Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the School of Health and Related Research, the University of Sheffield (see the "Companion Documents" field).
Clinical Effectiveness
Search Strategy
The searches aimed to identify all literature relating to the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of metastatic colorectal cancer (CRC) (see Appendix 4 of the Assessment Report [see "Availability of Companion Documents" field). The main searches were conducted in April and May 2005. No language, study/publication, or date restrictions were applied to the main searches. Searches were performed in Medline, Embase, CINAHL, BIOSIS, the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Controlled Trials Register (CCTR), the Science Citation Index and the National Health Services (NHS) Centre for Reviews and Dissemination databases (DARE, NHS, EED, HTA) and OHE HEED.
Inclusion and Exclusion Criteria
Phase III and Phase II randomised controlled trials (RCT) were included if they compared any of the proposed interventions with existing recommended comparators. Primary outcomes were identified as overall survival and/or progression-free survival. Secondary outcomes were identified as health-related quality of life, tumour response rates and adverse events. The use of data from Phase II studies and non-randomised studies was considered only where there was insufficient evidence from good quality Phase III trials, the former being studies appropriately powered to assess efficacy outcomes, rather than those directly associated with clinical effectiveness, and both being subject to selection bias.
For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment with bevacizumab. Only trials which compared bevacizumab in combination with irinotecan and/or established fluorouracil-containing or releasing regimens given as first-line therapy were included in this review.
For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth factor receptor (EGFR)-expressing metastatic CRC who had previously failed irinotecan-including therapy. The scope of this assessment was to compare treatment with cetuximab plus irinotecan as second- or subsequent-line therapy against oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) or active/best supportive care. It should be noted from the outset that no randomised or non-randomised studies of cetuximab met the inclusion criteria for this review. Therefore, all studies which included cetuximab as a second- or subsequent-line therapy for patients with metastatic CRC who were refractory to irinotecan were included in the review. The review of cetuximab is not a typical systematic review of clinical effectiveness, but rather represents a comprehensive and wide review of the current state of knowledge on the clinical effectiveness of cetuximab in the second- and subsequent-line treatment of patients with metastatic CRC.
Only trials which reported at least one of the primary outcomes, overall survival (OS) or progression-free survival (PFS) were included in the review. Survival duration was defined as the interval from randomisation to death. PFS was defined as the interval from randomization to disease progression or death during the study. Disease progression was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST). For patients alive and without disease progression at the time of analysis, PFS was censored at the time of analysis. Secondary outcomes, tumour response rates, toxicities, and health-related quality of life, were extracted where reported. Tumour response rates were defined as the number of patients in each group who achieved a partial or complete response, however defined. Toxicities and quality of life data were abstracted as reported, however defined.
Cost-Effectiveness
Search Methods
Systematic literature searches were undertaken to identify all relevant studies relating to the cost-effectiveness of:
- First-line treatment with bevacizumab in combination with 5-fluorouracil/folinic acid (5-FU/FA) or irinotecan plus 5-FU/FA as compared to 5-FU/FA or irinotecan plus 5-FU/FA in patients with metastatic CRC
- Second- and subsequent-line treatment with cetuximab in combination with irinotecan in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA in the treatment of patients with EGFR-expressing metastatic CRC who have previously failed on irinotecan-including cytotoxic therapy.
Medline search strategies for the cost-effectiveness review are presented in Appendix 4 of the Assessment Report (see "Availability of Companion Documents" field). Hand-searching of sponsor submissions to NICE was also undertaken in order to identify any further studies which were not identified by the electronic searches.
Studies Included in the Review of Cost-Effectiveness
The systematic searches did not identify any published studies relating to the cost-effectiveness of either bevacizumab or cetuximab in the treatment of metastatic CRC. The Roche submission to NICE included details of two mathematical models used to estimate the cost-effectiveness of bevacizumab in combination with irinotecan plus 5-FU/FA versus irinotecan plus 5-FU/FA alone, and bevacizumab in combination with 5-FU/FA versus 5-FU/FA alone. The Merck submission to NICE reported details of a mathematical model used to estimate the cost-effectiveness of second- and subsequent-line treatment using cetuximab plus irinotecan versus active/best supportive care. Appendix 5 of the Technology Assessment Report (see "Availability of Companion Documents" field) details the studies identified for inclusion in the review of cost-effectiveness.