Surveillance for Early Diagnosis of Hepatocellular Carcinoma in Intermediate and Advanced Cirrhosis

1. Surveillance for Early Diagnosis of Hepatocellular Carcinoma in Intermediate and Advanced Cirrhosis Narges Farahi, MD March 12, 2008

2. Background: Mr.. C 44 year-old man with h/o HBV and Child-Pugh Class C cirrhosis Screened with AFP - 8/04: 20, 3/05: 10, 6/05: 7, 11/07: 1355 (lost to follow-up 2005-2007) Followed with imaging - MRI abdomen after elevated AFP in 2004, 2005, 2007 12/07: Lesions consistent with multifocal HCC Diagnosed with Hepatocellular Carcinoma - by AFP and imaging criteria

3. Background: Screening Screening: A test performed on asymptomatic individuals that allows for early detection, therapeutic intervention, and decreased mortality from the disease Surveillance is the repeated application of screening test

4. Background: Screening Principles of Screening: Significant burden of disease in population Preclinical stage is detectable and prevalent Effective treatment available for disease Early detection and treatment improves outcome (mortality) with acceptable morbidity Screening tests are acceptable to population, inexpensive, and sufficiently accurate

5. Background: HCC Fourth most common cause of cancer death worldwide Increasing incidence in the United States Poor prognosis: 5-year survival rate 5% in the U.S. Diagnosis is often made at an advanced stage Small HCC can be cured: 5-year disease-free survival > 50% reported for both resection and liver transplantation

6. Background: The Guidelines(American Association for the Study of Liver Disease) Who to Screen? Patients at high risk (>1.5%) for HCC (LOE I) Note: Specific groups listed based expert opinion (LOE III)

7. Background: The Guidelines(American Association for the Study of Liver Disease) Who to Screen? Patients on liver transplant list (LOE III) In the U.S., development of HCC gives increased priority fo OLT

8. Background: The Guidelines(American Association for the Study of Liver Disease) How to Screen? Ultrasound (LOE II) Better than serologic tests Sensitivity 65-80%, Specificity >90% AFP should not be used alone (LOE II) Poor screening test 20ng/mL: 60% sensitivity, 41.5% PPV if 5% prevalence Screening interval 6 to 12 months (LOE II)

9. Background: The Evidence One large RCT showed that surveillance prolongs survival in patients with Hepatitis B 2 cohort studies found that surveillance: - prolonged survival in patients with Child-Pugh Class A cirrhosis - did not improve survival in Class C - role in Class B unclear Advances in both management of cirrhosis and treatments for HCC may increase the benefit of surveillance for patients with advanced cirrhosis

10. Background: Classifications

11. The Study Question

12. Methods: The Patients

13. Methods: The Patients

14. Methods: The Patients To minimize length bias, patients under surveillance who received US secondary to symptoms (41 patients) remained in Group 1 Length bias: apparent improvement in survival due to the preferential detection of prevalent, slower growing cancers by screening Most (80%) Group 1 patients were under the care of a ITA.LI.CA group clinician. Most Group 2 cases were referred from outside physicians.

15. Methods:Etiology and Diagnosis of Cirrhosis Classification of etiology of liver disease: HBV, HCV, Alcoholic Multietiology Others: hemochromatosis, primary biliary cirrhosis, cyptogenic Diagnosis of cirrhosis: Most based on clinical (radiologic/endoscopic) and laboratory features Histology in 168 patients Laparotomy/laparoscopy in 10 patients

16. Methods:Diagnosis of HCC Histology or cytology in 42 patients In the others, diagnosis made by: 1) Diagnostic AFP (>200 ng/mL) with a typical lesion on one imaging technique OR 2) Typical-appearing lesion on two imaging techniques in the absence of diagnostic AFP

17. Methods:Staging of HCC By both US and CT scan or MRI Macroscopic classification: unifocal, paucifocal (< or = 3 nodules), multifocal (>3 nodules), infiltrating, massive Scored by latest United Network for Organ Sharing (UNOS) TNM and Cancer of the Liver Italian Program (CLIP) systems

18. Methods: Statistical Analysis Primary outcome was all-cause mortality Survival time was adjusted for lead time bias No multivariate analysis was conducted for the primary outcome The following variables were tested as predictors of survival by univariate analysis: Age, sex, etiology, time of diagnosis, comorbidity, surveillance, ALT, AFP level, gross pathology, cancer size, portal vein/caval thrombosis, metastases, treatment Those significantly associated, were tested by multivariate analysis.

19. Results

20. Results In Child-Pugh C patients, no significant difference between groups in most demographic and clinical characteristics, except AFP levels

21. Results Tumor Features Group 1 with more favorable features in Class B and C: More single nodules Smaller tumor diameter and less vascular invasion Earlier stage cancer (62% T1 or T2 stage vs. 26% in group 2 in Class B, 53% vs. 26% in Class C) Treatment More surgery or percutaneous treatment in group 1 More systemic treatment and palliation in group 2 Difference more marked in Class B patients

22. Results Class B

23. Results: Survival Child-Pugh Class B: Prolonged survival in surveillance group Median survival 17.1 months vs. 12.0 months Survival adjusted for estimated lead time

24. Results: Survival Child-Pugh Class B: Subset analysis excluding transplanted patients showed that no statistically significant difference existed between groups No other subset analyses were completed Child-Pugh Class C: No statistically significant difference in survival between groups

25. Results: Predictors of Survival

26. Study Strengths Study addressed an important clinical question that affects a large number of patients with intermediate and advanced cirrhosis Measures were taken to reduce length bias and lead time bias in the evaluation of the efficacy of screening

27. Study Limitations Selection bias Non-randomized allocation of patients to surveillance led to significant differences among groups: - academic center vs. referring hospitals - etiology of cirrhosis (viral, alcoholic) These differences may have affected the therapeutic options available to the patients Example: patients in academic centers may have greater access to OLT

28. Study Limitations No true control arm: Some patients in group 2 did receive screening, although not in surveillance program It remains unclear who will benefit from surveillance: benefit only shown in patients with Child-Pugh Class B cirrhosis who underwent OLT, but no other sub-group analyses reported

29. Bottom Line This study supports surveillance for patients with Child-Pugh Class B Cirrhosis using ultrasound and AFP. This applies to those patients who would be candidates for treatment if HCC is detected. It does not support surveillance for Child-Pugh Class C Cirrhosis, which is consistent with prior studies This does not significantly impact the group of patients who should be offered screening, since practice guidelines in the United States do not differentiate who should receive screening based on severity of cirrhosis

30. Reference Trevisani F, Santi V, Gramenzi A, et al. Surveillance for Early Diagnosis of Hepatocellular Carcinoma: Is It Effective in Intermediate/Advanced Cirrhosis? Am J Gastroenterol 2007;102:2448-2457.

31. Other References 1. Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005;42:1208-36. 2. Yuen MF, Cheng CC, Lauder IJ, et al. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000;31:330-5. 3. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;127:35-50.

32. Acknowledgements Dave Thom, MD, PhD