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Original Research |

Utilization of Surveillance for Hepatocellular Carcinoma Among Hepatitis C Virus–Infected Veterans in the United States

Jessica A. Davila, PhD; Louise Henderson, PhD; Jennifer R. Kramer, PhD; Fasiha Kanwal, MD, MSHS; Peter A. Richardson, PhD; Zhigang Duan, MD, MS; and Hashem B. El-Serag, MD, MPH
[+] Article and Author Information

From the Houston Center for Quality of Care and Utilization Studies, The Michael E. DeBakey Veterans Affairs Medical Center, and Baylor College of Medicine, Houston, Texas; University of North Carolina, Chapel Hill, North Carolina; and St. Louis University School of Medicine, St. Louis, Missouri.


Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the official views of the U.S. Department of Veterans Affairs, Baylor College of Medicine, or the National Cancer Institute.

Grant Support: By the Houston Veterans Affairs Health Services Research and Development Center of Excellence (HFP90-020) and the National Cancer Institute (R01-CA-125487).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0880.

Reproducible Research Statement:Study protocol and statistical code: Not available. Data set: Available at http://vaww.publichealth.va.gov/research/surveillance/ccr_data_request.asp (also available by contacting vhaccradmins@va.gov).

Requests for Single Reprints: Jessica A. Davila, PhD, The Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard (152), Houston, TX 77030; e-mail, jdavila@bcm.tmc.edu.

Current Author Addresses: Drs. Davila, Kramer, Richardson, Duan, and El-Serag: The Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard (152), Houston, TX 77030.

Dr. Henderson: 2006 Old Clinic, Chapel Hill, NC 27599.

Dr. Kanwal: 3635 Vista Avenue, St. Louis, MO 63110-0250.

Author Contributions: Conception and design: J.A. Davila, L. Henderson, J.R. Kramer, P.A. Richardson, H.B. El-Serag.

Analysis and interpretation of the data: J.A. Davila, L. Henderson, J.R. Kramer, F. Kanwal, P.A. Richardson, Z. Duan, H.B. El-Serag.

Drafting of the article: J.A. Davila, P.A. Richardson, H.B. El-Serag.

Critical revision of the article for important intellectual content: J.A. Davila, L. Henderson, J.R. Kramer, F. Kanwal, H.B. El-Serag.

Final approval of the article: J.A. Davila, L. Henderson, J.R. Kramer, F. Kanwal, Z. Duan, H.B. El-Serag.

Provision of study materials or patients: J.A. Davila.

Statistical expertise: J.A. Davila, L. Henderson, P.A. Richardson, Z. Duan.

Obtaining of funding: J.A. Davila, J.R. Kramer, H.B. El-Serag.

Administrative, technical, or logistic support: J.A. Davila.

Collection and assembly of data: J.A. Davila, L. Henderson, J.R. Kramer, Z. Duan.


Ann Intern Med. 2011;154(2):85-93. doi:10.7326/0003-4819-154-2-201101180-00006
Text Size: A A A

This article has been corrected. For original version, click "Original Version (PDF)" in column 2.

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown.

Objective: To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States.

Design: Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry.

Setting: 128 VA medical centers.

Patients: HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005.

Measurements: Abdominal ultrasonography and measurement of α-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression.

Results: 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance.

Limitations: Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured.

Conclusion: Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice.

Primary Funding Source: Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute.

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Comments

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Prevention of hepatocellular carcinoma and Evidence Biased Screening
Posted on January 24, 2011
Alain Braillon
Gres
Conflict of Interest: None Declared

Davila et al showed that in a series of 13,002 patients with hepatitis C virus infection and hepatitis C virus (HCV) infection and cirrhosis, screening for hepatocellular carcinoma (HCC) is an enduring mistake.(1) Indeed, utilization of routine surveillance only occurred in 12.0%. This very poor surveillance may only suggest that the healthcare professionals do not trust the recommendation made by the screening advocates.

Screening is a complex issue which necessitates a national program to ensure a minimal participation, quality controls, and evaluation of the results, which is not the case.

The program must be defined by evidence based surveillance tests: a) AFP is inadequate whatever the cutoff is; b) ultrasonography is very operator dependent and many prefer CT scanning; c) the interval between tests range from to 4 to 12 months.

Last but not least the recommendation is not evidence based. Only inconclusive or negative observational studies are available. Negative because despite they concluded that screening improved survival, when looking at the raw data every one can see that screened patients died younger than non screened patients.(see 2 for references) This not only ignorance of time biases, it is also an enduring denial. I just reviewed a large series with similar biases but the authors resubmit to another journal without any change and the editor refused to publish a correspondence describing the severe limitations of the study.(3)

Why hepatologists cannot perform randomized trials for HCC, as gastroenterologists for colo-rectal cancer or urologist for prostate cancer, to investigate benefits and harms (overdiagnosis)? Recruiting is not the issue: HCC is the fifth most common cause of cancer.

Screening advocates must understand that patients deserve evidence- based treatments and that poor evidence is a leading cause of poor compliance, a situation precluding efficiency for any screening policies.

Promoting smoking cessation, informing on limitation of alcohol intake, and vaccinating against hepatitis B virus are the three most cost- effective measures to prevent HCC. How are they utilized?

References

1 Davila JA, Henderson L, Kramer JR et al Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med. 2011;154(2):85-93.

2 Braillon A. Screening for hepatocellular carcinoma: from lack of evidence to common sense. Hepatology. 2010;52(5):1863-4.

3 El-Zayadi AR, Badran HM, Shawky S, Emara S, El-Bareedy A, Sobhi M. Effect of surveillance for hepatocellular carcinoma on tumor staging and treatment decisions in Egyptian patients. Hepatol Int. 2010;4(2):500-6

Conflict of Interest:

None declared

Focussed surviellance for HCC
Posted on January 27, 2011
Praveen Guturu
University of Texas Medical Branch
Conflict of Interest: None Declared

We read the recent article by Davila et.al (1 ) with interest and agree with their conclusion that new strategy is needed to increase hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis. With recent advancements in treatment of HCC it becomes more important to identify patients with HCC at an early stage. According to current guidelines every patient with cirrhosis should get HCC surveillance, considering the very low surveillance rates reported in this article (12%) it seems we are a fair way away from the ideal situation.

So we raise this question: if we know which patient factors/characteristics are associated with advanced HCC, would that allow us to identify and focus on patients at greatest risk?

To address the question we performed a retrospective analysis at our institute to identify the factors predictive of advanced HCC at diagnosis. We identified the patients diagnosed with HCC at our institute (University of Texas Medical Branch) from 01/2007 till 05/2010 and categorized into early stage or advanced stage based on number and size of lesions, portal vein (PV) invasion, nodal, and distant spread. Patients with > 3 lesions, size > 3cm, bi-lobar disease, PV invasion, and metastases were defined as advanced stage HCC.

Total of 122 patients with HCC (55 in early group I and 67 in advanced group) were analyzed. In comparison to early stage HCC at diagnosis, patients with advanced disease at presentation were younger (mean age 58.5 ? 9 years vs. 55.4 ? 6 years; p=0.032) and more likely to be males (78 vs. 94%; p=0.0099). There were no differences between the two groups with regards to patient' race, previous known diagnosis of cirrhosis, indication for work-up (screening or for diagnosis), and laboratory parameters including AFP values. On logistic regression analysis, age of the patient independently predicted advanced stage HCC at the time of diagnosis: Odds ratio (OR) of 2.5 [95% CI: 1.25-5.01] for every decade decrease in age.

Analysis using age as a class variable, results showed that patients aged 50-59 years as compared to aged 60 or above were 2.8 times more likely to be in advanced stage HCC at presentation: Odds ratio (OR) of 2.8 (95% CI 1.02-7.80).

Results of our analysis of advanced stage HCC occurring more frequently in younger males could have implications in future surveillance strategies, if these data are confirmed in larger future studies.

Reference:

1) Davila JA, Henderson L, Kramer JR et al Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med. 2011;154(2):85-93.

Conflict of Interest:

None declared

Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States
Posted on January 28, 2011
Michael J. Kelley
Duke University Medical Center, Chief, Hematology/Oncology Durham Veterans Affairs Medical Center, D
Conflict of Interest: None Declared

Dear Editor,

In a recent report in the Annals, Davila et al. examined administrative data in the Veterans Health Administration (VHA) and observed low rates of screening for hepatocellular cancer (HCC) within the first four years after cirrhosis diagnosis (1). They conclude that new strategies are needed to improve the implementation of HCC "surveillance" in clinical practice.

There are no randomized controlled trials (RCT) that support screening for HCC among individuals with hepatitis C and cirrhosis. Neither the US Preventive Services Task Force nor the National Cancer Institute have recommended such screening and VHA has not adopted a practice guideline recommending screening for HCC in any population. The single "positive" RCT of screening for HCC was performed in Shanghai, China among middle-aged individuals, primarily those with hepatitis B without cirrhosis (2). This trial demonstrated a 37% (HR 95% CI 0.41- 0.98) reduction in HCC-attributed mortality but also suggested overdiagnosis (OR 1.37; 95% CI 0.99-1.87). Another RCT of screening in men with chronic hepatitis B infection did not show a reduction in HCC mortality despite also showing a shift to early stage at diagnosis and improvement in survival rates (3).

The hepatitis B virus is thought to be directly oncogenic and HCC frequently occurs in infected individuals without cirrhosis; thus, many such individuals are potentially eligible for curative-intent HCC treatments. In contrast, in individuals with hepatitis C, HCC occurs after development of much more advanced liver disease, which may limit the opportunity for curative treatment even among those with screen-detected HCC. In addition, potential overdiagnosis places screened individuals at risk of increased morbidity and mortality from unnecessary diagnostic and therapeutic interventions. In situations where there is the potential for harm, most ethicists place the burden of proof on those advocating action (in this case, screening) (4). In the absence of such proof, inaction (i.e., not screening) should be the recommended practice.

Given the lack of evidence to support HCC screening in individuals with hepatitis C and cirrhosis and the potential for harm from doing screening, it is reassuring that rates of such screening in VHA are not high. A more appropriate conclusion of Davila's et al.'s study is that strategies are needed to further reduce screening for HCC in patients without hepatitis B until and unless high level evidence is available to support broader screening for HCC.

Michael J. Kelley, MD, FACP Associate Professor of Medicine Duke University Medical Center Chief, Hematology/Oncology Durham Veterans Affairs Medical Center Durham, NC

References:

1. Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med. 2011;154(2):85-93.

2. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(7):417-22.

3. Chen JG, Parkin DM, Chen QG, Lu JH, Shen QJ, Zhang BC, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen. 2003;10(4):204-9.

4. Malm HM. Medical screening and the value of early detection. When unwarranted faith leads to unethical recommendations. Hastings Cent Rep. 1999;29(1):26-37.

Conflict of Interest:

None declared

Hepatocellular Carcinoma screening in Hepatitis C in the VA
Posted on January 28, 2011
Steven H Smoger
VA Louisville
Conflict of Interest: None Declared

I have two comments regarding Davila et al study regarding VA screening for HCC in hepatitis C patients.

First, in their Table one they list the number of women as over 12,000 and the number of men as very low. I believe these should be switched, as is evident from other tables.

Second, they make no mention in the article about the use of CT scanning as a technique in screening. Our facility has enacted an alert on any cirrhosis patient asking providers to use ultrasound screening for these patients. I find that not infrequently these patients have CT scans done for other reasons (such as abdominal pain, hematuria, admissions for ascites). Although not the recommended screening technique, the use of CT scanning may increase the screening numbers to some degree.

Conflict of Interest:

None declared

Rapid response to reader comments
Posted on March 6, 2011
Jessica A. Davila
Baylor College of Medicine
Conflict of Interest: None Declared

Hepatocellular carcinoma (HCC) is the fastest rising cancer in the United States. We recently reported an underutilization of surveillance for HCC in hepatitis C-infected patients with cirrhosis (1). In this study of US veterans, as well as in our previous study conducted in a non-VA population, we provide evidence that adherence to clinical practice guidelines for HCC surveillance is poor (1,2).

Practice guidelines disseminated from the American Association of the Study of Liver Diseases and the European Association for the Study of Liver recommend HCC surveillance every 6 to 12 months in patients with cirrhosis(3). Similarly, VA clinical practice guidelines also recommend that patients with cirrhosis undergo surveillance at 6 to 12 month intervals (4).

Liver ultrasound is the primary imaging modality recommended for HCC surveillance (3). Nevertheless, VA clinical practice guidelines allow for the substitution of a CT or MRI (4). In our study, only 1.3% of patients received a CT or MRI for any purpose in the first year following their cirrhosis diagnosis.

The absence of evidence from multiple randomized controlled trials to support HCC surveillance in hepatitis C patients is unfortunate. The only two randomized controlled trials have been conducted in China among individuals with hepatitis B infection. However, this is not equivalent to the unqualified statements of "lack of evidence" made by Drs. Braillon and Kelley, as in addition to the Chinese randomized trials, many observational studies from several countries have supported a modest effectiveness of surveillance in patients with cirrhosis.

Given the publication of practice guidelines, a randomized controlled trial of HCC surveillance with a placebo arm is unlikely. However, randomized controlled trials to evaluate different methods, frequency, and follow-up strategies are warranted and may provide answers about the efficacy of surveillance.

Until data from a randomized controlled trial are available, we (and multiple practice guidelines) contend that physicians should practice HCC surveillance in at-risk patients. With several efficacious treatments now available for HCC, early detection followed by stage-appropriate treatment remains the best strategy for reducing mortality from this highly fatal disease. The observed underutilization of HCC surveillance is not commendable, nor does it reflect a cognitive decision based on well-formulated opinions by practitioners about levels of evidence. Rather it is one part of suboptimal care for patients with chronic liver disease that spans a large spectrum including treatment for HCV, vaccination for viral hepatitis, low referral for liver transplant, and HCC treatment (5).

References

1. Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, El-Serag HB. Utilization of Surveillance for Hepatocellular Carcinoma Among Hepatitis C Virus-Infected Veterans in the United States. Ann Intern Med 2011;154-85-93.

2. Davila JA, Morgan RO, Richardson PA, Du XL, McGlynn KA, El-Serag HB. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology. 2010; 52:132-141.

3. Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology. 2011 Mar;53(3):1020-2.

4. VA Public Health Strategic Health Care Group. Hepatitis C. Accessed at www.hepatitis.va.gov on 26 February 2011.

5. Kramer JR, Hachem CY, Kanwal F, Mei M, El-Serag HB. Meeting vaccination quality measures for hepatitis A and B virus in patients with chronic hepatitis C infection. Hepatology. 2011 Jan;53(1):42-52.

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

Screening for Liver Cancer in Patients With Hepatitis C Virus Infection and Cirrhosis

The full report is titled “Utilization of Surveillance for Hepatocellular Carcinoma Among Hepatitis C Virus–Infected Veterans in the United States.” It is in the 18 January 2011 issue of Annals of Internal Medicine (volume 154, pages 85-93). The authors are J.A. Davila, L. Henderson, J.R. Kramer, F. Kanwal, P.A. Richardson, Z. Duan, and H.B. El-Serag.

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