Head and neck cancer - cetuximab: appraisal consultation document
Appraisal Consultation Document
Appraisal Committee's preliminary recommendations
The manufacturer's submission
Consideration of the evidence
Proposed recommendations for further research
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee
Appendix C: List of organisations involved in this appraisal
The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of cetuximab for treatment of locally advanced squamous cell cancer of the head and neck and to 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 consultees and by the representatives nominated by healthcare professional and patient/carer groups. The Committee has developed preliminary recommendations on the use of cetuximab for the treatment of locally advanced squamous cell cancer of the head and neck.
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.). This document should be read in conjunction with the manufacturer?s submission and Evidence Review Group report, which are available from 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 single technology appraisal process ? interim..
- The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
- At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
- After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
- Subject to any appeal by consultees, the FAD may be used as the basis for the Institute?s guidance on the use of the appraised technology in the NHS in England and Wales.
The key dates for this appraisal are:
Closing date for comments: 26th February 2007 at 17:00.
Second Appraisal Committee meeting: 15th March 2007
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||Cetuximab in combination with radiotherapy is not recommended for patients with locally advanced squamous cell cancer of the head and neck.|
|2.1||Cetuximab (Erbitux, Merck Pharmaceuticals) is a chimeric immunoglobulin G monoclonal antibody that competes for epidermal growth factor receptor (EGFR) binding sites on the external surface of the cell membrane. Binding of cetuximab to EGFR prevents activation of tyrosine kinase within cells, eventually resulting in apoptosis. Cetuximab, in combination with radiotherapy, is indicated for the treatment of patients with locally advanced squamous cell cancer of the head and neck. For further information see the summary of product characteristics.|
|2.2||The most common side effects of cetuximab are mild or moderate infusion-related reactions such as fever, chills, nausea, vomiting, headache, dizziness or dyspnoea that occur in a close temporal relationship mainly to the first cetuximab infusion. Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash and/or, less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (for example, paronychia). The majority of skin reactions develop within the first 3 weeks of therapy. For full details of side effects and contraindications, see the summary of product characteristics.|
|2.3||The summary of product characteristics states that cetuximab therapy is started 1 week before radiation therapy and that cetuximab therapy is continued until the end of radiation therapy. For the initial dose, the recommended infusion period is 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The infusion rate should not exceed 10 mg/min, equivalent to 5 ml/min of cetuximab 2 mg/ml.|
|2.4||The acquisition cost of cetuximab, is £136.50 for a 2-mg/ml, 50-ml vial (excluding VAT; ?British national formulary?, 52nd edition). The first dose is 400 mg/m2 body surface area. Subsequent weekly doses are 250 mg/m2 each. Based on an average body surface area of 1.7 m2, the cost of the first dose is approximately £950 and the cost of each subsequent weekly dose is approximately £680. Costs may vary in different settings because of negotiated procurement discounts.|
|3||The manufacturer's submission|
|The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of cetuximab and a review of this submission by the Evidence Review Group (ERG) (appendix B).|
|3.1||The manufacturer?s submission approached the decision problem by comparing cetuximab plus radiotherapy with radiotherapy alone. The manufacturer specified that the population under consideration consisted of people with locally advanced squamous cell cancer of the head and neck for whom chemotherapy is considered inappropriate but for whom radiotherapy is suitable. The outcome measures specified in the decision problem were duration of locoregional control, overall survival, progression-free survival and safety.|
|3.2||The manufacturer?s submission presented evidence on the clinical effectiveness of cetuximab plus radiotherapy based on a single randomised controlled trial (RCT) that compared cetuximab plus radiotherapy with radiotherapy alone in people with stage III or IV, nonmetastatic, squamous-cell cancer of the oropharynx, hypopharynx or larynx. Criteria for eligibility included a Karnofsky performance score of at least 60 and normal renal function. Patients were ineligible if they had undergone surgery or had previously received radiotherapy for head and neck cancer. The primary outcome measure was the duration of control of locoregional disease. The secondary end points were overall survival, progression-free survival, response rate and safety.|
|3.3||Final analyses of the trial showed that the 211 people in the cetuximab plus radiotherapy arm had a longer median duration of locoregional control than the 213 people in the radiotherapy-alone arm (24.4 versus 14.9 months, p = 0.005; hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.52 to 0.89), and greater median overall survival (49.0 months versus 29.3 months, p = 0.03, HR 0.74, 95% CI 0.57 to 0.97).|
|3.4||The manufacturer?s submission presented a de novo economic analysis that compared cetuximab plus radiotherapy with radiotherapy alone. The model used individual patient data from the RCT to estimate costs and health effects during the trial period for each patient. Where trial observations were censored, the model extrapolated costs and health effects.|
|3.5||The base-case analysis compared cetuximab plus radiotherapy with radiotherapy alone and resulted in an incremental cost effectiveness ratio (ICER) of £6,390 per quality adjusted life year (QALY). The manufacturer undertook a univariate sensitivity analysis, which demonstrated that the model was not sensitive to change when assessing uncertainty in a variety of inputs. Relatively large variability was observed when the timeframe of the analysis changed from a lifetime to the period of the trial follow-up, resulting in an ICER of £19,951 per QALY gained.|
|3.6||The Evidence Review Group (ERG) reviewed the evidence on clinical and cost effectiveness submitted by the manufacturer. The ERG judged that the one trial included in the manufacturer?s submission was well conducted and that the results for the primary end points appeared robust. However, the ERG noted that the trial population included a majority of patients with good performance status (Karnofsky performance score ranged from 60 to 100 but was most commonly 90), who would be expected to be suitable for chemoradiotherapy. Therefore, the population of the trial did not match the population described in the decision problem, that is, patients for whom chemoradiotherapy is considered inappropriate. Furthermore, there are differences between the radiotherapy regimens used predominantly in UK clinical practice and those that were used in the trial.|
|3.7||The ERG reviewed the economic model and identified a number of potential issues. The most important of these was that the only RCT informing the economic analysis did not match the patient population that was the focus of the manufacturer?s decision problem and that was reflected in the model. The manufacturer was requested to clarify the criteria to be used to define the group of patients who would be considered inappropriate for chemoradiotherapy but suitable for radiotherapy, and the number of patients in the RCT to which that definition would apply. The manufacturer provided a list of possible criteria for definition of patients who are inappropriate for chemoradiotherapy based on consultation with a number of oncologists. However, the manufacturer also stated that it was unable to provide analyses based on these criteria as the RCT was not designed or statistically powered to assess for sub-groups of patients who may be considered to be inappropriate for chemoradiotherapy treatment.|
|3.8||In addition, the ERG identified a series of issues and uncertainties about the methods for extrapolation of the trial data, assessment of health-related quality of life (HRQoL) and estimation of resource use and costs. The ERG concluded that the methods used were probably appropriate but was unable to determine, in the majority of cases, the likely influence of using alternative methods on the results of the economic model. However, the ERG concluded that altering the method of extrapolation would be unlikely to cause the ICER to increase above £20,000.|
|3.9||The ERG undertook additional work to examine the robustness of the base-case results to the assumptions made in the manufacturer?s cost-effectiveness model for HRQoL and resource use and cost. The ERG concluded that any inaccuracies would have to be very large to have a material effect on the conclusions of the manufacturer?s cost-effectiveness analysis.|
|3.10||Full details of all the evidence are in the manufacturer?s submission and the ERG report,|
|4||Consideration of the evidence|
|4.1||The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of cetuximab for the treatment of locally advanced squamous cell cancer of the head and neck, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of cetuximab by people with locally advanced squamous cell cancer of the head and neck, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.|
|4.2||The Committee considered the decision problem described in the manufacturer?s submission to be reasonable, but noted that the population specified excluded people for whom chemotherapy is suitable. Therefore the decision problem did not reflect the entire population of people with locally advanced squamous cell cancer of the head and neck for whom cetuximab might be considered as a treatment option.|
|4.3||The Committee considered current clinical practice in the treatment of locally advanced squamous cell cancer of the head and neck. It heard from the clinical specialist that chemoradiotherapy is the standard care for patients with stage lll and IV squamous cell cancer of the head and neck. However, there are patients for whom chemoradiotherapy is considered inappropriate because of co-existing medical conditions, poor performance status or age. Chemoradiotherapy (concomitant chemotherapy being either cisplatin or carboplatin-based) carries a high risk of adverse effects and requires patients to be willing and fit enough to cope with these. The clinical specialist and patient experts were of the opinion that for patients whose condition required an alternative to chemoradiotherapy, cetuximab plus radiotherapy was a useful option because of its relatively low toxicity profile compared with chemotherapy.|
|4.4||The Committee heard from the clinical specialist that there are considerable differences in practice across the UK. There are no clear definitions and criteria for patients for whom chemoradiotherapy is considered inappropriate and there are differences in the selection of initial treatment modality (surgery versus chemoradiotherapy), radiation dose intensities and the means of delivery of chemotherapy. More intensive radiotherapy regimens require suitable infrastructure and patients need to attend hospital all day (which some are unable to do).|
|4.5||The Committee considered the evidence on the clinical effectiveness of cetuximab in combination with radiotherapy for the treatment of locally advanced squamous cell cancer of the head and neck. It noted that there was only one relevant RCT, which compared cetuximab plus radiotherapy with radiotherapy alone in people with non-resected disease. No trials were available that compared cetuximab plus radiotherapy directly with chemoradiotherapy. The Committee accepted that cetuximab with radiotherapy had been shown to be more effective than radiotherapy alone in the relatively fit patient population represented in the trial. The Committee understood that chemoradiotherapy is considered to be standard treatment in patients with good performance status, and that cetuximab plus radiotherapy might have advantages over chemoradiotherapy in terms of reduced toxicity. However, in the absence of evidence comparing cetuximab plus radiotherapy with chemoradiotherapy the Committee could not recommend it as an alternative to chemoradiotherapy.|
|4.6||The Committee also considered the use of cetuximab in combination with radiotherapy in the sub-group of patients for whom chemoradiotherapy was unsuitable. The Committee noted that the manufacturer had not provided information on the number of patients in the RCT for whom chemoradiotherapy was considered inappropriate on the basis that the trial was not designed or statistically powered to identify these subgroups.|
|4.7||The Committee noted that most patients in the RCT had a Karnofsky performance score of 90 or more. It therefore considered the situations in which chemoradiotherapy (concomitant chemotherapy being either cisplatin or carboplatin-based) might not be not suitable for patients with good performance status and in doing that also reviewed the criteria provided by the manufacturer. The Committee concluded that there were likely to be few patients with a Karnofsky performance score of 90 or more who have contraindications to both chemoradiotherapy options.|
|4.8||The Committee considered the possibility that the subgroup with lower performance status might best represent the population for whom chemoradiotherapy would be considered inappropriate in clinical practice. However, it noted that no clinical benefit could be demonstrated in patients with a Karnofsky performance score of 80 or less based on the evaluation of the principal registration trial data presented in the ?European public assessment report? (EPAR) published by the regulatory authority, the European Medicines Agency (EMEA). The Committee noted that the EMEA had considered it credible that cetuximab had a poorer add-on effect in patients with poor performance status. In addition, the Committee heard from the clinical specialist that those patients with contraindications to chemoradiotherapy would represent a higher-risk population with shorter median survival. It concluded that the absolute benefit, and therefore the cost-effectiveness of treatment, in this sub-group might be expected to be considerably less than was suggested by the modelling. The Committee concluded that there was no evidence to support the use of cetuximab in combination with radiotherapy for people with low performance status.|
|4.9||The Committee was not persuaded that the evidence presented provided a robust demonstration of the clinical and cost effectiveness of cetuximab plus radiotherapy compared with radiotherapy alone for patients with locally advanced squamous cell cancer of the head and neck for whom chemoradiotherapy is contraindicated.|
|5.1||The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ?Standards for better health? issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.|
|5.2||'Healthcare Standards for Wales? was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months|
|5.3||NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued]|
|6||Proposed recommendations for further research|
|6.1||The Committee recommended that head-to-head trials of cetuximab in combination with radiotherapy versus chemoradiotherapy be conducted.|
7.1 NICE has issued the following cancer service guidance.
Improving outcomes in head and neck cancer. NICE cancer service guidance (November 2004).
|8||Proposed date for review of guidance|
|8.1||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.|
|8.2||It is proposed that the guidance on this technology is considered for review in June 2010. The Institute would particularly welcome comment on this proposed date.|
Chair, Appraisal Committee
Appendix A. Appraisal Committee members and NICE project team
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 three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. 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.
Professor David Barnett
Dr David W Black
Mr Brian Buckley
Dr Carol Campbell
Dr Peter Clarke
Dr Christine Davey
Dr Mike Davies
Mr Richard Devereaux-Phillips
Dr Rachel A Elliott
Mrs Eleanor Grey
Dr Dyfrig Hughes
Dr Catherine Jackson
Dr Peter Jackson
Professor Peter Jones
Professor Jonathan Michaels
Dr Eugene Milne
Dr Simon Mitchell
Dr Richard Alexander Nakielny
Dr Martin J. Price
Mr Miles Scott
Professor Mark Sculpher
Professor Andrew Stevens
B. NICE Project Team
Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical advisor and a project manager.
Appendix B. Sources of evidence considered by the Committee
The following manufacturer/sponsor provided a submission for this appraisal.
The evidence review group report for this appraisal was prepared by Centre for Health Economics, University of York & NHS Northern and Yorkshire Regional Drug and Therapeutics Centre, Newcastle.
The following individuals were selected from clinical specialist and patient advocate nominations from the professional/specialist and patient/carer groups. They gave their expert personal view on cetuximab by providing written and oral evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).
Appendix C. List of organisations involved in this appraisal
The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the ACD and consultee organisations are provided with the opportunity to appeal against the FAD:
Commentator organisations (without the right of appeal):
This page was last updated: 30 March 2010