Glioma (newly diagnosed and high grade) - carmustine implants and temozolomide (appraisal consultation)
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal Consultation Document
Carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma
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The Department of Health and the National Assembly for Wales have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct an appraisal of Carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma 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 Carmustine implants and temozolomide. 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 | Carmustine implants are not recommended for the treatment of newly diagnosed high-grade glioma, except in well-designed clinical studies. |
| 1.2 | Temozolomide is not recommended for the treatment of newly diagnosed high-grade glioma, except in well-designed clinical studies. |
| 1.3 |
Clinical studies on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma in adults and children should include research into:
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| 2 | Clinical need and practice |
| 2.1 | Gliomas are the most common type of brain tumour. They develop from the glial cells that support the nerve cells of the brain and spinal cord. There are four main types: astrocytoma, ependymoma, oligodendroglioma and mixed tumours. Gliomas are graded according to their likely rate of growth, from grade 1 (slowest growing) to grade 4 (fastest growing). Grade 3 and 4 gliomas are considered high-grade gliomas. Grade 3 gliomas include anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma. Grade 4 gliomas are usually glioblastoma multiforme (GBM). |
| 2.2 | Brain tumours account for less than 2% of all primary cancers. Approximately 1860 new cases of malignant glioma are diagnosed in England and Wales each year. High-grade gliomas are more common in men than women and the incidence increases with age. People diagnosed with GBM are on average older than people diagnosed with grade 3 tumours. |
| 2.3 | Symptoms of high-grade glioma are dependent on the size, location and degree of infiltration of the tumour. They include headache, nausea, vomiting, seizures, visual disturbance, speech and language problems, and changes in cognitive and/or functional ability. |
| 2.4 | Approximately 30% of adults with high-grade tumours (grades 3 and 4) survive 1 year, and 13 % survive 5 years. The median survival of patients with anaplastic astrocytoma is around 2?3 years, and approximately 1 year for patients with GBM. Age, performance status and tumour histology are indicators of pretreatment prognosis. Patients have a better prognosis if they are younger, have better performance status, or have a grade 3 tumour, or tumour with an oligodendrocytic component. |
| 2.5 | Diagnosis of high-grade glioma is provisionally made through computed tomography (CT) scan or magnetic resonance imaging (MRI). The diagnosis is then confirmed and the tumour classified histologically, either at the time of surgical resection or by a single-event biopsy if surgery is not possible. There is a growing understanding of the molecular genetics of gliomas, which is allowing a more accurate classification of glioma and may give an indication of prognosis and likely response to treatment. |
| 2.6 | In the UK, treatment usually consists of surgical resection where possible, followed by radiotherapy. Surgery may achieve either a complete resection or partial resection (also known as ?debulking?) of the tumour. If the tumour is inoperable, treatment will usually consist of palliative medical management. Radiotherapy has been demonstrated to prolong survival and is usually recommended post surgery. Adjuvant chemotherapy is not considered part of standard therapy in the UK, but is used more routinely in the USA. The most frequently used regimens are a combination of procarbazine, lomustine and vincristine (PCV therapy), or single-agent treatment with carmustine (BCNU) or lomustine (CCNU). |
| 3 | The technologies |
| 3.1 | Carmustine implants (Gliadel, Link Pharmaceuticals) are biodegradable copolymer discs impregnated with an alkylating agent called carmustine (BCNU). They are about the size of a 5p coin and are implanted into the resection cavity at the time of surgery. Each implant contains 7.7 mg of carmustine, which interacts with DNA and RNA and may prevent the proliferation of tumour cells. |
| 3.2 | Carmustine implants are indicated for the treatment of newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation. They are also indicated as an adjunct to surgery in patients with recurrent GBM for which surgical resection is indicated. |
| 3.3 | Adverse effects include brain oedema, convulsions, healing abnormalities and intracranial infections. For full details of side effects and contraindications, see the Summary of Product Characteristics. |
| 3.4 | The cost of one carmustine implant is £650.38 (excluding VAT; BNF 50th edition, September 2005). Up to eight implants may be used, depending upon the shape and size of the resection cavity. Costs may vary in different settings because of negotiated procurement discounts. |
| 3.5 | Temozolomide (Temodal, Schering Plough Ltd.) undergoes hydrolysis in the body to produce monomethyl triazenoimidazole carboxamide (MTIC). MTIC is thought to act as an alkylating agent. Alkylating agents cause cross-linking of guanine bases in DNA thereby preventing cell division. |
| 3.6 | Temozolomide has a UK marketing authorisation for the treatment of newly diagnosed GBM concomitantly with radiotherapy and subsequently as monotherapy treatment. It is also licensed for the treatment of malignant glioma showing recurrence or progression after standard therapy. |
| 3.7 | Temozolomide is available as 5-mg, 20-mg, 100-mg and 250-mg tablets. It is administered at 75 mg/m2 daily for 42 days concomitantly with radiotherapy (60 Gy administered in 30 fractions), and then as monotherapy at 150 mg/m2 daily for 5 days, followed by 23 days without treatment, for a maximum of six cycles. The dose may be increased to 200 mg/m2 daily in the second and subsequent cycles. |
| 3.8 | The cost of temozolomide is £17.30 for 5 x 5-mg tablets, £69.20 for 5 x 20-mg tablets, £346.00 for 5 x 100-mg tablets, and £865.00 for 5 x 250-mg tablets (excluding VAT; BNF 50th edition, September 2005). Costs may vary in different settings because of negotiated procurement discounts. |
| 3.9 | Adverse effects include anorexia, constipation, fatigue, headache, lymphopenia, nausea, neutropenia, thrombocytopenia and vomiting. For full details of side effects and contraindications, see the Summary of Product Characteristics. |
| 4 | Evidence and interpretation |
| The Appraisal Committee considered evidence from a number of sources (see appendix B). | |
| 4.1 | Clinical effectiveness |
| 4.1.1 | The Assessment Group (AG) identified two randomised controlled trials (RCTs) that compared the effectiveness of carmustine implants plus radiotherapy with that of placebo plus radiotherapy, and two RCTs of temozolomide plus radiotherapy compared to radiotherapy alone. No studies comparing carmustine implants to temozolomide, or comparing carmustine implants or temozolomide to other antineoplastic agents (for example, the PCV chemotherapy regimen), were identified. |
| Carmustine implants | |
| 4.1.2 | The largest RCT of carmustine implants was a multinational trial with a minimum of 12 months' follow-up. Patients with grade 3 and 4 gliomas, aged between 18 and 65 years with a Karnofsky Performance Status (KPS) score of 60 or greater, were randomised following surgery to receive carmustine implants (n = 120) or placebo implants (n = 120). Patients also received radiotherapy at 55-60 Gy administered in 30-33 fractions. |
| 4.1.3 | The AG reported that the Food and Drugs Agency (FDA) in the USA expressed several concerns when it evaluated the trial. In particular, it was concerned about an imbalance between the types of tumours in study arms, which could have favoured carmustine implants. It was also concerned that the diagnosis made by one referee pathologist had been considered definitive, so recommended a sensitivity analysis using diagnosis from an alternative pathologist. Another concern was that the measurement of the time to decline of neurological symptoms and time of decline of KPS included death as an event rather than as censored data. The AG noted that three patients withdrew from the RCT and that it was unclear from which arm of the trial the patients withdrew. In addition, the manufacturer analysed the data which included stratification by country, and the FDA reanalysed this data without stratification. The data reported below relate to the unstratified analysis unless otherwise stated. |
| 4.1.4 | The median survival was 13.8 months (95% CI: 12.1 to 15.1) in the carmustine implant group, and 11.6 months (95% CI: 10.2 to 12.7) in the placebo group. The Kaplan-Meier hazard ratio was 0.77 (log rank statistic: p = 0.08). Based on data from longer-term follow-up, the Kaplan-Meier hazard ratio was 0.73 (log rank statistic: p = 0.02). At 12 months 59.2% of the carmustine implant group and 49.6% of the placebo group were alive, at 24 months survival was 15.8% and 8.3%, and at 36 months survival was 9.2% and 1.7% in each group respectively (all estimates calculated on the basis of survival data censored at the relevant time period). |
| 4.1.5 | There was no difference in progression-free survival between treatment groups. The median time to progression was 5.9 months (95% CI: 4.4 to 8.3) in the carmustine implant group and 5.9 months (95% CI: 4.7 to 7.4) in the placebo group (using stratified analysis). The manufacturer's analysis suggested that the time to decline of KPS and time to progression on neurological indices were statistically significantly improved in the carmustine implant group. However, a reanalysis of these data was conducted, which treated deaths as censored. This reanalysis found that the differences were a result of survival times between the treatment arms, which suggests that there was no independent effect by treatment on the time to decline of neurological indices and KPS. |
| 4.1.6 | In a subgroup of patients with GBM, the median survival was 13.5 months (95% CI: 11.4 to 14.8) in the carmustine implant group and 11.4 months (95% CI: 10.2 to 12.6) in the placebo group. The Kaplan-Meier hazard ratio was 0.82 (log rank statistic: p = 0.20). There was no statistically significant difference between treatment groups in progression-free survival for patients with GBM (stratified log rank test: p = 0.62). |
| 4.1.7 | Intracranial hypertension was the only adverse event in the largest RCT to have a significantly increased incidence in the carmustine implant group (9.2% compared to 1.7%; p = 0.02). |
| 4.1.8 | The second RCT was based in Scandinavia and had a minimum follow-up of 24 months. The design and inclusion criteria were similar to those for the other RCT of temozolomide. However, the sample size was smaller (n = 32) and recruitment to the study was terminated early as the investigators were unable to source additional carmustine implants. In this RCT, fewer patients had a diagnosis of GBM in the carmustine implant group (69%) compared to the placebo group (100%). Median survival in the carmustine implant group was 13.4 months (full CI not reported), compared to 9.2 months (95% CI: 8.7 to 10.4) in the placebo group. This difference was statistically significant (log rank: p = 0.01). Survival at 12 months was 62.5% in the carmustine implant group and 18.8% in the placebo group; at 24 months survival was 31.3% and 6.3% respectively (estimates based on censored data). There was no statistically significant difference in progression-free survival between treatment groups. |
| Temozolomide | |
| 4.1.9 | The inclusion criteria for the largest RCT specified that patients aged 18-70 years with grade 4 glioma and a WHO performance status of 2 or better should be randomised following surgery to receive radiotherapy plus temozolomide (n = 287) or radiotherapy alone (n = 286). Temozolomide was administered in accordance with its UK Marketing Authorisation. The median age of patients was 56 years (range 19-70 years) in the radiotherapy plus temozolomide group and 57 years (range 23-71 years) in the radiotherapy alone group. A diagnosis of GBM was confirmed by histology in 92-93% of patients; the proportion of grade 3 tumours was similar in both treatment groups. In the radiotherapy plus temozolomide group, tumour removal was complete in 44% of patients and partial in 39%, and only a biopsy was possible in 17% of patients. The extent of surgery was similar in the radiotherapy only group (45% complete, 40% partial, and 16% biopsy only). Median follow-up time was 28 months. |
| 4.1.10 | Median survival was 14.6 months (95% CI: 13.2 to 16.8 months) in the radiotherapy plus temozolomide group and 12.1 months (95% CI: 11.2 to 13.0 months) in the radiotherapy only group. Survival rates at 12 months, based on censored data, were 61.1% for the radiotherapy plus temozolomide group and 50.6% for the radiotherapy alone group. At 24 months corresponding survival rates were 26.5% and 10.4% respectively. Median time to disease progression was 6.9 months (95% CI: 5.8 to 8.2) in the temozolomide plus radiotherapy group and 5.0 months (95% CI: 4.2 to 5.5 months) in the radiotherapy alone group. |
| 4.1.11 | A retrospective subgroup analysis of patients with reduced O6-methylguanine-DNA methyltransferase (MGMT) activity was conducted. MGMT is an enzyme that repairs DNA damage at a site commonly targeted by cytotoxic drugs, thereby inhibiting the effect of chemotherapy on tumours. Reduced MGMT activity has been associated with extended overall survival and progression-free survival. MGMT methylation status was determined in 100 patients in the radiotherapy only arm, and 46 of these patients had reduced MGMT activity. In the radiotherapy plus temozolomide arm, MGMT methylation status was determined in 106 patients, and 46 of these patients had reduced MGMT activity. Patients with reduced MGMT activity had a median survival gain from radiotherapy plus temozolomide compared to radiotherapy alone of 6.4 months and median progression-free survival gain of 4.4 months. In the group with normal MGMT activity, both the median survival gain and median progression-free survival gain from radiotherapy plus temozolomide compared to radiotherapy alone were less than 1 month, although the gain in progression-free survival was statistically significant (p = 0.02). |
| 4.1.12 | In addition, the manufacturer reported the results of a subgroup analysis by extent of tumour resection. For patients who underwent a complete resection, the median survival was 14.2 months (95% CI: 12.7 to 16.2) in the radiotherapy only group and 18.3 months (95% CI: 15.7 to 22.5) in the radiotherapy plus temozolomide group. For patients who underwent a partial resection, the median survival was 11.7 months (95% CI: 9.7 to 13.1) and 13.5 months (95% CI: 11.9 to 16.3) respectively. |
| 4.1.13 | Severe myelosuppression (a reduction in the ability of bone marrow to produce blood cells) was reported in 16% of patients in the radiotherapy plus temozolomide group. Of the reported serious (grades 3 and 4) adverse events, fatigue, unspecified constitutional symptoms and infection were statistically significantly more frequent in the radiotherapy plus temozolomide group, as were moderate (grade 2) fatigue, nausea/vomiting and rash. |
| 4.1.14 | Another RCT conducted in Greece randomised patients to receive radiotherapy plus temozolomide (n = 57) and radiotherapy alone (n = 53). Patients generally had a worse prognosis than those in the larger trial. In the radiotherapy plus temozolomide group, tumour removal was complete in 18% of patients and partial in 40%, and only a biopsy was possible in 42% of patients. The extent of surgery in the radiotherapy only group was 15% complete, 43% partial and 42% biopsy only. Median survival was 13.4 months (95% CI: 9.5 to 17.1) in the radiotherapy plus temozolomide group and 7.7 months (95% CI: 5.3 to 9.2) in the radiotherapy only group. At 12 months survival was 56.3% in the radiotherapy plus temozolomide group and 15.7% in the radiotherapy only group, and at 18 months survival was 24.9% and 5.4% respectively (all estimates calculated on the basis of survival data censored at the relevant time period). Median time to progression was 10.8 months (95% CI: 8.1 to 14.7) in the radiotherapy plus temozolomide group and 5.2 months (95% CI: 3.9 to 7.4) in the radiotherapy only group. |
| 4.2 | Cost effectiveness |
| 4.2.1 | The manufacturer of carmustine implants submitted an economic model that estimated the cost per life year gained of carmustine implants plus radiotherapy, compared to placebo plus radiotherapy. The manufacturer of temozolomide submitted a within-trial economic analysis of temozolomide plus radiotherapy, compared to radiotherapy alone. The AG reviewed both manufacturers' analyses and constructed their own economic model. |
| 4.2.2 | The structure of the economic model submitted by the manufacturer of carmustine implants incorporated the assumption that following surgery, patients experience a constant level of quality of life. This continues until the onset of symptoms, after which time they experience a constant deterioration in quality of life until death. Data from the largest RCT were used to estimate survival and time to symptoms (which was estimated from the median time to deterioration in neurological performance scores). |
| 4.2.3 | The AG expressed concern about the estimation of time to symptoms using this approach because it was based on median values rather than mean values. No statistically significant differences were found between treatment arms in the time to decline of functional status and time to deterioration of neurological performance scores in 10 of 11 indices when the data were reanalysed by the FDA. It was assumed that the only difference in costs between the two treatment groups was the cost of the implants themselves (mean: 6.54 wafers per patient). A utility value of 0.8 was assumed for patients without symptoms. Costs and quality-adjusted life years (QALYs) were not discounted. |
| 4.2.4 | The estimated mean incremental cost of carmustine implants was £4250 and estimated mean QALYs gained were 0.16. The base-case incremental cost-effectiveness ratio (ICER) was £28,000 per QALY gained. A probabilistic sensitivity analysis suggested that if the maximum acceptable amount to pay for an additional QALY is £20,000, then the probability of carmustine implants being cost effective is 0.28. This probability rises to 0.57 if the maximum acceptable amount was £30,000 per additional QALY. The manufacturer of carmustine implants also included cost-effectiveness estimates for temozolomide plus radiotherapy compared to radiotherapy alone (mean ICER: £53,700 per QALY gained) and for PCV plus radiotherapy compared to radiotherapy alone (mean ICER: £34,200 per QALY gained). The AG considered the model structure to be sound, but concluded that the main ICER of £28,000 per QALY gained was underestimated because of the assumptions used to estimate survival and the omission of treatment costs other than those of the implants. |
| 4.2.5 | The manufacturer of temozolomide submitted an economic evaluation based on the largest RCT. Resource-use data were collected for a subgroup of 224 patients from the original trial. Data included the number of radiotherapy sessions, temozolomide cycles and dosages, concomitant medications, laboratory tests, hospitalisations due to serious adverse events and the frequency of serious toxicity-related events. Health benefits were expressed in terms of life years gained based on data from the largest RCT. Costs and life years gained were discounted at 3.5%. |
| 4.2.6 | Two analyses were presented: one based on the subgroup for which resource-use data had been collected, and the other based on extrapolating these data to the full trial cohort. In addition, two methods of estimating survival were employed: one included survival to 2 years post randomisation only, and the other extrapolated from time of randomisation until death. Base-case results with extrapolated survival were £11,000 per life year gained from temozolomide for the full trial cohort and £19,160 per life year gained from temozolomide for the subgroup with resource-use data. For the analysis restricted to 2 years post randomisation, the corresponding ICERs were £19,440 for the full trial cohort and £33,590 for the subgroup with resource-use data. |
| Assessment Group's economic evaluation | |
| 4.2.7 | The AG constructed a Markov model to estimate the cost effectiveness of the treatments for patients with operable grade 3 and 4 gliomas and a mean age of 55 years. The time horizon for the model was 5 years, and each cycle of the model represented 1 week. Six health states were included in the model: surgery; postoperative recovery; radiotherapy; stable disease; progression; and death. Patients surviving the postoperative recovery period were assumed to undergo a course of radiotherapy at 60-Gy fractions (5 fractions per week) for a maximum of 6 weeks. Aside from perioperative mortality, the risk of death in the model was considered to be time dependent rather than state dependent. It was estimated from the two largest RCTs using a Weibull curve fitted to the data. Health-related utility values were elicited from 93 members of the general population, and were based on scenarios developed by the AG describing various states of health of people with glioma. Patients in the progressive disease state were assumed to experience constantly deteriorating quality of life (modelled as a reduction of health-related utility of 0.5% per week). Resource use and cost data were taken from the published literature, manufacturer submissions and expert opinion. Costs were discounted at 6% and benefits at 1.5%. A range of one-way sensitivity analyses were conducted as well as a probabilistic simulation. |
| 4.2.8 | In the base-case analysis comparing carmustine implants to placebo, the mean incremental costs of carmustine implants were £6100 and mean QALYs gained were 0.107. The additional cost per QALY gained was £57,000. The one-way sensitivity analyses suggested that the model was most sensitive to changes in overall survival gain, progression-free survival and the risk of death due to surgery. The probabilistic analysis found that carmustine implants were likely to be a cost-effective treatment option if the maximum acceptable amount to pay for an additional QALY gained is £50,000 or more. In addition, a speculative analysis of patients with a better prognosis found that the mean incremental cost per QALY was just under £37,000. |
| 4.2.9 | In the base-case analysis of temozolomide plus radiotherapy compared to radiotherapy alone, the mean incremental cost of temozolomide plus radiotherapy was £8560 and mean QALYs gained were 0.187. The additional cost per QALY gained was £45,800. The one-way sensitivity analyses showed that the model was most sensitive to survival gain and progression-free survival. The probabilistic analysis found that temozolomide was likely to be a cost-effective treatment option if the maximum acceptable amount to pay for an additional QALY gained is £50,000 or more. A speculative analysis of patients with a better prognosis found that the mean incremental cost per QALY was just under £43,000. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Committee reviewed the data available on the clinical and cost effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed glioma. It considered evidence on the nature of the condition and the value placed on the benefits of carmustine implants and temozolomide by carers of people with glioma, those who represent people with glioma, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. |
| 4.3.2 | The Committee were mindful in considering the use of carmustine and temozolomide as initial therapy for newly diagnosed high-grade glioma that, to date, this disease has had a very poor prognosis despite various treatments being available. In addition, it understood that following an initial response to early treatment, once progression of disease has occurred, a rapid decline is usual thereafter. The Committee was also fully aware that the quality of life of patients is paramount at all stages of the disease, especially during the period after initial diagnosis and treatment before further progression occurs. |
| 4.3.3 | The Committee considered the evidence on the effectiveness of temozolomide. It noted that the RCTs suggested a gain in progression-free survival and overall survival. The Committee considered the testimony of the experts that there was some evidence suggesting that chemotherapy with the PCV regimen may also be an effective treatment option. It acknowledged that there were no trials comparing temozolomide to other chemotherapy regimens such as PCV. The Committee noted that the proportion of patients with longer-term survival appeared to be greater in the temozolomide arm of the trial, but considered the number of patients affected was too small to draw conclusions about the effectiveness of temozolomide in increasing the likelihood of longer-term survival. |
| 4.3.4 | The Committee considered testimony from the clinical experts that the length of survival of patients in the control arm of the largest RCT for temozolomide was better than is currently the norm in UK clinical practice. It was also mindful that temozolomide is part of a mixed treatment regimen given as adjunct specifically to radiotherapy. They were persuaded by the expert's testimony of the importance of optimising both the timing and extent of radiotherapy in order to achieve the best results for all glioma patients irrespective of the use of other therapies. |
| 4.3.5 | The Committee considered the evidence of effectiveness of carmustine implants. It acknowledged that the RCTs showed a small gain in overall survival from carmustine implants. It considered that the concerns regarding the estimates of effectiveness of temozolomide (including the length of survival in the placebo arm), and also the concerns regarding the lack of RCTs comparing the treatments to other chemotherapy regimens, would also apply to the estimates of effectiveness of carmustine implants. |
| 4.3.6 | The Committee also carefully considered the concerns expressed by the FDA and AG regarding the analysis of the largest RCT of carmustine implants, specifically the different approaches to stratification of the data. It also noted that the clinical experts shared some of these concerns. The Committee considered that as the analyses conducted by the manufacturer and FDA produced different results regarding the statistical significance of survival gain, this added to the uncertainty of the effect of treatment on survival. However, it concluded that the gain in overall survival shown in the trial was small, irrespective of the concerns expressed by the FDA. |
| 4.3.7 | The Committee acknowledged the difficulty in measuring disease progression. It considered evidence from the experts that progression-free survival, measured using imaging techniques, is influenced by the frequency with which the imaging is conducted and may not correlate with neurological or functional status and the patients' perception of their health. It also considered that the use of measures of functional status can be problematic due to the variable impact of tumour progression upon physical and cognitive functioning. Additionally, it considered evidence from the experts that glioma can have a considerable impact upon the quality of life of patients, which may deteriorate rapidly after the onset of disease progression. The Committee was mindful that the largest RCT did not show any gain in progression-free survival when measured using imaging techniques. It was also mindful that the reanalysis of time to neurological deterioration by the FDA failed to show a statistically significant benefit in favour of carmustine implants on most indices. The Committee concluded that the evidence to illustrate a beneficial impact on progression-free survival of carmustine implants was weak. |
| 4.3.8 | The Committee also took account of the difficulties in making a definitive pathological diagnosis of high-grade glioma, in particular the distinction between grade 3 and grade 4 disease. The Committee was persuaded that it was appropriate to consider the pragmatic evidence on pathological diagnosis from the RCTs as a reflection of the realities of current clinical practice. |
| 4.3.9 | The Committee considered the evidence on the cost effectiveness of carmustine implants and temozolomide. It noted that the economic evaluation submitted by the manufacturer of temozolomide expressed health outcomes in life years gained. The Committee considered the testimony from the experts that glioma can have a large impact upon the quality of life of patients. It concluded that the assessment of cost effectiveness should incorporate the effects of the disease and treatment upon quality of life in addition to survival. The Committee was aware that the main driver of the economic model submitted by the manufacturer of carmustine implants was the difference in progression-free survival, as measured in the largest RCT by the time to decline in neurological symptoms. It recognised the uncertainty around the ability of carmustine implants to extend progression-free survival. The Committee concluded that the economic analysis submitted by the AG was the most appropriate. This was because estimates of survival were based on measures of overall survival from the two largest RCTs. Additionally, this economic analysis incorporated an estimate of the effect of the disease on health-related quality of life. |
| 4.3.10 | The Committee considered the assumptions adopted in the AG's economic model. It noted that the model included an assumption that the probability of death was based on the length of survival, and not whether patients' disease had progressed. The Committee was aware that the probability of death increases significantly upon tumour progression and that time to death following progression may be very short. It accepted that the AG's assumption enabled the model to use data on overall survival from the RCTs. It was also aware that a sensitivity analysis demonstrated that the model was not sensitive to this assumption. The Committee considered that fitting a Weibull curve to the RCT survival data resulted in a slight underestimate of the median survival gain from carmustine implants, and slight overestimate of the survival gain from temozolomide. The Committee concluded that the general approach to the estimation of survival was appropriate. It also concluded that the results of the sensitivity analyses showed the survival gain from treatment would have to increase considerably for the incremental cost-effectiveness ratios to decrease substantially. |
| 4.3.11 | The Committee understood that the choice of treatment used after disease progression following initial therapy with either carmustine implants or temozolomide could impact on the results of the cost-effectiveness analysis. It therefore considered an additional analysis conducted by the AG. This explored the effect of several different assumptions relating to different treatments patients could receive upon disease progression. The Committee was mindful of testimony from the experts that there is considerable uncertainty regarding the appropriate treatment for patients whose disease progresses following chemotherapy after initial diagnosis. The Committee concluded on the balance of the economic evidence, including the consideration of ?second and subsequent line? treatments (as far as was possible), that the use of carmustine implants and temozolomide for the treatment of newly diagnosed glioma would not be a cost-effective use of NHS resources. |
| 4.3.12 | The Committee was mindful that glioma affects people of all ages, including children, but was mindful that the RCT and economic evidence related to the use of the technologies in adults. The Committee accepted that this evidence would be likely to apply to children. It concluded that the issues regarding effectiveness and cost effectiveness outlined above were also relevant to the use of the technologies for the same condition in children, and that this should continue to be an area of further research. |
| 4.3.13 | The Committee considered whether there might be subgroups of patients for who the use of treatments may be more effective and cost-effective. It acknowledged the results of a retrospective analysis of patients with reduced MGMT activity in the largest RCT of temozolomide. The Committee was aware of continued research in this area. The Committee concluded that this early research was promising and that further research into biological markers of chemosensitivity and the use of such markers to identify subgroups of patients in whom the treatments may be more effective should be pursued. |
| 5 | Proposed recommendations for further research |
| 5.1 | The Committee noted that a large trial is planned to compare low-dose temozolomide with dose-intense temozolomide, and that the trial includes stratification of patients by MGMT status. |
| 5.2 |
The Committee considered that further research into the effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma is required. Such studies should include:
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| 6 | Preliminary views on the resource impact for the NHS |
| 6.1 | Carmustine implants and temozolomide are not recommended for use in the NHS except in the context of clinical trials. Therefore, this guidance is not expected to lead to a change in NHS expenditure or have any impact on other NHS resources. |
| 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 | NHS hospitals and clinicians who care for people who have newly diagnosed high-grade glioma should review their current practice and policies to take account of the guidance set out in section 1. |
| 7.2 | Carmustine implants and temozolomide should be used only in well-designed clinical studies as described in section 5.2. |
| 8 | Related guidance |
| 8.1 | Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer). NICE technology appraisal guidance no. 23 (2001). Available from: www.nice.org.uk/TA023 |
| 8.2 | Cancer service guidance for improving outcomes for people with brain and other central nervous system tumours. Expected publication date is June 2006. |
| 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 whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. |
| 9.2 | It is proposed that the guidance on this technology is considered for review in August 2009. The Institute would particularly welcome comment on this proposed date. |
| David Barnett |
| Chair, Appraisal Committee |
| December 2005 |
| Appendix A. Appraisal Committee members |
| 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 two branches, with the chair, vice chair and a number of other members attending meetings of both 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 Jane Adam Radiologist, St George's Hospital, London |
| Professor A E Ades MRC Senior Scientist, MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol |
| Dr Tom Aslan General Practitioner, Stockwell, London |
| Professor David Barnett (Chair) Professor of Clinical Pharmacology, University of Leicester |
| Mrs Elizabeth Brain Independent Patient Advocate |
| Dr Karl Claxton Health Economist, University of York |
| Dr Richard Cookson Senior Lecturer in Health Economics, School of Medicine Health Policy and Practice, University of East Anglia |
| Mrs Fiona Duncan Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool |
| Professor Christopher Eccleston Director Pain Management Unit, University of Bath |
| Dr Paul Ewings Statistician, Taunton & Somerset NHS Trust, Taunton |
| Professor Terry Feest Professor of Clinical Nephrology, Southmead Hospital |
| Ms Alison Forbes Lay Representative, Health Consultant Associate, Eden Insight |
| Professor John Geddes Professor of Epidemiological Psychiatry, University of Oxford |
| Mr John Goulston Director of Finance, Barts and the London NHS Trust |
| Mr Adrian Griffin Health Outcomes Manager, Johnson & Johnson Medical Ltd |
| Ms Linda Hands Consultant Surgeon, John Radcliffe Hospital |
| Dr Elizabeth Haxby Lead Clinician in Clinical Risk Management, Royal Brompton Hospital |
| Dr Rowan Hillson Consultant Physician, Diabeticare, The Hillingdon Hospital |
| Dr Catherine Jackson Clinical Lecturer in Primary Care Medicine, Alyth Health Centre, Angus, Scotland |
| Professor Richard Lilford Professor of Clinical Epidemiology, Department of Public Health and Epidemiology, University of Birmingham |
| Dr Simon Mitchell Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester |
| Ms Judith Paget Chief Executive, Caerphilly Local Health Board, Wales |
| Dr Katherine Payne Health Economist, The North West Genetics Knowledge Park, The University of Manchester |
| Dr Ann Richardson Independent Patient Advocate |
| Mrs Kathryn Roberts Nurse Practitioner, Hattersley Group Practice , Cheshire |
| Professor Philip Routledge Professor of Clinical Pharmacology, College of Medicine, University of Wales, Cardiff |
| Dr Stephen Saltissi Consultant Cardiologist, Royal Liverpool University Hospital |
| Mr Mike Spencer General Manager, Clinical Support Services, Cardiff and Vale NHS Trust |
| 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, & Associate Professor, 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 |
| Professor Mary Watkins Professor of Nursing, University of Plymouth |
| Dr Paul Watson Medical Director, Essex Strategic Health Authority |
| Dr David Winfield Consultant Haematologist, Royal Hallamshire Hospital, Sheffield |
| NICE Project Team |
| Each appraisal of a technology is assigned to a Technical Lead, Technical Advisor and a Technology Appraisal Project Manager within the Institute. |
| Louise Longworth Technical Lead, NICE project team |
| Janet Robertson Technical Advisor, NICE project team |
| Alana Miller Project Manager, NICE project team |
| Appendix B. Sources of evidence considered by the Committee | |
| A | The assessment report for this appraisal was prepared by Peninsula Technology Assessment Group (PenTAG) Peninsula Medical School, Wessex Institute for Health Research and Development, University of Southampton |
| I Garside R, Pitt M, Anderson R et al. The effectiveness and cost effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma: A systematic review and economic evaluation, September 2005 | |
| 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 ACD and consultee organisations are provided with the opportunity to appeal against the FAD: |
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I Manufacturers/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 Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma 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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This page was last updated: 30 March 2010