Frank A. Lederle, MD; Christine Pocha, MD, PhD
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2678.
Requests for Single Reprints: Frank A. Lederle, MD, Department of Medicine (111-O), Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417; e-mail, mailto:firstname.lastname@example.org.
Current Author Addresses: Drs. Lederle and Pocha: Veterans Affairs Medical Center (111-O), 1 Veterans Drive, Minneapolis, MN 55417.
Author Contributions: Conception and design: F.A. Lederle, C. Pocha.
Analysis and interpretation of the data: F.A. Lederle, C. Pocha.
Drafting of the article: F.A. Lederle, C. Pocha.
Critical revision of the article for important intellectual content: F.A. Lederle, C. Pocha.
Final approval of the article: F.A. Lederle, C. Pocha.
Statistical expertise: F.A. Lederle.
Administrative, technical, or logistic support: F.A. Lederle.
Collection and assembly of data: F.A. Lederle, C. Pocha.
Lederle F., Pocha C.; Screening for Liver Cancer: The Rush to Judgment. Ann Intern Med. 2012;156:387-389. doi: 10.7326/0003-4819-156-5-201203060-00012
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Published: Ann Intern Med. 2012;156(5):387-389.
In 2005, a professional society issued a level I recommendation to use ultrasonography to screen the 3 million Americans with cirrhosis for hepatocellular carcinoma (HCC) every 6 months. This designation was based on a large randomized trial from China that reported a reduction in HCC deaths from screening in carriers of hepatitis B surface antigen. However, besides the difference in population, this trial did not report all deaths, excluded patients after randomization, and would almost certainly have found no significant difference if the cluster randomization had been accounted for in the analysis. Misplaced confidence in the Chinese trial has led many writers to accept the effectiveness of HCC screening as proven, making it more difficult to conduct the high-quality randomized trials that are needed to ensure optimal patient care.
MorrisSherman, MB BCh PhD FRCP(C), Jordi Bruix on behalf of the American Association for Study of Liver
Toronto General Hospital
March 14, 2012
Reply to Lederle and Pocha
Drs. Lederle and Pocha criticize the 2005 AASLD recommendations for hepatocellular carcinoma (HCC) screening (1,2) arguing that the trial on which the recommendation was based (3) was incorrectly analyzed and invalid. Furthermore, they suggest the study is not necessarily applicable to Western populations, as it was conducted in a hepatitis B population in China, whereas most HCC in North America is caused by hepatitis C. In their view, because level I evidence is lacking, screening should not be recommended.
As indicated by Lederle and Pocha, however, other guidelines, including those from the World Gastroenterology Association (4), European Association for Study of the Liver (5) and several Asian countries (6,7) consider the Chinese study to be valid, and recommend screening for HCC. These recommendations recognize the presence of a well identified at-risk population (cirrhotics of almost any etiology) and the availability of effective treatment applicable at all disease stages. Lederle and Pocha don’t appear to recognize that in cirrhosis the risk of HCC is not age-related and even the young with cirrhosis can get HCC. We emphasize that only patients at high enough risk who would be treated should be screened. That does include all patients with cirrhosis, regardless of age. Ignoring age may be unprecedented in other forms of screening, but is appropriate here. To reduce the possibility of ineffective invasive procedures and over-diagnosis, we recommended avoiding investigation of nodules <_10 mm="mm" in="in" size.="size." p="p">Lederle and Pocha call for a randomized controlled trial (RCT) of screening vs. no screening in the West. We would all like such as study. Any future plans to attempt such a RCT in North America or Europe would have a number of hurdles to overcome as has been the experience of others over the last 2 to 3 decades (8). Interestingly, Drs Lederle and Pocha note an Australian study suggesting that about 90% of potential subjects would refuse randomization into such a screening study (9). Despite this Drs Lederle and Pocha claim such a trial is possible. A trial including only the 10% who would agree would suffer from severe selection bias. Drs. Lederle and Pocha are correct that the only cost efficiency data on screening are unpublished. However, this is the only information available and several analyses indicate that screening for HCC in cirrhosis is effective and cost effective.
The AASLD guideline emphasized the limitations of available data addressing HCC screening. The bulk of available evidence, however, suggests screening is beneficial. It is incumbent upon us to act on that knowledge. Awaiting only high quality evidence risks actually doing harm. HCC is a major cause of death among cirrhotics and early stage diagnosis is the sole option for long-term cure. Symptomatic presentation of HCC has an almost universally fatal outcome, whereas screen-detected small cancers are curable in close 100% of cases, with a very low risk of adverse events. Furthermore, ongoing work to reduce over-diagnosis of dysplastic nodules (rather than HCC) requires on-going screening.
Drs Lederle and Pocha advocate perfection, and will accept only a RCT to establish the benefit of screening. They do not give credit to lesser degrees of evidence suggesting screening is effective. Although not the best evidence, the publication of the Zhang study resulted in a change in the practice of hepatology in the US and elsewhere that has resulted in the timely diagnosis and treatment of large numbers of small HCC’s and saved many lives.
1. Frank A. Lederle, MD, and Christine Pocha, MD, PhD. Screening for Liver Cancer: The Rush to Judgment. Ann Int Med 2012;156:387-389.
2. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53: 1020-2. [PMID: 21374666].
3. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(7):417-22. [PMID: 15042359]
4. Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M et al. Hepatocellular carcinoma (HCC): a global perspective. J Clin Gastroenterol. 2010;44:239-45.
5. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012, 56 (4), 908-943
6. Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 2011;29(3):339-64
7. Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009 Nov;10(11):1111-8.
8. Poutschi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology. 2011 Dec;54:1998-2004
9. Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology. 1995 Aug;22(2):432-8.
10. Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008 Jan;47(1):82-9
David B.Ross, MD, PhD, Director, National Hepatitis C Program
Veterans Health Administration
April 3, 2012
Response to Lederle FA, Pocha C. Screening for liver cancer: the rush to judgment. Ann Intern Med. 2012 Mar 6; 156(5): 387-9.
In response to Lederle and Pocha’s challenge to regular surveillance for hepatocellular carcinoma (HCC) in cirrhotic patients, I wish to clarify that the Veterans Health Administration’s (VHA’s) National Hepatitis C (HCV) Program, the largest HCV care provider in the U.S., recommends HCC surveillance of cirrhotic patients, consistent with the American Association for Study of Liver Disease’s (AASLD’s) consensus guidelines and VHA’s Hepatitis C Resource Centers’ published cirrhosis management guidelines (1, 2).
While the authors’ critique of the Chinese randomized controlled trial (RCT) of HCC surveillance is well taken, it’s important to recognize that they do not call for suspending such surveillance, and I strongly believe that HCC surveillance is warranted despite the absence of a U.S. RCT. While the benefits of HCC surveillance in cirrhosis can be debated and the available evidence criticized, it’s important to recognize that we are in the midst of an HCC epidemic that will peak over the next decade, driven by accelerating age-related liver fibrosis in baby boomers. HCC is the most rapidly increasing cause of cancer deaths in the U.S. The cumulative number of HCV-infected Veterans developing HCC increased over twenty-fold between 2000 and 2008, with further increases expected for another decade (3, 4). HCC-associated mortality remains unacceptably high, with five-year survival in the U.S. only 14%.
Abundant and persuasive evidence supports HCC surveillance, extending well beyond the one study discussed by the authors (1, 4). At-risk patients can be readily identified in the primary care setting. Ultrasound is widely available, safe, inexpensive, and reasonably sensitive for HCC detection. Early HCC detection frequently allows cure by liver transplantation, surgical resection, or radiofrequency ablation (1). Surveillance is associated with earlier stage at diagnosis, greater likelihood of receiving curative treatments, and better outcomes, while absence of surveillance is associated with later diagnosis and worse outcomes (4, 5).
These considerations led the AASLD’s expert consensus panels to recommend ultrasound surveillance of cirrhotic patients. Despite the title of the authors’ article, there has not been a rush to judgment on HCC surveillance, which has been studied for decades in high-risk populations. The AASLD did not formally recommend HCC surveillance until 2005, several years after its European counterpart. The strengths and weaknesses of the evidence, including the lack of prospective RCTs outside of China and the potential biases in published studies, were taken into account in constructing the guidelines.
I also take issue with the authors’ comments on the ethics of surveillance and clinical equipoise. The statement that “professional ethics prohibits providing unproven diagnostic screening tests” is quoted out of context from a discussion of direct-to-consumer marketing of high-technology screening, not an evidence-based guideline issued by a major professional organization. Their assertion of clinical equipoise about HCC surveillance’s benefits is contradicted by their comment that 99.5% of potential enrollees in a surveillance RCT designed by motivated clinical investigators declined participation (6). Lastly, in considering potential biopsy-related harms from surveillance, they do not mention that the majority of HCCs are diagnosed radiologically (1, 7).
The authors do not discuss real-world problems in conducting and completing a HCC surveillance RCT, which would face enormous obstacles to patient enrollment and would require many years to complete, during which time standards for surveillance and treatment would evolve. The likelihood of noncompliance and crossover would obscure interpretation of a negative outcome. These considerations underscore why the authors’ cogent critique of the Chinese RCT should not necessarily be taken as a warning to stop surveillance while waiting for a RCT, which might well be inconclusive. Given the projected peak in HCC incidence over the next decade, doing so would effectively deny the potential benefits of surveillance to the majority of at-risk patients who could ever benefit from surveillance, and make the results largely of academic interest by the time the trial reached completion.
Finally, the authors do not discuss observational studies as an alternative to RCTs, For example, recommendations to routinely offer HIV testing to pregnant women, which virtually eradicated pediatric HIV infection in the U.S, relied heavily on such data rather than a RCT of screening (8). Of note, VHA’s National HCV Clinical Case Registry has been used for observational studies of interventions in patients at risk for HCC (9).
Public health policies always involve trade-offs between the imperative to act and the need for evidence (10), and additional data on HCC surveillance would be helpful. However, given the cumulative experience supporting surveillance, the rising incidence of HCC, and the rapidly vanishing opportunity to intervene, the AASLD’s consensus guidelines constitute a prudent guide on which the VHA’s National HCV Program’s recommendations are based.
1. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53: 1020-2.
2. Garcia-Tsao G, Lim JK; Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol. 2009 Jul;104(7):1802-29.
3. Veterans Health Administration. The State of Care for Veterans with Hepatitis C. http://www.hepatitis.va.gov/provider/policy/HCV-state-of-care-2010.asp, accessed 2 April 2012.
4. Pocha C. Hepatocellular Carcinoma in Veterans: Are We Prepared for an Epidemic? Fed Pract. 2010; 27(suppl 6):1-6.
5. Stravitz RT, Heuman DM, Chand N, Sterling RK, Shiffman ML, Luketic VA, Sanyal AJ, Habib A, Mihas AA, Giles HC, Maluf DG, Cotterell AH, Posner MP, Fisher RA. Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome. Am J Med. 2008 Feb; 121(2):119-26.
6. Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology. 2011; 54:1998-2004.
7. Abraham JM, Pocha C. Hepatocellular Carcinoma: To Biopsy or Not? Fed Pract. 2011; 28 (8):34-36, 38.
8. Centers for Disease Control and Prevention. Reduction in Perinatal Transmission of HIV Infection — United States, 1985–2005. MMWR 2006;55 (No. 21):592-3.
9. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol. 2011 Jun;9(6):509-516
10. Bayer R and Oppenheimer GM. Routine HIV Screening – What Counts in Evidence-Based Policy? New Engl J Med 2011; 365: 1265 – 1268
Frank A.Lederle, Professor of Medicine, Christine Pocha
Minneapolis VA Medical Center
April 11, 2012
Reply to Drs Sherman and Bruix
We are in agreement with Drs Sherman and Bruix on three important points. First, they do not dispute our main thesis that there is no Level I evidence to support screening for liver cancer. Guideline recommendations should therefore be downgraded accordingly and, in our view, not used as performance measures. Second, we agree that a randomized trial of liver cancer screening will be difficult. Randomized trials are usually difficult, especially when the emotional issues surrounding cancer screening are involved. Nevertheless, they are necessary, as shown by the considerable literature describing bias in evaluating screening tests which supports Malcolm Law's conclusion that "Before any screening for cancer is introduced, large randomized trials with mortality endpoints should be conducted to establish and quantify any benefit" (1). In de Koning's words, "Randomized screening trials are bothersome", but "there is no second-best option" (2).
Furthermore, randomized trials of cancer screening are possible, as has been demonstrated for cancer of the breast, prostate, lung, colon, and ovary. Similar concerns were raised prior to these trials, and yet they were completed and produced results that could not have been predicted beforehand. The Australian survey that suggested a trial of liver cancer screening was not possible, cited in our article and their letter, provided patient information that strongly suggested an increase in life expectancy without mention of potential harms from biopsy or surgical resection (3), so it is not surprising that few patients favored randomization. We see no persuasive reason why liver cancer should be different from the other cancers listed above in terms of the need or feasibility of randomized trials to evaluate screening. However, the likelihood of successfully completing a trial is greatly reduced without the support of the expert community.
Drs Sherman and Bruix affirm that they would like to see a randomized trial of liver cancer screening, and this is the third point on which we are in agreement. We have submitted a proposal for such a trial to the VA Cooperative Studies Program, and hope that veterans with liver disease and their physicians will join us in seeking better answers to the questions we have raised. We call upon Drs Sherman and Bruix and the American Association for the Study of Liver Diseases to publicly endorse this effort.
1. Law M. Screening without evidence of efficacy. BMJ. 2004;328:301- 2. [PMID: 14764465]
2. de Koning HJ. Mammographic screening: evidence from randomised controlled trials. Ann Oncol. 2003;14:1185-9. [PMID: 12881373]
3. Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology. 2011;54:1998-2004. [PMID: 21800340]
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