The primary goal of the HALT-C Trial was to determine if ongoing therapy with pegylated interferon monotherapy could suppress the Hepatitis C virus and slow disease progression, including the development of liver cancer in patients who were not able to achieve SVR using pegylated interferon and ribavirin.
Detection of Hepatocellular Carcinoma at Advanced Stages Among Patients in the HALT-C Trial: Where Did Surveillance Fail?
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In this retrospective analysis of HALT-C data, we found that even among patients closely followed by expert hepatologists in academic centers, nearly one-third of patients had inconsistent HCC surveillance. Only 20% of patients who developed HCC were found at a very early stage (TNM stage T1) and over one-fourth of tumors were found beyond Milan criteria. This study is the first that describes the contribution of surveillance process failures to the occurrence of more advanced HCC stage. We found that patients with tumors beyond stage T1 were significantly more likely to have experienced an absence of screening or follow-up, and these surveillance process failures potentially contributed to more advanced tumors in one-third of patients.
The strongest predictor for receipt of consistent surveillance was study site, after adjusting for differences in patient characteristics. Although consistent surveillance was associated with patient-level factors including platelet count and clinic visit adherence, these factors explained a smaller proportion of the variance in surveillance rates. This implies that variations in physician- and system-level factors are more important than patient-level factors in determining surveillance rates, as suggested from prior studies ((14,23)). We examined several potential system-level factors, including general clinical research center support and the number of enrolled patients, but could not identify any factor correlated with consistent surveillance rates. Site-level variation in visit adherence did not explain inter-site difference in consistent surveillance rates. However, we were unable to fully analyze why study site was an important predictor of consistent surveillance given limited data on physician- and system-level factors. We did not have data regarding which study sites covered screening costs or the timing and location of ultrasonography (e.g., on-site on the day of the visit vs. performing locally on a different day). Finally, potentially relevant factors, such as number of study coordinators and study team commitment toward HCC screening, are difficult to measure and may vary during the study.
In clinical practice, inconsistent surveillance could be related to physician-level factors, including under-recognition of at-risk individuals or lack of provider knowledge, clinic time constraints, or physicians forgetting to order surveillance given competing clinical concerns. Several potential barriers, such as under-recognition of the at-risk population, were not present in this setting given that all patients had known advanced fibrosis related to HCV and were followed by hepatologists in academic centers with the aid of a clinical protocol. Furthermore, surveillance rates were similar among patients with and without cirrhosis, so inconsistent surveillance was not related to lower surveillance rates among those without cirrhosis. If physicians forgetting to order surveillance is an important determinant of surveillance underuse, intervention such as reminder systems may be a more effective means to increase HCC surveillance rates than physician education.
Although studies have suggested breakdowns in follow-up may contribute to advanced breast, cervical, and colon cancer, ((9,10)) our study is the first to examine this issue in HCC surveillance. The effectiveness of HCC surveillance is dependent on timely follow-up with cross-sectional imaging among patients with an abnormal surveillance test. We found that follow-up was not completed within 6 months of positive surveillance testing, and therefore may have contributed to more advanced tumor stage, in 25% of patients diagnosed with HCC. Follow-up rates for positive surveillance testing may be even lower in clinical practice, given other potential barriers such as lack of provider knowledge about appropriate follow-up testing, financial barriers, and limited access to CT/MRI imaging. Further studies are necessary to determine specific barriers to follow-up in clinical practice and if there are subgroups of patients at higher risk for not receiving timely follow-up testing.
Although an absence of screening or follow-up was present in one-third of patients with HCC, the most common reason for detecting HCC at a late stage was an absence of detection. Surveillance failure was attributed to an absence of detection in nearly 70% of patients with tumors beyond Milan criteria despite use of both ultrasound and AFP. Ultrasound and AFP had a complementary role in surveillance, as there were several patients whose HCC diagnosis was triggered by AFP without a suspicious mass on ultrasound (19). An effectiveness study recently demonstrated that ultrasound only had a sensitivity of 32% for early stage tumors, which was significantly increased to 63% when used in combination with AFP (24). The variable effectiveness of ultrasound may be related to differences in operator experience and technique, with many patients in the United States receiving their ultrasounds in local community centers instead of tertiary care centers. Furthermore, the ability of ultrasound to accurately visualize the liver in patients with morbid obesity or a very nodular liver may be impaired (25). Although we did not find a difference in detection rates according to BMI, we could not assess the impact of truncal obesity, which might be more important than BMI. Similarly, we did not find a difference in detection rates according to cirrhosis; however, some patients without cirrhosis on baseline biopsies might have had cirrhosis at the time of HCC related to progression of fibrosis or the initial liver biopsy being understaged because of sampling error. It is clear that better surveillance tools, including more accurate biomarkers or more cost-effective advanced imaging with lower radiation risk, are necessary to help improve the sensitivity of finding tumors at an early stage. Until that time, removal of AFP from the AASLD guidelines may decrease the sensitivity of surveillance to find HCC at an early stage.
Our study has several limitations. We used data from the HALT-C Trial, which followed highly compliant patients in a near optimal setting, so our findings may not be generalizable to other clinical settings. However, surveillance process failures are likely to be more prevalent in conventional clinical practice where additional barriers to care are present. Second, it is possible that some patients had imaging performed, for surveillance or follow-up purposes, without being recorded in the HALT-C database. Although HCC surveillance was not the primary focus of HALT-C, the development of HCC was an important study outcome and the protocol included a standardized HCC surveillance algorithm. Given the prospective nature of HALT-C and that HCC outcomes were a secondary aim, we believe this would account for a minority of surveillance process failures. Finally, our analysis was limited by missing data given that this was a secondary analysis of the HALT-C Trial. We were only able to determine follow-up rates for positive surveillance testing among patients with HCC given that data regarding CT or MRI imaging was not routinely collected on all patients. Our ability to examine why study site was an important predictor of consistent surveillance was restricted by limited data on physician- and system-level factors. The study's strengths include its large well-characterized cohort and prospective data collection system, providing near optimal conditions for a surveillance study.
Although optimal surveillance protocols, including novel effective biomarkers, are still evolving, these data provide insights into the contribution of surveillance process failures to the occurrence of advanced HCC. The most common reason for finding HCC at a late stage was an absence of detection by ultrasound and AFP. However, patients with tumors beyond stage T1 were also significantly more likely to have experienced an absence of screening or follow-up, and these surveillance process failures potentially contributed to more advanced tumors in over one-third of patients under near-optimal conditions. Further studies are needed to determine the prevalence and impact of surveillance process failures in clinical practice.
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