This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) considered inappropriate for chemoradiotherapy but appropriate for radiotherapy, based upon the evidence submission from Merck Pharmaceuticals to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's submission was generally of good quality and was an accurate representation of the original reference data. One good-quality randomised controlled trial comparing radiotherapy plus cetuximab with radiotherapy alone in patients with stage III or IV non-metastatic LA SCCHN was included, demonstrating that the duration of locoregional control was significantly longer with radiotherapy plus cetuximab than with radiotherapy alone; also, overall and progression-free survival were significantly longer and the overall response rate was significantly better with the combination therapy. Cetuximab did not exacerbate the common toxic effects associated with radiotherapy of the head and neck. No supporting evidence for these findings are available. The patient population in the trial included a high proportion of patients who would be expected to be suitable for chemoradiotherapy and therefore does not DOI: 10.3310/hta13suppl1/08 Cetuximab plus radiotherapy for the treatment of LA SCC of the head and neck50 match the population described in the submission's decision problem. Also, the radiotherapy regimens used in the trial are not typical of current UK practice. The ERG considered the manufacturer's economic evaluation to comprise the only relevant evidence to consider for the purposes of this STA. The economic model was considered appropriate for the decision problem. The results suggested that cetuximab plus radiotherapy was cost-effective compared with radiotherapy alone under a broad range of different assumptions on the basis of a cost-effectiveness threshold of £20,000. In the base case the incremental cost-effectiveness ratio of cetuximab plus radiotherapy compared with radiotherapy alone in the treatment of patients with LA SCCHN was £6390 per additional QALY. Simple sensitivity analyses to examine the robustness of the results were undertaken, suggesting that areas of uncertainty that emerged in the modelling are unlikely to have a material effect on the conclusions. The guidance issued by NICE in May 2007 as a result of the STA states that cetuximab in combination with radiotherapy is not recommended for patients with LA SCCHN.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of fludarabine phosphate or fludarabine plus cyclophosphamide for the firstline treatment of chronic lymphocytic leukaemia, based upon the evidence submission from Schering Health Care (SHC) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission was of good quality with no major errors or omissions in the clinical evidence. Two published studies and seven abstracts were included in the company submission, which showed improvements in overall response and progression-free survival (PFS) and a higher complete response rate in the fludarabinecontaining arms; however, until the complete data are made available for evaluation these results must be interpreted with caution. The manufacturer's decision-analytic Markov model to estimate the cost-effectiveness of treatment with fludarabine monotherapy, fludarabine plus cyclophosphamide and chlorambucil was considered to be the most relevant source for informing this STA; it was appropriate for the decision problem and the data sources used to inform the model were appropriate from a UK NHS perspective. The incremental cost-effectiveness ratio of fludarabine plus cyclophosphamide compared with chlorambucil from the revised model presented in the manufacturer's addendum was £3244 per additional quality-adjusted life-year. The results were robust to a range of subgroup Discussion of ERG reports is invited. Visit the HTA website correspondence forum (www.hta.ac.uk/ correspond). DOI: 10.3310/hta13suppl1/06Fludarabine phosphate for the first-line treatment of chronic lymphocytic leukaemia 36 and sensitivity analyses. Additional sensitivity and survival analyses were carried by the ERG to investigate possible bias in the results. This brought into question the validity of the assumptions underpinning the extrapolation of data over a lifetime time horizon and showed that the ICER estimates submitted by the manufacturer were not calculated correctly and uncertainty surrounding the decision problems was not expressed fully. Based on these analyses the ERG suggests that further evidence is needed to enable an accurate assessment to be made of the clinical and costeffectiveness of fludarabine as first-line treatment for chronic lymphocytic leukaemia. The guidance issued by NICE in December 2006 as a result of the STA states that fludarabine monotherapy, within its licensed indication, is not recommended for the first-line treatment of chronic lymphocytic leukaemia; no recommendations have been made with respect to fludarabine plus cyclophosphamide combination therapy because the current marketing authorisation does not specifically provide a recommendation that fludarabine should be used concurrently with other drugs for the treatment of chronic lymphocytic leukaemia.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of paclitaxel in the management of early stage breast cancer based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope was not clearly defined in the manufacturer's submission. Two of the three clinical trials included in the submission report showed that the addition of four cycles of paclitaxel to four cycles of doxorubicin and cyclophosphamide (AC-P) resulted in modest improvements in the two end points of diseasefree survival (DFS) and overall survival (OS). The third unpublished study evaluating four cycles of AC followed by paclitaxel or docetaxel in breast cancer did not show any statistically significant differences in DFS or OS between any group. The economic evaluation of paclitaxel for adjuvant therapy in early breast cancer was based on two of the three trials submitted as clinical evidence and used a probabilistic Markov state-transition model. The measure of health benefit was quality-adjusted life-years (QALYs) and the model included direct costs using a UK NHS perspective. The primary analysis compared AC-P with four cycles of AC. The reported incremental cost-effectiveness ratio (ICER) for this comparison was £4726 per additional QALY for AC-P compared with four cycles of AC. The submission did not include a DOI: 10.3310/hta13suppl1/03The use of paclitaxel in the management of early stage breast cancer 16 systematic review for clinical or cost-effectiveness evidence. As a result, potentially relevant trials and previously published studies were omitted. The main comparator used did not represent standard care in the UK NHS and a large number of relevant comparators were omitted, including docetaxel. The manufacturer did not consider potentially important patient subgroups defined by baseline risk, and the cost-effectiveness result in the average overall patient population may conceal important variation between subgroups. Overall, although the economic model may have indicated that the addition of four cycles of paclitaxel to four cycles of AC may be cost-effective compared with providing four cycles of AC only, this comparison is not informative to current clinical practice in the UK NHS. In the context of this review it is not possible for the ERG to predict the cost-effectiveness of paclitaxel compared with more appropriate, and potentially more effective, relevant comparators. The guidance issued by NICE in July 2006 as a result of the STA states that paclitaxel is not recommended as an option for the adjuvant treatment of women with early nodepositive breast cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of paclitaxel in the management of early stage breast cancer based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope was not clearly defined in the manufacturer’s submission. Two of the three clinical trials included in the submission report showed that the addition of four cycles of paclitaxel to four cycles of doxorubicin and cyclophosphamide (AC-P) resulted in modest improvements in the two end points of disease-free survival (DFS) and overall survival (OS). The third unpublished study evaluating four cycles of AC followed by paclitaxel or docetaxel in breast cancer did not show any statistically significant differences in DFS or OS between any group. The economic evaluation of paclitaxel for adjuvant therapy in early breast cancer was based on two of the three trials submitted as clinical evidence and used a probabilistic Markov state-transition model. The measure of health benefit was quality-adjusted life-years (QALYs) and the model included direct costs using a UK NHS perspective. The primary analysis compared AC-P with four cycles of AC. The reported incremental cost-effectiveness ratio (ICER) for this comparison was £4726 per additional QALY for AC-P compared with four cycles of AC. The submission did not include a systematic review for clinical or cost-effectiveness evidence. As a result, potentially relevant trials and previously published studies were omitted. The main comparator used did not represent standard care in the UK NHS and a large number of relevant comparators were omitted, including docetaxel. The manufacturer did not consider potentially important patient subgroups defined by baseline risk, and the cost-effectiveness result in the average overall patient population may conceal important variation between subgroups. Overall, although the economic model may have indicated that the addition of four cycles of paclitaxel to four cycles of AC may be cost-effective compared with providing four cycles of AC only, this comparison is not informative to current clinical practice in the UK NHS. In the context of this review it is not possible for the ERG to predict the cost-effectiveness of paclitaxel compared with more appropriate, and potentially more effective, relevant comparators. The guidance issued by NICE in July 2006 as a result of the STA states that paclitaxel is not recommended as an option for the adjuvant treatment of women with early node-positive breast cancer.

292 Background: Several factors are involved in pancreatic cancer’s (PC) resistance to therapy. Cancer Stem cells (CSCs) represent a small and unique population of cancer cells, that are resistant to chemotherapy and radiotherapy and have the capability to differentiate and produce further resistant clones. Our hypothesis was that stem cell frequency would differ in treated vs. untreated pancreatic cancers. Methods: Resected FFPE PC specimens were collected under IRB- approved protocols and were separated into two group categories: cases that received neoadjuvant therapy (NA) and matched control cases with no treatment prior to surgical resection (SU). Immunostaining with CD24 and ALDH1 was performed using the DAKO FLEX SYSTEM. Each slide was scanned using the Aperio Whole Digital Imaging System. The digital scans were analyzed using the standard positive pixel algorithm for immunostains (brown positive, blue negative) that gives a percent of positive pixels in the cross section of the tissue. Care was taken to exclude false-positive staining sections of intact physiologic acinar and islet cells. Positivity data was compared between the two groups using a two-sample t-test using unequal or equal variances where an F-test deemed each appropriate. Results: Twenty cases were examined (10 NA and 10 SU). Patients in the NA arm received the following treatments (4 FOLFIRINOX, 2 nab-Paclitaxel + gemcitabine, 2 treated with concurrent gemcitabine/radiotherapy and 2 patients’ details are not available). Using two-sample t-test analysis, we found a statistically significant difference of median expression (percent positive pixels) of CD24 (20.5% vs. 66.9% expression, P <0.01,) and ALDH1 (41.5% vs. 60.5%, P= 0.04) between NA vs. SU respectively. This small study demonstrates lower expression of CSCs markers in patients receiving NA therapy in comparison to SU treated patients, indicating an effect from neoadjuvant therapy on CSCs. Conclusions: This is the first analysis of CSCs markers in patients with PC receiving NA therapy compared to surgery. In this small group, CSCs markers reflecting CSCs numbers in patients’ tumors were lower in the group receiving NA therapy prior to surgery; suggesting that CSCs may in fact be sensitive to standard chemotherapy.