Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
This Practice Corner illustrates how busy general practitioner (GPs) can use a journal club to keep up to date with the best current research, to support care decisions for individual patients, to communicate with researchers about questions for which no satisfactory evidence exists, and to improve our daily clinical work.
A 58 year old man was diagnosed with a 7 × 6 cm liver tumor on ultrasound (US) after presenting with abdominal distension for 1 week. He was a chronic hepatitis B carrier, detected 3 years ago in an insurance health check. Yearly blood tests have been performed since then. Four months ago, both alanine transaminase (ALT) and alpha feto protein (AFP) were in the normal range (ALT = 35 IU/l; AFP = 1.25 ng/ml).
Subsequently, left hepatectomy was performed with a pathology report of hepatocellular carcinoma (HCC) TNM Stage III. In the letter, the surgeon estimated his 5 year survival rate to be 25% according to local data. His wife, daughter, and son are asymptomatic hepatitis B carriers with normal ALT. The wife and daughter are HBe Ag positive while the son is HBe Ag negative. Understandably, they are all very concerned about the risk of having HCC in the future, and they wish to be “checked” and “treated earlier.”
Working in an endemic area for chronic hepatitis B, this scenario is not uncommon. The Hong Kong Cancer Registry in 2000 showed 1584 new cases and 1424 deaths from HCC. Lifetime risk was 1 in 30 for men and 1 in 110 for women.
Our question was: in asymptomatic chronic hepatitis B carriers, will screening by AFP and/or liver US reduce mortality from liver cancer?
SEARCH STRATEGY & APPLICATION OF THE EVIDENCE
A relevant Cochrane systematic review was retrieved using the terms chronic hepatitis B, screening, and liver cancer. We were amazed at the paucity of controlled trials. The systematic review was done in a rigorous way, but the rate limiting step in EBM seems to lie at the research level.
Based on the evidence (see CAT below), we could give our patients this information:
About 5000 patients need to have a blood test and ultrasound every 6 months to reduce 1 death from liver cancer in 1 year. It costs about US $120 per year. There is the possibility of detecting the cancer when it is smaller, hence surgery could be an option, after which one might live 6 months longer. Our knowledge is still limited; the hope to “catch the disease” earlier and hence live longer is not based on firm evidence.
CAT: SCREENING OF LIVER CANCER BY AFP AND/OR US IN CHRONIC HEPATITIS B MAY BE EFFECTIVE
Clinical bottom line:
1. AFP and US performed every 6 months in patients with chronic hepatitis B result in a reduction in HCC mortality, but the difference is not significant. (OR 0.81, CI 0.54 to 1.22, NNS = 937/5 y).
2. Screening appears to detect more HCC in 5 years (but not so when updated to 7 y follow up).
3. Screening significantly detects more resectable HCC (<5 cm) (OR 7.14, CI 3.53 to 14.43).
4. 5 year survival rate after resection in the screened group is longer, with lead time 5.4 months.
Search terms in Cochrane library:
chronic hepatitis B, screening, liver cancer
1. The systematic review: randomised trials on screening for liver cancer irrespective of language. Of the 550 journal abstracts, only 2 trials met the selection criteria (!)
2. Shanghai trial (Yang 1999): 18 816 randomised to screening by biannual AFP plus US (9372) or control (9443), followed up for 5 years. Outcomes include HCC mortality, number of HCC detected, HCC resectability, and mortality of resected patients. Personal communication provides additional information equivalent to a 7 year follow up.
3. Toronto trial (Sherman 1995): 1069 randomised to screening by AFP (531) or screening by AFP plus US (538), followed up for 26 months. Sample size not adequate to compare the 2 screening methods.
See table 1.
1. Not enough quality trials to support or refute screening. People recruited for screening should be informed that to date “any screening performed more in hope of benefit than with certainty.”
2. Marked difference in cost of screening in different locality. Quoted as US $0.60 per AFP and US $1.20 for each ultrasound. In Hong Kong, the corresponding cost is about USD $40 and $20, respectively. A difference of ∼70 times.
3. No data on NNH, eg. anxiety if result is falsely positive.
Appraised by: Amy Chan /JASPA* Feb 2004.
HOW WE LEARN TOGETHER
Our journal club has 5 GPs working in different sectors: government, group practice, and solo practice. We have used the 3 part agenda depicted in Sackett’s book (ie, discussing clinical problems and formulating them in an answerable PICO (patient, intervention, comparison, and outcome) format, searching and photocopying articles, critical appraisal of a selected piece of evidence worth studying (the beef), and assigning people to write up a “critically appraised topic” (CAT). In addition, we also spare some time to brainstorm, “buzz,” and “fish bowl” one another on such issues as patients’ preferences and values and clinical circumstances.
For the above scenario, we role played and learnt, by multiple attempts, the best way to explain the evidence to our patients in simple terms. We also raised queries among ourselves from the patients’ perspectives. It is during this process that many new questions arose and thereby uncovered our knowledge gap.
“Will I have a higher chance of developing HCC if I am HBe Ag positive?”
“What should I do if my liver enzymes are raised, even though the AFP & US are normal?”
“I have heard of the drug lamivudine; should I take that? Will the drug cure the disease?”
“Is it safe to try herbal medicine?”
Striving for closure by the end of every session is antithetical, so we usually leave plenty of issues to reflect upon between sessions. Instead of having educational prescriptions stuffed in whitecoat pockets during clinical rounds (GPs seldom have ward rounds!) and tossing them in a tray, we circulate our clinical questions online. In the interim period, we can take a look at our “Bank of questions” (see table 2), and vote on the next question that we think is worth our time and effort. In this way, we make sure that the next topic is of interest to the group and that ample time is allowed for preparing the relevant articles.
THE NEXT MOMENTUM
By searching PubMed using Hepatitis B, chronic[MeSH] and limiting to “Practice Guidelines,” 2 relevant guidelines were retrieved: the Asian-Pacific Consensus Statement published in 2003, and another one by the American Association of Study of Liver Disease (AASLD) published in 2001. Although published 3 years ago, we decided that the AASLD one is more evidence-based. While surfing Google in search of other existing guidelines, the 2004 International Liver Congress co-organised by AASLD was noted. We decided 1 member could attend the congress and share the latest evidence online (see the letter below). We planned to critically appraise the latest guideline published in March 2004. Still, our baskets of unanswered questions were bothering us so much that we decided to pose our burning queries to the researchers via the website of the Congress, hoping (remotely) to generate a pragmatic agenda for future health research.
HOW WE PLAN TO MOVE ON
As seen in our form for voting (table 2), a long queue of questions await answers. We plan to alternate our problem-based learning with sessions for prepared discussion: members will share their search on their individual educational prescriptions that could be answered swiftly on one’s own. We hope that by doing so, we can incorporate deep learning with broad learning.
Meanwhile, we are circulating many of our findings to other colleagues on the internet. Of course, we also circulate our secret roster—“Who Is going to bring bubbling grape juice for the next session?” Perhaps this is the reason we attracted visitors to our last 2 meetings!
Letter sharing learning points in a congress
I attended the HK-Shanghai International Liver Congress 2004 and here are some learning points:
(1) Experts from 3 continents (USA, Europe, Asia) all started their presentation with one statement: management must be INDIVIDUALISED. There can be no hard and fast rule or any global consensus, just a balance of evidence and resources.
(2) Both the AASLD (American Association for the Study of Liver Disease) and the EASL (European Association for the Study of the Liver) have guidelines developed under a rigorous process. The boards (or jury) are mainly expert hepatologists in the AASLD; while for EASL, independent other-field doctors are also involved. The guideline drafted by the APASL (Asian Pacific Association for the Study of the Liver) seems to be least evidence-based, but they have considered more local issues—for example, the use of herbal medicine and the YMDD mutations, which are seen more often in the Asian Pacific region.
(3) HBeAg positive and HBeAg negative patients are considered 2 separate diseases: the current practice is to use interferon more in the e +ve, and oral anti-virals (lamivudine/adefovir) more in the e -ve. Another consensus is to wait for longer (6 mo) if a flare up occurs in an e+ve before embarking on treatment.
The other focus is "who are the candidates that might benefit from treatment", or "whom should be referred to the hepatologists for a liver biopsy?"
But these questions keep ringing in my mind:
i) What is the relationship of e antigen status to the development of HCC?
ii) It seems quite clear to the hepatologists whom/how they are going to “treat”, but based on what evidence should GPs monitor our asymptomatic HB carriers with normal LFT? How often are we to check the ALT? 3 months? 6 months? Do we just go by the pockets of our patients? Are there any subgroups that worth a closer monitoring?
iii) Screening for HCC, well, sorry, no one mentioned this.
I had no chance to raise these questions in the meeting–too many other “specialist questions.” Anyway, any comments?
Having a group is cost effective: it helps to stimulate and maintain our interest and enthusiasm, and makes the practice of EBM faster, easier, and merrier. We hope you will enjoy your time as well.