Colorectal cancer (advanced) - bevacizumab & cetuximab (appraisal consultation document)
Appraisal Consultation Document
Bevacizumab and cetuximab for metastatic colorectal cancer
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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 an appraisal of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer and provide guidance on their 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 bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. 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 these technologies.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 | Bevacizumab in its licensed indication (that is, in combination with 5-fluorouracil/folinic acid with or without irinotecan) is not recommended for the first-line treatment of metastatic colorectal cancer. |
| 1.2 | Cetuximab in its licensed indication (that is, in combination with irinotecan) is not recommended for the second-line or subsequent treatment of metastatic colorectal cancer. |
| 2 | Clinical need and practice |
| 2.1 | Colorectal cancer is a malignant neoplasm arising from the lining (mucosa) of the large intestine (colon and rectum). Colorectal cancer is the third most common cancer in the UK, with approximately 30,000 new cases registered in England and Wales in 2002. This represents 12% of all new cancer cases in women and 14% of all new cancer cases in men. The incidence of colorectal cancer increases with age. In people between the ages of 45 and 49 years the incidence is 20 per 100,000. Amongst those over 75 years of age, the incidence is over 300 per 100,000 for men and 200 per 100,000 per year for women. The median age of patients at diagnosis is over 70 years. The overall 5-year survival rate for colorectal cancer in England and Wales is approximately 50%; however, large differences in survival exist according to the stage of disease at diagnosis. |
| 2.2 | Metastatic colorectal cancer, where the tumour has spread beyond the confines of the lymph nodes to other parts of the body, is generally defined as stage IV of the American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system or stage D of Dukes? classification. |
| 2.3 | The population of patients with metastatic colorectal cancer includes both those who present with metastatic disease and those who develop metastatic disease after surgery. Estimates of people presenting with metastatic colorectal cancer range from 20% to 55% of new cases. Out of those who have undergone surgery for colorectal cancer with apparently complete excision, approximately 50% will eventually develop advanced disease and distant metastases (typically presenting within 2 years of initial diagnosis). The 5-year survival rate for metastatic colorectal disease is 12%. |
| 2.4 | The management of metastatic colorectal cancer is mainly palliative and involves a combination of specialist treatments (such as palliative surgery, chemotherapy and radiation), symptom control and psychosocial support. The aim is to improve both the duration and quality of the individual?s remaining life. Clinical outcomes such as overall survival, response and toxicity are important, but alternative outcomes such as progression-free survival, quality of life, convenience, acceptability and patient choice are also important. |
| 2.5 | The most frequent site of metastatic disease is the liver. In up to 50% of patients with metastatic disease, the liver may be the only site of spread. For these patients surgery provides the only chance of longer-term survival. Approximately 10% of patients with metastatic colorectal cancer present with potentially resectable liver metastases and for approximately 14% chemotherapy may render unresectable liver metastases operable. |
| 2.6 | Individuals with metastatic disease who are sufficiently fit (those with World Health Organization performance status 2 or better) are usually treated with active chemotherapy as first- or second-line therapy. First-line active chemotherapy options include infusional 5-fluorouracil + folinic acid or leucovorin (calcium folinate) (5-FU/FA, 5-FU/LV), oxaliplatin + infusional 5 FU/FA (FOLFOX), and irinotecan + infusional 5-FU/FA (FOLFIRI). For those patients first receiving FOLFOX, irinotecan may be a second-line treatment option, whereas for patients first receiving FOLFIRI, FOLFOX may be a second-line treatment option (in accordance with its licensed indication). Patients receiving 5-FU/FA or oral therapy (capecitabine or tegafur with uracil) as first-line treatment may receive treatment with FOLFOX and irinotecan as second-line and subsequent therapies. |
| 2.7 | Survival estimates for patients with metastatic colorectal cancer receiving best supportive care are approximately 6 months. The use of infusional 5-FU/FA can increase survival to approximately 10-12 months, whereas combinations of FOLFIRI followed by FOLFOX, or FOLFOX followed by irinotecan, have been reported to increase survival to 20-21 months. |
| 3 | The technology |
| 3.1 | Bevacizumab |
| 3.1.1 | Bevacizumab (Roche Products) is a recombinant humanised monoclonal IgG1 antibody that acts as an angiogenesis inhibitor. It targets the biological activity of human vascular endothelial growth factor, which stimulates new blood vessel formation in the tumour. Bevacizumab is licensed in the UK in combination with intravenous 5-FU/FA with or without irinotecan for first-line treatment of patients with metastatic carcinoma of the colon or rectum. |
| 3.1.2 | Bevacizumab is contraindicated in patients who are pregnant, have untreated central nervous system metastases, have hypersensitivity to the active substance or to any of the excipients, or have hypersensitivity to products derived from Chinese hamster ovary cell cultures or other recombinant human or humanised antibodies. The ?Summary of Product Characteristics? (SPC) lists the following conditions that may be associated with bevacizumab treatment: gastrointestinal perforation, wound healing problems, hypertension, proteinuria, arterial thromboembolism, haemorrhage and cardiomyopathy. For full details of side effects and contraindications, see the SPC. |
| 3.1.3 | Bevacizumab is administered as an intravenous infusion at a dose of 5 mg/kg body weight once every 14 days. Bevacizumab treatment is recommended until there is underlying disease progression. The net price for a 100 mg vial is £242.66 (excluding VAT; British National Formulary, 50th edition). If vial wastage is assumed, a 75 kg person would receive four vials of bevacizumab per dose, equating to a cost of £970.64. Patients in the key registration trial received an average of 18.2 doses, equating to an average total cost of drug acquisition of £17,665.65 per patient. Costs may vary in different settings because of negotiated procurement discounts. |
| 3.2 | Cetuximab |
| 3.2.1 | Cetuximab (Merck Pharmaceuticals) is a recombinant monoclonal antibody that blocks the human epidermal growth factor receptor (EGFR) and thus inhibits the proliferation of cells that depend on EGFR activation for growth. Cetuximab is licensed in the UK in combination with irinotecan for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of cytotoxic therapy that included irinotecan. |
| 3.2.2 | The UK marketing authorisation stipulates that before being treated with cetuximab patients should be tested to identify whether or not the tumour is expressing EGFR. This is currently done using the commercially available DakoCytomation kit, which uses immunohistochemistry to identify EGFR expression (£995.00 for a set of 35 tests [information supplied by manufacturer]). |
| 3.2.3 | One common side effect of cetuximab therapy is the development of an acne-like rash. The SPC notes that if a patient experiences a grade 3 or 4 skin reaction cetuximab treatment must be interrupted, with treatment being resumed only if the reaction resolves to grade 2. In addition, the SPC lists infusion-related reactions and respiratory disorders that may be associated with treatment with cetuximab. For full details of side effects and contraindications, see the SPC. |
| 3.2.4 | Cetuximab is given as an intravenous infusion with an initial loading dose of 400 mg/m2 of body surface area and subsequent weekly doses of 250 mg/m2. Cetuximab treatment is recommended until there is underlying disease progression. Cetuximab is provided in 50 ml vials containing 2 mg cetuximab per ml. The net price for a 50 ml vial is £136.50 (excluding VAT; British National Formulary, 50th edition). Assuming vial wastage, an average person with body surface area of 1.75 m2 would receive seven vials per loading dose and five vials per maintenance dose, equating to a cost of £955.50 for the loading dose and £682.50 for each maintenance dose. Patients in the key registration trial received an average of 16.8 doses, equating to an average total drug acquisition cost of £11,739 per patient. Costs may vary in different settings because of negotiated procurement discounts. |
| 4 | Evidence and interpretation |
| 4.1 | Clinical effectiveness |
| Bevacizumab | |
| 4.1.1 |
Three randomised controlled trials (RCTs) have investigated the effectiveness of bevacizumab as a first-line treatment for metastatic colorectal cancer.
For two of the studies the primary end point was overall survival, while in the smaller study that used 5-FU/LV as the comparator the primary end points were time to disease progression and best tumour response. In all three studies participants tended to have a good performance status (Eastern Cooperative Oncology Group [ECOG] status 0 or 1; unrestricted by disease or only restricted in strenuous physical activity), although in the larger study that used 5-FU/LV as a comparator, 7% had an ECOG status of 2 (ambulatory and capable of all self-care but unable to carry out any work activities). |
| 4.1.2 | Data taken from the manufacturer?s submission are based on analyses taken directly from the clinical trials database, which is subject to updates and revisions. Therefore in some instances the results presented here differ from the results in earlier published journal articles. |
| 4.1.3 | The addition of bevacizumab to IFL led to a statistically significant difference in median overall survival compared with IFL alone (20.3 months vs 15.6 months, respectively; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54 to 0.81). In the studies that used 5-FU/LV as comparator there were no statistically significant differences in median overall survival. In the larger study the median overall survival in the bevacizumab-containing arm was 16.6 months compared with 13.2 months in the control arm (HR 0.77, 95% CI 0.56 to 1.05). In the smaller study the median overall survival in the bevacizumab containing arm was 17.7 months compared with 13.6 months in the control arm (HR 0.52, 95% CI not reported; p = 0.07). |
| 4.1.4 | Progression-free survival (which was defined as time from randomisation until tumour progression or death) was measured in two of the studies. In both, there was a statistically significant difference in median progression-free survival. In the study comparing bevacizumab and IFL with IFL alone, the median progression-free survival was 10.6 months in the bevacizumab arm and 6.2 months in the control arm (HR 0.54, 95% CI 0.45 to 0.66). In the larger study comparing bevacizumab and 5-FU/LV with 5-FU/LV alone, the median progression-free survival was 9.2 months in the bevacizumab arm and 5.5 months in the control arm (HR 0.50, 95% CI 0.34 to 0.73). The smaller study that used 5-FU/LV as a comparator reported the median time to disease progression. There was a statistically significant difference favouring the bevacizumab arm over the control arm (9.0 months vs 5.2 months, respectively [HR 0.44, 95% CI not reported; p=0.005]). |
| 4.1.5 | All three studies measured tumour response rate (as partial or complete reduction in tumour size). In two studies, the differences in tumour response rate reached statistical significance. In the study with IFL as a comparator, the tumour response rate in the bevacizumab arm was 44.8% compared with 34.8% in the control arm (incremental difference 10.0%, 95% CI 3.3 to 16.7). In the smaller study that used 5-FU/LV as a comparator, the tumour response rate was 40.0% in the bevacizumab arm and 16.7% in the control arm (incremental difference 23.3%, 95% CI not reported; p = 0.029). In the larger study that used 5-FU/LV as a comparator, the difference in tumour response rate did not reach statistical significance (26.0% and 15.2% for treatment and control arms, respectively [incremental difference 10.8%, 95% CI not reported; p=0.055]). |
| 4.1.6 |
In all the studies there was a higher incidence of grade 3 and 4 adverse events in the groups receiving bevacizumab than in the control groups:
Higher incidences of grade 3 and 4 hypertension were also reported in the groups receiving bevacizumab than in the control groups:
For other grade 3 and 4 toxicities there were no consistent patterns of effects. An increased incidence of diarrhoea was reported in the study that used IFL as the comparator (32.4% vs 24.7%), and there was an increased incidence of thrombotic events in the smaller study that used 5-FU/LV as the comparator (14.3% vs 2.9%). |
| Cetuximab | |
| 4.1.7 | The assessment group identified no studies that compared cetuximab with current standard treatments (FOLFOX or active/best supportive care [ASC/BSC]). One RCT was identified that compared cetuximab monotherapy with cetuximab combined with irinotecan (n = 329). Three single-arm studies were also identified, two of which measured the effect of cetuximab monotherapy (one with 346 participants and one with 57 participants) and one that measured the effect of cetuximab combined with irinotecan (n = 138). The primary outcome for all studies was tumour response rate. The participants included in the studies tended to be younger than the average age of patients receiving chemotherapy in England and Wales; a median age of 56 years was reported in two of the trials and a median age of 59 years in the other two. In all four studies the populations tended to have good performance status (ECOG 0 to 1 or Karnofsky 80 to 100). |
| 4.1.8 | In the RCT there was no statistically significant difference in median overall survival between treatment groups. The median overall survival was 8.6 months in the cetuximab plus irinotecan arm and 6.9 months in the cetuximab monotherapy arm (HR 0.91, 95% CI 0.68 to 1.21). In the single-arm studies of cetuximab monotherapy, the median survival duration was 6.6 months (95% CI 5.6 to 7.6) in the larger and 6.4 months (95% CI 4.1 to 10.8) in the smaller. In the single-arm study of cetuximab plus irinotecan, median overall survival duration was 8.4 months (95% CI 7.2 to 10.3). |
| 4.1.9 | In the RCT there was a statistically significant difference in median time to progression between treatment groups. The median time to progression was 4.1 months in the cetuximab combined with irinotecan arm and 1.5 months in the cetuximab monotherapy arm (HR 0.54, 95% CI 0.42 to 0.71). Median time to progression was reported in two of the single-arm studies: 1.4 months (95% CI 1.3 to 2.8) in the larger cetuximab monotherapy study and 2.9 months (95% CI 2.6 to 4.1) for cetuximab combined with irinotecan. |
| 4.1.10 | All four cetuximab studies measured tumour response rate. In the controlled study there was a statistically significant difference between treatment groups. Tumour response rate was 22.9% in the cetuximab combined with irinotecan arm and 10.8% in the cetuximab monotherapy arm (incremental difference 12.1%, 95% CI 4.1 to 20.2). The rate of response in the single-arm studies were 8.8% (95% CI 2.9 to 19.3) and 12.0% (95% CI 8.4 to 15.4) in the two cetuximab monotherapy studies and 15.2% (95% CI 9.7 to 22.3) in the study that combined cetuximab with irinotecan. |
| 4.1.11 | Data from the manufacturer?s submission suggest that the response to cetuximab may be associated with an acne-like rash. Post hoc analyses of pooled data from the two studies in which patients received cetuximab combined with irinotecan (combined total of 339 patients) show 153 patients had stable disease at 6 weeks, of who 50% had an acne-like rash of grade 2 or above (n=76). Of these, 26% (n = 20) went on to get a partial response compared with 13% (n = 10) of those without an acne-like rash of grade 2 or above (p = 0.043). |
| 4.1.12 | Data in the RCT show that patients in the cetuximab plus irinotecan arm with an acne-like rash of grade 2 or above had an overall survival of 10.8 months compared with 5.8 months for those with either no rash or a grade 1 rash. In the single-arm study of cetuximab plus irinotecan, patients who had a grade 3 acne-like rash had a median survival of 13.1 months, compared with 10.6 months for those with a grade 2 rash, 6.2 months for those with grade 1 rash and 4.3 months for those with no rash (p = 0.0008, grade 0 vs grade 1-3). |
| 4.1.13 | In the RCT the incidence of some adverse events was higher in patients receiving cetuximab plus irinotecan than in those receiving cetuximab alone: grade 3 and 4 adverse events (65.1% vs 43.5%); diarrhoea (21.2% vs 1.7%); neutropenia (9.4% vs 0%); grade 3 or 4 acne-like rash (9.4% vs 5.2%). |
| 4.2 | Cost effectiveness |
| 4.2.1 | No published economic analyses of either bevacizumab or cetuximab were identified. The manufacturers of bevacizumab and cetuximab both submitted cost-effectiveness models, and the assessment group developed two models for each drug. Bevacizumab ? manufacturer?s models |
| 4.2.2 | The manufacturer submitted two simple-state transition models with three health states: pre-progression, post-progression and death. Each model was based on data from a different bevacizumab study. The first was based on the study that compared bevacizumab plus IFL with IFL, while the second was based on the larger of the two studies that compared bevacizumab plus 5 FU/LV with 5-FU/LV. In both models the analysis was carried out from the perspective of the NHS. Data on progression-free survival for the treatment and control arms were taken from trial data, and an equal risk of death was applied following progression irrespective of treatment group. The models assumed equivalent utility scores for both the intervention and control groups, with a utility of 0.80 given to the pre-progression health state and 0.50 to the post-progression health state. Utility decrements associated with adverse events were not included. Pre-progression costs were calculated from the trials, augmented with data from other published sources. For post-progression costs an assumption of £2000 a month was used, applied equally to both arms. |
| 4.2.3 | With discounting for 6% for costs and 1.5% for benefits, the cost per quality-adjusted life year (QALY) gained was £88,364 for bevacizumab combined with IFL compared with IFL alone. With the same discounts, the cost per QALY gained for bevacizumab combined with 5-FU/LV was £56,628 compared with 5-FU/LV alone. One-way sensitivity analyses resulted in estimates of cost per QALY gained of between £82,577 and £106,770 for bevacizumab combined with IFL, and between £39,136 and £69,439 for bevacizumab combined with 5-FU/LV. Probabilistic sensitivity analyses suggest that the likelihood of cost effectiveness at a willingness-to-pay of £30,000 per QALY is 0.16 for bevacizumab combined with IFL, and 0.24 for bevacizumab combined with 5-FU/LV. |
| Bevacizumab ? assessment group models | |
| 4.2.4 | The methods used for the models produced by the assessment group were similar to those used in the NICE appraisal of irinotecan, oxaliplatin and raltitrexed (technology appraisal TA 93). The assessment group presented two models based on the same trials as used in the manufacturer?s models. The models were simple-state transition models with costs and effects calculated from the perspective of the NHS. Unlike the manufacturer?s models the outcome data were based on published overall survival curves from the two studies. The utility value for pre-progression was the same as used in the manufacturer?s models (0.80), whereas that for post-progression was slightly higher (0.60). Data on second-line and subsequent therapies were taken from a study that investigated the optimal sequence of FOLFOX and FOLFIRI as first- and second-line therapies, and were applied equally to treatment and control groups. Costs were calculated from study data and augmented from a range of sources including published literature and personal communications. No discounting was used in the models because the distribution of costs incurred over time was unknown. An additional sensitivity analysis was carried out in response to comments from the manufacturer describing proposals for a registry programme in which the administration costs of bevacizumab and other associated infusional drugs would be covered by the manufacturer. In this sensitivity analysis the administration costs were therefore reduced to zero. |
| 4.2.5 | The base case costs per QALY gained for the assessment group models were £62,857 for bevacizumab combined with IFL and £88,436 for bevacizumab combined with 5-FU/LV, compared with IFL or 5-FU/LV alone, respectively. Sensitivity analyses based on the proposals for the registry programme produced costs per QALY gained of £49,197 for bevacizumab combined with irinotecan and £69,045 for bevacizumab combined with 5-FU/LV. One-way sensitivity analyses of the base case produced a cost per QALY gained of £60,430?£76,831 for bevacizumab combined with IFL, and £51,355 and higher for bevacizumab combined with 5-FU/LV. Probabilistic sensitivity analyses suggest that, with a willingness-to-pay threshold of £30,000, the likelihood of bevacizumab being cost effective is zero. |
| 4.2.6 | The differences in the costs per QALY gained between the assessment group?s and manufacturer?s models is likely to be caused by different ways of calculating survival. The manufacturer?s model resulted in more favourable estimates of costs per QALY than the assessment group?s when the comparator was 5-FU/LV because the difference in progression-free survival was greater than the difference in mean overall survival. Conversely, the assessment group?s model results in more favourable costs per QALY estimates when the comparator was IFL, because the difference in overall survival was greater than the difference in progression-free survival. |
| Cetuximab ? manufacturer?s model | |
| 4.2.7 | The manufacturer?s model for cetuximab used survival modelling to estimate the lifetime costs and benefits for patients receiving cetuximab combined with irinotecan compared with ASC/BSC. Two sets of analyses were presented. The first was based directly on survival data from the RCT, whereas in the second analysis adjustments were made to the survival data to reflect a proposed continuation rule. Under the continuation rule patients would only continue to receive cetuximab beyond 6 weeks if there is either a partial or complete tumour response or an acne-like rash of grade 2 or above. |
| 4.2.8 | The duration of survival of patients receiving cetuximab combined with irinotecan was extrapolated from data in the RCT. The survival of patients receiving ASC/BSC was calculated from the survival of the patients in the cetuximab monotherapy arm of the RCT. The data from the monotherapy arm were adjusted to remove the impact of cetuximab using an HR taken from an RCT of second-line irinotecan compared with ASC/BSC. Therefore the model assumes that the relative hazard of overall survival between cetuximab monotherapy and ASC/BSC as second-line and subsequent treatment is exactly equivalent to the relative survival hazard between irinotecan and ASC/BSC as second-line treatment. The modelling was carried out from the perspective of the NHS, with costs and resource data taken from the RCT comparing cetuximab monotherapy with cetuximab plus irinotecan and augmented from the published literature. Outcomes were presented as life years gained, with three sensitivity analyses to examine the impact of quality of life assuming utility of either 0.95 or 0.71 constant over the life time based on published data, or [information held as CIC until June 30th] based on unpublished data from the MABEL trial. Costs and benefits were discounted at an annual rate of 3.5%. |
| 4.2.9 | The base case analysis suggests a cost per life year gained of £33,263 if the continuation rule were applied. One-way sensitivity analyses present costs per QALY estimates of £35,014 with a utility value of 0.95, £46,849 with a utility value of 0.71 or [information held as CIC until June 30th]. Cost-effectiveness acceptability curves suggest that at a willingness-to-pay threshold of £30,000 per life year gained the likelihood of cost effectiveness is 0.10. |
| Cetuximab assessment group models | |
| 4.2.10 | In the absence of direct comparisons of cetuximab plus irinotecan with ASC/BSC or FOLFOX, the assessment group developed two models. The first was a threshold analysis considering the incremental benefit that cetuximab combined with irinotecan would have to provide over ASC/BSC in order to be considered cost effective. The second model was an indirect comparison of data from the arm receiving cetuximab and irinotecan in the controlled study of cetuximab with data from other published studies of second-line ASC/BSC. |
| 4.2.11 | Overall survival in both models was estimated from patient-level data in the RCT. In the threshold analysis, the survival of patients receiving ASC/BSC was held as an unknown variable, whereas in the indirect comparisons different values for mean overall survival were taken from three published studies. Health-related quality of life was estimated in the same way as in the bevacizumab model, applying a utility of 0.80 to pre-progression disease states and 0.60 to post-progression states. For the cetuximab arm, measures of the quantity of pre-progression survival as a proportion of overall survival were estimated using data from the RCT. For the comparator arm, they were derived from a trial that compared the farnesyl transferase inhibitor R115777 and BSC in refractory advanced colorectal cancer. In this study the duration of pre- progression survival was approximately 37% of overall survival. Resource use and costs were taken from the controlled study as reported in the manufacturer?s submission and augmented from the published literature and personal communication with clinical experts. Discounting was not used in the model. |
| 4.2.12 | The base case threshold analysis suggests it is not possible for cetuximab combined with irinotecan to have a cost per QALY gained of less than £20,000, irrespective of the application of the continuation rule. When the proposed continuation rule is applied, cetuximab plus irinotecan must provide 0.65 additional life years (7.8 months) compared with ASC/BSC in order to achieve a cost per QALY gained of £30,000. This would imply that survival for patients receiving ASC/BSC would have to be 0.14 life years (1.7 months) or less. It was not possible to achieve a cost per QALY gained of less than £30,000 without the continuation rule. Indirect comparisons are associated with a high level of uncertainty, but they yielded costs per QALY gained that ranged from £77,210 to £370,044. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab and cetuximab for metastatic colorectal cancer, having considered evidence on the nature of the condition and the value placed on the benefits of bevacizumab and cetuximab by people with metastatic colorectal cancer, those who represent them, 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 heard from clinical specialists that it is accepted that multiple chemotherapy treatments lead to incremental gains in survival if patients are sufficiently fit to receive therapy. The Committee further heard from clinical specialists that treatment regimens frequently involve combination therapy with 5-FU/FA and irinotecan or oxaliplatin as first-line therapies, followed where patients are sufficiently fit by irinotecan as a second line therapy where oxaliplatin has been given and by oxaliplatin plus 5-FU/FA as a second-line therapy where irinotecan has been given. The experts argued that it would be of merit to add further options and lines of therapy to this sequence. |
| Bevacizumab. | |
| 4.3.3 | The Committee reviewed the clinical effectiveness evidence from the bevacizumab studies and noted that the age of the population in the largest study was lower than the age of patients normally receiving chemotherapy in England and Wales. However, clinical specialists agreed that fitness, rather than age, was the primary factor when considering whether chemotherapy is appropriate. The Committee therefore agreed that the patients included in the bevacizumab trials could be considered to reflect a population of relatively fit patients with metastatic colorectal cancer in England and Wales. |
| 4.3.4 | The Committee noted that all bevacizumab studies demonstrated statistically significant gains in progression-free survival and that some studies also demonstrated statistically significant gains in overall survival and tumour response rate. However, the Committee was aware that the comparators in the studies cannot be considered current standard practice in the NHS in England and Wales because the 5-FU treatment schedules involved administration by bolus rather than administration by infusion. It heard from clinical specialists that the benefits associated with bevacizumab in combination with bolus 5-FU are expected to be seen in infusional regimens because the two drugs have different mechanisms of action and their effects are therefore likely to be independent. This was also said to be supported by interim results from ongoing clinical studies. The Committee was therefore persuaded that the results seen in the studies could be considered generalisable to NHS practice in England and Wales. |
| 4.3.5 | The Committee then considered the estimates of cost effectiveness of bevacizumab. It noted that the models from the manufacturer and assessment group were similar in their methods and data sources; the models differed chiefly in their use of progression-free survival and overall survival, respectively, as the primary outcome data. The Committee noted that this difference resulted in different estimates of cost effectiveness between the manufacturer and assessment group. However, the Committee considered that neither source resulted in a cost-effectiveness estimate that was compatible with the best use of NHS resources. |
| 4.3.6 | The Committee also considered proposals for the registry programme proposed by the manufacturer, which included a payment to cover the administration costs of receiving bevacizumab therapy. The Committee noted the uncertainties around the long-term implementation of such a programme. Irrespective of these concerns, the costs per QALY gained remained above levels considered compatible with the best use of NHS resources. The Committee therefore concluded that bevacizumab in combination with 5 FU/FA with or without irinotecan as a first-line treatment for metastatic colorectal cancer would not be a cost-effective use of NHS resources |
| Cetuximab | |
| 4.3.7 | The Committee considered the clinical effectiveness evidence from the cetuximab studies. The Committee was mindful that there was a group of patients eligible for cetuximab for whom there were no other active chemotherapies currently available. It recognised that some of these patients may still have a high performance status, meaning that further chemotherapy regimens could be considered appropriate. The Committee heard from clinical specialists and patient experts that they believed cetuximab could prolong survival for a number of months where the disease responded to the drug. |
| 4.3.8 | The Committee was concerned that there were no studies that compared cetuximab with current standard care. The Committee heard testimonies from clinical experts that progression-free survival and tumour response without treatment in patients who had exhausted other chemotherapy options were likely to be negligible. They were therefore persuaded that cetuximab demonstrated some evidence of effectiveness. However, the relative effectiveness against current standard care remains uncertain. |
| 4.3.9 | The Committee heard from patient experts and clinical specialists about the impact of the acne-like rash associated with treatment on patients? quality of life. They heard from patient experts that, for some patients, the side effects of the drugs were tolerated willingly because of the perceived benefit, whereas for others the side-effect profile may be more of a consideration. The Committee heard from clinical specialists that the acne-like rash was generally well managed with antibiotics, treatment breaks or dose reduction. The Committee was therefore satisfied that the side-effect profile of cetuximab should not be a determining factor in their deliberations. |
| 4.3.10 | The Committee noted the contradiction that although the UK marketing authorisation stipulates that patients need to be tested for the presence of EGFR, the presence of EGFR does not predict response to treatment. However, the Committee heard from clinical specialists that this reflected increasing knowledge of the mechanism of action of cetuximab and that it is now thought that the antibody identified through EGFR testing is different from that which cetuximab targeted. The Committee noted the difficulties in identifying patients who were likely to respond to cetuximab, but was fully aware that decisions about its use in the NHS would have to be based on the current licensed indication. |
| 4.3.11 | The Committee considered the continuation rule proposed by the manufacturer. The Committee expressed concern about conflicts with the SPC, but it agreed that this would only be an issue for the small proportion of patients who experience grade 3 and 4 acne rash. Although it acknowledged that there was some evidence to suggest that the presence of a rash may predict response to cetuximab, the Committee had reservations about using it to decide whether to continue or discontinue treatment because no studies have so far prospectively tested the continuation rule. |
| 4.3.12 | The Committee considered the cost-effectiveness evidence for cetuximab. It agreed that cost-effectiveness estimates provided by both the manufacturer and the assessment group were not compatible with the best use of NHS resources. The Committee also noted that these estimates were associated with a high level of uncertainty because they were based on indirect comparisons. The Committee therefore considered the threshold analysis completed by the assessment group, where the survival in the comparator arm was held as unknown. The threshold analysis suggested that, with the application of the continuation rule, cetuximab would need to provide an additional 7.8 months of survival over ASC/BSC to achieve a cost per QALY gained of £30,000. This could only be achieved if survival with ASC/BSC is less than 2 months, which was agreed to be an unrealistic assumption. Considering all available evidence on the clinical and cost effectiveness evidence, the Committee therefore concluded that cetuximab as a second-line and subsequent treatment for metastatic colorectal cancer would not be a cost-effective use of NHS resources. |
| 5 | Implementation |
| 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 |
| Ongoing research | |
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Ongoing research includes investigations of bevacizumab and cetuximab as part of different treatment regimens. A list of a number of these studies is given below.
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| Recommendations for research | |
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The Committee considered that the following investigations would be of value.
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| 7 | Related guidance |
| 7.1 | NICE has issued the following related guidance. |
| Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. NICE Technology Appraisal Guidance no. 93 (2005). Available from www.nice.org.uk/TA093 | |
| Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE Technology Appraisal Guidance no. 61 (2003). Available from www.nice.org.uk/TA061 | |
| Improving outcomes in colorectal cancers: manual update. Guidance on Cancer Services (2004). Available from www.nice.org.uk/csgcc |
| 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 May 2009 to reflect the rate of change surrounding the use of the technologies. The Institute would particularly welcome comment on this proposed date. |
| Andrew Stevens |
| Chair, Appraisal Committee |
| May 2006 |
| Appendix A. Appraisal Committee members |
| 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 regularly and 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 Darren Ashcroft Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester |
| Professor David Barnett Professor of Clinical Pharmacology, University of Leicester |
| Dr Peter Barry Consultant in Paediatric Intensive Care, Leicester Royal Infirmary |
| Mr Brian Buckley Vice Chairman, InContact |
| Professor John Cairns Public Health and Policy, London School of Hygiene and Tropical Medicine |
| Professor Mike Campbell Statistician, University of Sheffield |
| Professor David Chadwick Professor of Neurology, Walton Centre for Neurology and Neurosurgery |
| Dr Mark Chakravarty Head of Government Affairs and NHS Policy, Procter and Gamble Pharmaceuticals (UK) Ltd |
| Dr Peter I Clark Consultant Medical Oncologist, Clatterbridge Centre for Oncology, Merseyside |
| Dr Mike Davies Consultant Physician, University Department of Medicine & Metabolism, Manchester Royal Infirmary |
| Mr Richard Devereaux-Phillips Public Affairs Manager, Medtronic Ltd |
| Professor Jack Dowie Health Economist, London School of Hygiene |
| Dr Fergus Gleeson Consultant Radiologist, The Churchill Hospital, Oxford |
| Ms Sally Gooch Former Director of Nursing & Workplace Development, Mid Essex Hospital Services NHS Trust |
| Mr Sanjay Gupta Stroke Services Manager, Basildon and Thurrock University Hospitals NHS Trust |
| Professor Philip Home Professor of Diabetes Medicine, University of Newcastle upon Tyne |
| Dr Peter Jackson Clinical Pharmacologist, University of Sheffield |
| Professor Peter Jones Professor of Statistics & Dean Faculty of Natural Sciences, Keele University |
| Dr Mike Laker Medical Director, Newcastle Hospitals NHS Trust |
| Dr George Levvy Chief Executive, Motor Neurone Disease Association, Northampton |
| Ms Rachel Lewis Nurse Advisor to the Department of Health |
| Mr Terence Lewis Mental Health Consultant, National Institute for Mental Health in England Professor |
| Jonathan Michaels Professor of Vascular Surgery, University of Sheffield |
| Dr Neil Milner General Medical Practitioner, Sheffield |
| Dr Ruairidh Milne Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology |
| Dr Rubin Minhas General Practitioner, CHD Clinical Lead, Medway PCT |
| Dr Rosalind Ramsay Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital |
| Mr Miles Scott Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust |
| Dr Lindsay Smith General Practitioner, East Somerset Research Consortium |
| Mr Roderick Smith Director of Finance, Adur, Arun and Worthing PCT |
| Dr Ken Stein Senior Lecturer, Peninsula Technology Assessment Group (PenTAG), University of Exeter |
| Professor Andrew Stevens (Chair) Professor of Public Health, University of Birmingham |
| NICE Project Team |
| Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute. |
| Zoe Garrett Technical Lead, NICE project team |
| Elisabeth George Technical Advisor, NICE project team |
| Emily Marschke Project Manager, NICE project team |
| Appendix B. Sources of evidence considered by the Committee | |
| A The assessment report for this appraisal was prepared by School of Health and Related Research (ScHARR), The University of Sheffield: | |
| I Paul Tappenden, Roy Jones, Suzy Paisley, and Chris Carroll: ?The use of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer?, 21 February 2006. | |
| 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 and consultee organisations are provided with the opportunity to appeal against the Final Appraisal Determination. | |
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I Manufacturers/sponsors:
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II Professional/specialist and patient/carer groups:
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III National Council for Palliative Care
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IV Commentator organisations (without the right of appeal):
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A 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 Bevacizumab and cetuximab for the treatment of advanced colorectal cancer by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document.
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This page was last updated: 30 March 2010