National Institute for Health and Clinical Excellence Appendix C Sorafenib for advanced hepatocellular carcinoma Comment 1: the draft remit Appropriateness Patients with HCC have a poor prognosis, with a life expectancy of 3-6 months if unresectable. For those patients where surgical or locoregional therapies have failed or are unsuitable sorafenib is the only systemic treatment that has proved to prolong survival compared to best supportive care alone. This is an appropriate topic. Sorafenib has an increasing profile locally and the incidence of hepatitis B and C is likely to rise which in turn will increase the incidence of this cancer. According to a debate in the House of Commons on 18.12.07 it was stated that in the year 2000 liver disease killed more men than Parkinson's disease and more women than cancer of the cervix and we understand that the Government is investigating the possibility of developing a strategy for liver disease. HCC accounts for 80-90 percent of all the cases of primary liver tumours. It is wholly appropriate that NICE should be considering relevant drugs at this time. Sorafenib is indicated for the treatment of hepatocellular carcinoma. It is suitable for patients with advanced hepatocellular carcinoma who are unsuitable for or have progressed after surgical or locoregional therapies. Wording
Timing Issues We would like to see consideration of the use of this therapy at all appropriate stages of the disease. Proposed wording - To appraise the clinical and cost effectiveness of sorafenib for the treatment of hepatocellular carcinoma If the issues of clinical cost and effectiveness of this technology are to be judged fairly then it is vital that relevant and up to date figures regarding prevelance are used and this background paper does use these figures. Patients who have failed or who are unsuitable for surgical or loco-regional therpaies have a poor prognosis. If left untreated these patients would only have 3-6 months to live. Sorafenib has been shown to extend survival versus best supportive care by 44% (HR=0.698; p=0.00058). This is a relatively rare cancer in the UK and there is a high unmet and urgent clinical need for this patient group. We would like to have final guidance within 12 months. As liver cancer is growing the need for this treatment is urgently needed. This issue was discussed at the scoping workshop and consultees agreed that the remit of the appraisal should be restricted to patients with advanced hepatocellular carcinoma who are unsuitable for or have progressed after surgical or locoregional therapies. Scope amended. It should also be noted that prevalence figures are not expected to impact on the cost effectiveness of this technology.
Additional comments on the draft remit Comment 2: the draft scope It would be helpful if not more professional if NICE referenced its material in the same manner that patient organisations and indeed manufacturers are oblidged to. This will would help with the accuracy of these papers. Definition of the cases that would mertit treatment by Sorafenib needs to be much clearer. For instance, the first line of treatment when tumours are small (< 5cm in diameter) is by ablation techniques and with these cure can be obtained. New tumours, however, may develop in the liver and effective chemotherpay to prevent this, ie, the use of Sorafenib could represent an effective use. Survival in HCC cases is also largly effected by severity of the underlying cirrhosis, ie, Child Grade C cases even with small tumours have very poor outlook. Use of Sorafenib therefore needs to be related to functional category of underlying cirrhosis. All evidence used in the appraisal phase is clearly referenced. The purpose of the scope is to define the questions to be asked. The suggestions made were taken in consideration and, if evidence permits, the appraisal will seek to identify subgroups of individuals for whom sorafenib may be particularly clinically and cost effective. Background information When referring to systemic therapy it should be noted that various reviews, meta-analyses and systematic reviews published over the past decade conclude that no anti-cancer treatment has clearly been identified as either a gold standard or to demonstrably improve overall survival. For these reason may patients receive palliative care. Adequate for our purposes. This issue was discussed at the scoping workshop and consultees have agreed that the comparator should be standard care which may include doxorubicin, cisplatin or biological agents depending on performance status and disease severity
The technology/ intervention You state "Approximately 2,000 new cases of hepatocellular carcinoma are diagnosed in England and Wales per year. However, it is thought that the incidence will increase in the next years mainly as a result of the prevalence of hepatitis C virus infections." This statement ignores the rising prevalence of chronic hepatitis B virus (HBV) infection in the UK population. In Rising Curve: Chronic Infection in the UK, estimates that there are around 326,000 people with chronic HBV infection in the UK (November 2007). The majority of these people are migrants who acquired the infection at a young age (at birth or in childhood). It is therefore likely that, in the future, indeed the near furture hepatocellular carcinoma related to chronic HBV infection will affect younger people and the average age of diagnosis will fall. Sorafenib has a marketing authorisation for patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy, or are considered unsuitable for such therapy. Sorafenib is also licensed for the treatment of hepatocellular carcinoma. Sorafenib has been studied in clinical trials in people with hepatocellular carcinoma with advanced stage disease who had not received previous systemic therapy, a life expectancy of at least 12 weeks, Child-Pugh A & B and ECOG performance status of 0, 1 or 2, adequate organ function and measurable tumours. Yes, the description of the technology is appropriate. The description of the technology is not accurate as it is our understanding that from 5/11/07 specialists in the UK were able to prescribe this treatment for patients with hepatocellular carcinoma (HCC), the most common form of primary liver cancer, who are unsuitable for loco-regional therapies. Sorafenib), an oral treatment, was approved by the EMEA and is licensed for the treatment of patients with HCC. It could be that the agent is even more effective when started at an earlier stage when the tumour mass is small. Comment noted and scope amended accordingly.
Population Comparators The relevant population is patients with advanced hepatocellular carcinoma who are unsuitable for or have progressed after surgical or locoregional therapies. In our opinion, population is not defined appropriately. Given that the marketing authorisation for sorafenib states that the drug "is indicated for the treatment of hepatocellular carcinoma" we feel it would be unhelpful to restrict NICE's appraisal only to patients who have had no previous local therapy. Those who develop liver cancer are more likely to do so due to hepatocellular infection and importantly hepatitis B. These people are usually those who were born abroad or whose mothers were born abroad and there needs to be equality of treatments for this patient group The different functional categories of cirrhosis and different size with widely differing natural histories are important considerations in the use of this new agent with greater chemotherapeutic efficacy in HCC. The relevant comparator is best supportive (palliative) care. Various reviews, meta-analyses and sytematic reviews published over the past decade conclude that no anti-cancer treatment has clearly been identified as either a gold standard or to demonstrably improve overall survival. This drug is only approved for primary liver cancer for those unsuitable for locoregional therapies and so all the comparators do not compare. Comment noted and scope amended following discussion in the scoping workshop. Comment noted and scope amended following discussion in the scoping workshop. The suggestions made were taken in consideration and, if evidence permits, the appraisal will seek to identify subgroups of individuals for whom sorafenib may be particularly clinically and cost effective. Following the discussion in the scoping workshop the comparator was amended to standard care which may include doxorubicin, cisplatin or biological agents depending on performance status and disease severity.
Outcomes Economic analysis Equality Other considerations Yes, stated outcomes will capture the most important health related benefits (and harms) of the technology. QALY for liver cancer treatment will be difficult but, as liver cancer is the sixth most commonly diagnosed cancer and the third most common cause of death from cancer worldwide and many of these people now live and work in the country, treatments are needed. In addition, it is important to note that this is oral therapy and the cost of delivering this therapy as compared to day patient care should be considered Agree with what is outlined in scope. Time horizon is always too long. We need guidance to be explicit about those groups of patients who may receive greatest clinical benefit - which might include age. The patient group is likely to be from a BME migrant worker group and frequently that is in deprived areas this treatment should promote equality of service We agree that the appraisal should seek to identify sub-groups of individuals for whom sorafenib may be more clinically and cost effective. This drug is licensed. The appraisal will take into consideration all the characteristics of the technology within the standard methods currently used by NICE.
Questions for consultation Additional comments on the draft scope. Already patients are being recommended for use of this agent when other treatment measures have failed. Please ensure correct potential patient figures based on recent prevelance studies are considered Many more patients are being diagnosed with an early stage of HCC by regular ultrasound surveillance follow-up. The place of chemotherapy with sorafenib needs the most careful consideration. Previously chemotherapeutic agents had little efficacy and their use has declined to a major extent in recent years, because of lack of efficacy and also of severity of side effects particularly with those with Child B and C categories of cirrhosis. Comment 4: Regulatory issues Section Consultees Comments Action Remit Sorafenib (Nexavar) is indicated for the treatment of hepatocellular carcinoma. Based on the trial evidence it is suitable for patients with advanced hepatocellular carcinoma who are unsuitable for or have progressed after surgical or locoregional therapies. Current or proposed marketing authorisation Sorafenib is licensed for the use in patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy, or are considered unsuitable for such therapy. Sorafenib is also licensed for the treatment of heapatocellular carcinoma. Sorafenib is also under investigation for non small cell lung cancer and target date for centralised regulatory submission is xxxx. The following consultees/commentators indicated that they had no comments on the draft remit and/or the draft scope Department of Health NHS Quality Improvement Scotland
National Public Health Service for Wales Board of Community Health Councils in Wales British Liver Nurses Forum Marie Curie Cancer Care Sanofi-aventis Appendix C