Hepatocellular carcinoma is a common cancer worldwide. The incidence in the East is very much higher due to endemic chronic hepatitis B virus (HBV) infection in the population. The incidence of HCC has been increasing steadily in USA and the major risk factor for HCC in US is chronic hepatitis C virus (HCV) infection. In 1975, the total incidence of HCC was approximately 1.59 per 100,000 person-years. By 2006, this had reached 4.82 per 100,000 person-years and this increase has been attributed to the increasing numbers of Asian immigrants in the United States. However, a presentation at the recent 101^st Annual Meeting of the American Association for Cancer Research (AACR) has come up with a surprising culprit (Abstract 1816, presented Arpil 19, 2010).

Researchers from the National Cancer Institute (NCI) reviewed data from the NCI SEER database. The case population studied consisted of 5607 people diagnosed with HCC. They examined the odds ratio of an individual developing HCC with the risk factors of HCV infection, HBV infection, alcohol-related disease, rare metabolic disease, diabetes and obesity. (Odds ratio tells you how much more likely it is that you are going to develop the condition compared with someone without the risk factor.) HCV infection has the highest odds ratio of 44.26 (ie 44 x more likely than a non HCV infected person). The odds ratios for HBV infection, alcohol-related disease, rare metabolic disorder, diabetes and obesity were 13.37, 4.43, 3.51, 2.37 and 1.53, respectively. However, the researchers found that diabetes was associated with the greatest percentage of cases (33.5%). The other associations were alcohol-related disorders (23.9%), HCV infection (20.7%), HBV infection (5.7%), rare metabolic disorders (3.1%) and obesity (2.7%).

The incidence of obesity and diabetes mellitus is increasing worldwide and the Asian population has not been spared. While chronic HBV infection is the most important risk factor for HCC in Asia, the general population and clinicians need to be aware that diabetes and obesity are also associated with HCC. The above study found that 67.9% of Asians with HCC had one or more of the identified risk factors. Both obesity and diabetes can be helped by adopting a prudent life style - maintaining a healthy body starts with you!

Two weeks ago I saw a patient who is known to be a carrier of hepatitis C virus (HCV). He was diagnosed in 2005 but for the last few years had not had regular surveillance of his liver. He had felt bloated for a few months and saw his doctor recently. Subsequent investigations showed he had bilobe liver cancer (hepatocellular carcinoma, HCC) in a cirrhotic liver. Curative surgical resection was not an option as he had lesions in both the right and left lobes of the liver. [The best scenario for any patient with HCC is the presence of a small (< 2cm in diameter) tumour confined to one lobe of the liver (i.e. stage I / II cancer).] Would the situation be different if he had had regular surveillance?

Researchers from Hiroshima Prefectural Hospital reported the results of a study evaluating the usefulness of regular check-ups by ultrasonography and contrast-enhanced imaging for early detection of HCC in patients infected with HCV (J Gastroenterol 2009, Oct 29; epub). From April 2001 to March 2007, 240 consecutive HCV patients with HCC were studied. These patients could be classified into 3 groups:- Group A patients had their HCC diagnosed by regular, imaging surveillance; Group B patients had their HCC detected during scheduled doctor visits for liver disease or other diseases such as diabetes and Group C patients had their HCC detected when they felt a need to visit a doctor. The study found that the prevalence of single tumour at the time of diagnosis was 66% in group A patients. Group B patients had a prevalence of 48% while it was only 24% in group C patients. The percentage of stage I and II patients were 83% for group A, 53% for group B and 24% for group C. The number of patients who underwent curative procedure (surgical resection / ablation) was 99/124 (80%) in group A, 42/79 (53%) in group B and 10/37 (27%) in group C.

At the present moment, we cannot, with one blood or x-ray test, predict the risk of developing HCC in anyone who is a carrier of the hepatitis B (HBV) or C virus. The only way we can help these carriers is to perform regular blood and x-ray screening at 6 monthly intervals. The surveillance / screening is to afford us a chance to detect the liver cancer at an earlier stage. It does not stop the development of the cancer. If the liver cancer can be detected at an earlier stage, the chance of having a curative treatment is much higher.     

To all HBV & HCV carriers and people with liver cirrhosis, please remember to go for regular screening. Please do not wait until you have symptoms. It could be a bit late by then.

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?