When your doctor tells you that you have developed an early cancer, your most likely response would be ‘Can it be completely removed?’ or ‘What needs to be done in order to cure me?’  Imagine what your response would be if your doctor said “Just wait and see. Doing nothing is just as good”. You might accuse him of being negligent and proceed to change your doctor.  However, according to one recent study, masterly inaction may well be the best option for some patients with early prostate cancer.

Researchers from the University of New Jersey studied 14,516 men aged 65 years or older diagnosed with stage T1 or T2 prostate cancer during the period 1992 – 2002. These patients did not have surgery or radiation treatment and were followed up for a median of 8.3 years by active surveillance only (JAMA 2009; 302: 1202 – 1209). The median age of these patients was 78 years. The 10-year overall survival of these patients was 94%. Indeed, it would be difficult for active surgical treatment to better this survival figure as shown in an earlier Scandinavian study (N Engl J Med 2005; 352: 1977 – 1984). This study compared the survival of prostate cancer patients treated with prostatectomy against watchful waiting in 695 men (mean age of 64.7 years) with early prostate cancer. The 10-year overall survival of the prostatectomy group versus the watchful waiting group was 90.3% versus 85%; this difference was statistically significant.

The best way to treat early prostate cancer detected by prostate specific antigen (PSA) screening is still being debated. That is why there are many ongoing randomized trials investigating various approaches for treating early prostate cancer. What the above US observational study has demonstrated is that there is increasing evidence showing that a vast majority of men with early prostate cancer, detected by PSA, have a very good prognosis. Even if they are not treated with surgery, radiation or hormone therapy, they are unlikely to die of prostate cancer or suffer serious consequences from its spread at 10 years or more. While this may be the right approach for patients who are 70 or older, it may well not be the right approach for someone who is 50. The question of early intervention or masterly inaction is being addressed in 2 ongoing randomized clinical trials – PIVOT in the United States and PROTECT in the United Kingdom. The aims of these trials are to evaluate the overall and disease-specific survival and quality of life after early treatment versus conservative management in men with localized prostate cancer detected primarily with PSA testing. The results should be available in a few years.

In medicine, masterly inaction is practiced and sometimes doing nothing can turn out to be the best treatment. It is natural for any patient to find it difficult to accept the fact that doing nothing can be the best treatment in some medical conditions. The doctor’s job is to weigh up the pros and cons of being active or doing nothing. After presenting you with the facts, you still have to decide.

The next time your doctor suggests some management option which sounds controversial to you, hear him out before firing him.

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?

Hepatocellular carcinoma (HCC) is the 5^th most common cancer worldwide. Its incidence is very high in Asia and Africa and the incidence in Europe and the US is increasing. HCC can grow to a significant size before becoming symptomatic. Consequently, most HCC are diagnosed late and are not amenable to curative treatments, namely surgical resection and liver transplantation. Surgical treatment for patients with early stage HCC provides good long term survival. In patients with good liver function and a single HCC lesion < 5cm in diameter, the 5-year survival rate following surgical resection is 70%. In patients with HCC meeting the Milan criteria, the 5-year survival rate following liver transplantation is about 74%. The median survival of patients with advanced HCC on supportive care is about 14 – 16 weeks. Thus, early detection of HCC leads to a much better prognosis. At present, the only viable option for early detection of HCC is to undergo regular surveillance with blood tests for the tumour marker, alpha feto-protein (AFP), and ultrasound scan of the liver. However, the number, type and interval of tests can vary among physicians, institutions and countries. So what is the best schedule for the at-risk population?

Researchers from the University of Michigan recently performed a meta-analysis on 13 published studies using ultrasound and AFP for early HCC detection in patients with liver cirrhosis (Aliment Pharmacol Ther 2009; 30: 37 – 47). The study showed that the pooled sensitivity and specificity for ultrasound in detecting HCC at any stage is 94%. For detection of early HCC, the pooled sensitivity is 63%. However, surveillance intervals affected ultrasound sensitivity in detecting early HCC. When the surveillance interval was < 6 months, the pooled sensitivity is 70.1%. The pooled sensitivity drops to 50.1% when the surveillance intervals are between 6 and 12 months. (There is no difference in the sensitivity of ultrasound between European and Asian studies and between studies conducted before and after 1992. This suggests technological advances did not play a major role.) When AFP is added to ultrasound surveillance, the pooled sensitivity for early HCC detection increases to 69%.

The current guidelines from the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver recommend surveillance of cirrhotic patients with ultrasound with or without AFP every 6 – 12 months. The study above demonstrated a significantly higher sensitivity for early HCC detection when ultrasound scanning is performed at or less than 6 monthly intervals. In Japan, some institutions have a policy of screening the at risk population every 3 months and analysis of their data showed earlier detection of HCC which are also smaller in size at diagnosis. Although the above study only dealt with patients with liver cirrhosis, regular surveillance is recommended for all patients who are carriers of the hepatitis B (HBV) and C (HCV) virus, with or without liver cirrhosis. While it is tempting for an HBV and HCV carrier to think that “It will never happen to me so I don’t need surveillance”, I would certainly not take that chance if I were a carrier.