NICE says NO

Since the publication of the SHARP study in the New England Journal of Medicine in July 2008, the drug sorafenib (Nexavar, Bayer Schering Pharma) has been considered the standard drug of choice for treating patients with advanced hepatocellular carcinoma (HCC). It is widely available in France, Germany, Italy, Spain, Romania and Greece. It is widely available in USA, Japan, Indonesia, Malaysia and Singapore. In May 2009, the National Institute for Health and Clinical Excellence (NICE) rejected the application to make sorafenib freely available to NHS patients in the United Kingdom. Bayer Schering, the manufacturer of sorafenib, resubmitted its application. On 9^th September 2009, NICE published its appraisal consultation document (http://www.nice.org.uk/guidance/index.jsp?action=article&o=45361) again not recommending sorafenib for the treatment of advanced HCC for NHS patients on the grounds that it is not cost-effective. As expected, there was uproar about this decision. Dr Harpreet Wasan, Medical Oncologist at the Hammersmith Hospital, Imperial College, London was quoted as saying ‘… we are left with nothing to offer advanced HCC patients apart from supportive and palliative care, thus denying them the life-preserving benefits of modern treatments”.  The chief executive of the British Liver Trust, Alison Rogers, was quoted as saying “This is a very poor decision for patients with HCC in the UK”.

The SHARP study (N Engl J Med 2008; 359: 378 – 390)  randomised 602 patients with advanced HCC to receive either sorafenib (400 mg twice daily) or placebo (ie best supportive care, in other words, no active treatment). The median time to symptomatic progression was not significantly different between the groups. The overall median survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group. Statistically this was highly significant. The side-effects of diarrhoea, weight loss, hand-foot skin reaction and hypophosphataemia were more frequent in patients taking sorafenib. The result of this trial was pivotal in securing FDA approval for the use of sorafenib in treating patients with advanced HCC.

The incidence of HCC in East Asia is many times more than that in USA and Europe. As most HCC patients have advanced disease at the time of presentation, most of these patients in the East are offered a variety of loco-regional treatments before the clinicians resort to best supportive care. Here, best supportive care is usually offered to patients who are in poor clinical state or who have failed loco-regional treatment. (The patients involved in the SHARP study would likely have been suitable for loco-regional treatment.) These loco-regional treatments include trans-arterial chemo-embolization (TACE), trans-arterial embolization (TAE), radio-frequency ablation (RFA) or selective internal irradiation therapy (SIRT) with yttrium-90 (Y-90) microspheres. (The average number of TACE treatments for a patient with advanced HCC is 2 – 3; for SIRT it is a single infusion only.) For example, the use of Y-90 microspheres in patients with advanced HCC has been shown in published studies (not randomised) to prolong survival, to downstage the initially inoperable tumour to a stage suitable for surgical resection with a potential chance of cure or to downstage the tumour to a stage where the patient is suitable for liver transplantation with a potential chance of cure. The statement by the UK medical oncologist  “… we are left with nothing to offer advanced HCC patients apart from supportive and palliative care ..” is perhaps a trifle over-dramatic.

Since the approval of sorafenib, various studies comparing loco-regional treatment modality combined with sorafenib against sorafenib alone have been suggested and embarked upon. When sorafenib was made available in Singapore, I suggested to the manufacturer of Y-90 microspheres to conduct a study comparing the efficacy of sorafenib alone versus Y-90 SIRT alone in patients with advanced HCC. This did not materialise. Several months later, I heard that a small international study comparing Y-90 SIRT+sorafenib versus sorafenib alone would be carried out in patients with advanced HCC. Soon after, on a subsequent occasion, I told the Y-90 manufacturer representative that I would predict patients in the Y-90 SIRT+sorafenib arm would no doubt survive significantly longer than those treated with sorafenib alone. (If another study comparing TACE+sorafenib versus sorafenib alone is conducted, I would also predict that patients in the TACE+sorafenib arm will survive longer.) Loco-regional therapies such as Y-90 SIRT and TACE are accepted treatment modalities and known to be effective in prolonging survival in patients with advanced HCC. While it is not as convenient as taking a tablet (sorafenib), how will the cost of TACE / SIRT compare to sorafenib in treating a patient with advanced HCC? As far as I know, the overall cost of treating a patient with TACE or SIRT versus sorafenib in order to achieve the same duration of survival prolongation is not known. (If a cost analysis study were to be conducted, I would not be surprised if the study were to show that sorafenib is not the most cost effective.)

In UK where health care cost is “covered” by the state, not making sorafenib freely available to NHS patients with advanced HCC is certainly “a very poor decision” according to some. However, in countries like Indonesia, Myanmar, Cambodia and China, the state will not bear the cost of sorafenib treatment and the cost of a one month supply of sorafenib is approximately 10,000 Singapore dollars. That is a significant amount of money. If a patient with advanced HCC had to take sorafenib for, say, 10 months to get a 2 months survival prolongation, the patient and his / her family would have to come up with 100,000 Singapore dollars. For most of these patients, that is a fortune!

For the patient population I see, cost consideration unfortunately does come into the decision equation. I am sure these patients would wish that their country’s health care system was free, flush with unlimited resources and would allow them access to all available drugs on the market irrespective of cost.

Should cost-effectiveness be a consideration in health-care provision? What do you think?