CR) | Complete disappearance of all measurable and evaluable disease. No new lesions. No disease related symptoms. No evidence of non-evaluable disease, including normalisation of markers and other relevant abnormal lab values. All measurable, evaluable and non-evaluable lesions and sites must be assessed using the same technique as baseline. |
| Partial response (PR) | Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. All measurable and evaluable lesions and sites must be assessed using the same techniques as baseline. |
| Stable disease (SD) | Does not qualify for CR, PR, progression or unknown. All measurable and evaluable sites must be assessed using the same technique used at baseline. |
| Progressive disease (PD) | 50% increase or an increase of 10 cm² (whichever is smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, or clear worsening from previous assessment of any evaluable disease, or reappearance of any lesion which had disappeared, or appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). For 'scan-only' bone disease, increased uptake does not constitute clear worsening. Worsening of existing non-evaluable disease does not constitute progression. |
| Exceptions: (1) In cases for which initial tumour flare reaction is possible (hypercalcaemia, increased bone pain, erythema of skin lesions), either symptoms must persist beyond 4 weeks or there must be additional evidence of progression. (2) Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to have progressed. | |
| Unknown | Progression has not been documented and one or more measurable or evaluable sites have not been assessed. |
This page was last updated: 19 November 2010