HCC (Liver cancer) Screening Improves Survival
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from Jules: many HCV+ patients who should be screened for HCC are not but they are supposed to be screened. HCC screening is a must with HCV+ patients with advanced liver disease (ultrasound, MRI). Even after an SVR is achieved an MRI every 6 months forever is required because the risk of HCC still persists although due to achieving an SVR at a much lower risk level
AASLD: THE RISK FOR HCC AMONG PATIENTS WITH CHRONIC HCV INFECTION AND ADVANCED HEPATIC FIBROSIS FOLLOWING SVR - (11/08/13)
AASLD: HCV Treatment Reduces Liver Disease/Death/Transplant - (11/18/13)
"Effective ....birth cohort screening.......and widespread use of highly effective therapies reduces the burden of liver disease" from Jules: looking at the graphs in this report show a reduction of 80% in liver disease, deaths, transplantation etc.
"combination of an increased rate of access and optimal effectiveness of HCC screening would increase the LE by 31 months and decreased HCC mortality at 5 years by 20% (P<0.001)"
"The efficacy of HCC screening described in RCTs (16-17) may be due to highly experienced operators and centers, standard quality US material, selection of patients and strict follow-up. Therefore, we strongly recommend that clinicians and policymakers target the effectiveness of US screening to improve survival in HCC patients.
In summary, the present study shows that US screening for HCC in compensated HCV-related cirrhosis improves survival, and emphasizes the importance of screening effectiveness. Policy makers and experts should recommend better training for US operators, standard quality US materials,
better education of patients in terms of compliance, better quality follow-up and an improved multidisciplinary network to increase awareness of the benefits to survival of HCC screening in patients and for general practitioners."
HCC screening in patients with compensated HCV-related cirrhosis aware of their HCV-status improves survival: A modeling approach
Hepatology Nov 2013
Because of the ongoing debate on the benefit of ultrasound (US) screening for HCC, we assessed the impact of screening on HCV-related compensated cirrhosis aware of their HCV status. A Markov model simulated progression from HCC diagnosis to death in 700 patients with HCV-related compensated cirrhosis aware of their HCV status to estimate life expectancy (LE) and cumulative death at 5 years.
Five scenarios were compared: S1, no screening; S2, screening by currently existing practices (57% access and effectiveness leading to the diagnosis of 42% at stage BCLC-0/A); S3, S2 with increased access (97%); S4, S2 with an efficacy of screening close to that achieved in a randomized controlled trial leading to the diagnosis of 87% of patients at stage BCLC-0/A; S5, S3+S4. The analysis was corrected for lead-time bias. Currently existing practices of HCC screening increased LE by 11 months and reduced HCC mortality at 5 years by 6% compared to no screening (P=0.0013). Compared to current screening practices we found that: a) increasing the rate of access to screening would increase the LE by 7 months and reduced HCC mortality at 5 years by 5% (P= 0.045); b) optimal screening would increase the LE by 14 months and reduced HCC mortality at 5 years by 9% (P=0.0002); c) combination of an increased rate of access and optimal effectiveness of HCC screening would increase the LE by 31 months and decreased HCC mortality at 5 years by 20% (P<0.001).
Conclusion: The present study shows that US screening for HCC in patients with compensated HCV-related cirrhosis aware of their HCV status improves survival and emphasizes the crucial role of screening effectiveness.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and represents 7% of all cancer-related deaths (1). HCC mainly develops in patients with cirrhosis. Patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) have a yearly risk of HCC of approximately 2-5% (2-3). Prognosis is very poor due to late diagnosis, which often prevents curative treatment (4).
Recent EASL and AASLD guidelines (4-5) have recommended the Barcelona Clinic Liver Cancer (BCLC) classification staging system for the management of HCC (6). A therapeutic algorithm was developed based on the BCLC classification with four stages (0/A, B, C and D). Curative treatment (surgical resection, liver transplantation (LT) and radio-frequency ablation) is destined for patients with early stage HCC (BCLC-0/A). These curative treatments are the only chance of survival, with an overall three-year survival rate of approximately 80% (4, 7). Patients with intermediate stage disease (BCLC-B) can benefit from transarterial chemo-embolization, with a three-year survival rate of approximately 30% (8). Sorafenib is the only therapeutic option for patients with advanced HCC
Screening of patients with cirrhosis includes tests or examinations to detect early stage cancer and increase the chance of optimal therapeutic options. Screening has been shown to effectively diagnose early stage HCC in randomized controlled trials (RCTs) (10-11), controlled and uncontrolled studies (12-15). The benefit of ultrasound (US) in the detection of early stage HCC has also been confirmed in RCTs (16-17). Screening is considered to be validated when there is strong evidence that it improves survival. Although International guidelines recommend US screening of patients with cirrhosis every 6 months by experienced personnel (4-5), experts continue to seek conclusive evidence that HCC screening improves survival (10-11, 18-20). The most effective way to
evaluate the impact of HCC screening on survival would be to perform a RCT assessing the influence of screening in patients with compensated cirrhosis who are candidates for curative treatment. However, randomization is considered to be unethical by patients and clinicians, who refuse to prevent patients from receiving the benefits of screening, i.e. early stage diagnosis (21). Controlled or
uncontrolled cohort studies may be an alternative approach. However, besides their well known limitations, non-RCTs also have a lead-time bias (an apparent improvement in survival due to early diagnosis) although certain studies have taken this bias into account (19, 22-24). A recent cohort study questioning the impact of HCC screening on survival in patients with alcoholic cirrhosis has
added to this controversy (25). However, that study had a major bias because it included patients with decompensated cirrhosis in whom curative therapies are usually not indicated.
The use of a model based approach is complementary to controlled and uncontrolled studies because it has different goals and uses an analytic methodology that accounts for events over time and across populations. Because of the methodological issues of HCC screening, modeling can be
interesting to determine the impact of HCC screening on survival and to test different screening protocols with corresponding therapeutic options according to tumor stage. It can also take into account the lead-time bias. To develop a model, data on the progression of HCC, on the impact of therapeutic options on survival, on the availability of liver grafts for HCC patients and on the probability of entering into a screening program and being treated according to tumor stage, must all be robust (16, 26). Because these data are often available for HCV patients and because most patients with decompensated cirrhosis are not candidates for treatment, we focused on an HCV related HCC population with compensated cirrhosis to optimize the accuracy of the model.
The goal of this study was to assess the influence of routine US screening for HCC in patients with compensated HCV-related cirrhosis aware of their HCV status upon survival using a model-based analysis by comparing current HCC screening practices to: a) no screening; and b) different scenarios that increase the rate of access to HCC screening and improve the effectiveness of screening.
Our working hypothesis was that HCC screening is related to the awareness of HCV status. Patients had to be aware of their HCV status and have been diagnosed with compensated cirrhosis to be screened for HCC. We first estimated the existing rate of screening for HCC in HCV-related cirrhosis based on data from literature (27). In that cohort (27), 28.5% of all patients with HCV related cirrhosis (aware or not of HCV status) had access to HCC screening. Considering that 49.7% of the HCV patients were aware of their HCV-status (28), we assumed that 57% of these patients had access to HCC screening (i.e.
(49.7%A~access-rate)HCV-known+(50.3%A~0%)HCV-unknown=28.5% => access rate HCV- known=57%). The rates of currently existing practices of HCC screening correspond to the percentage of patients with cirrhosis who have access to HCC screening.
Validity of the model
We validated the predictive performance of the model for yearly HCV-related HCC deaths and yearly LT for compensated HCV-related HCC. First, the relative mean difference between estimated and observed HCV-related HCC deaths from 2002 to 2010 was 1% (range, 0-5%) (Supplementary Figure1). Second, the relative mean difference between estimated and observed numbers of LT for compensated HCV-related HCC was 6% (range, 2-10%) (Supplementary Figure2).
Current HCC screening practices (scenario 2) were associated with a 9-month increase in LE compared to the absence of screening (scenario 1), (Figure 3A). Compared to currently existing practices of HCC screening practices (scenario 2): a) increasing the rate of access to HCC screening from 57% to 97% (scenario 3) increased the LE by 7 months; b) increasing the effectiveness of HCC
screening from 42% to 87% (scenario 4) increased the LE by 14 months; c) improving the rate of access to HCC screening as well as its effectiveness (scenario 5) increased the LE by 31 months (Figure 3B).
HCV-related HCC mortality at 5 years
The five-year risk of HCV-related HCC death was 90.8%, 85.3%, 81.4%, 77.6% and 68.4% in scenarios 1, 2, 3, 4 and 5, respectively (Figure 4). Thus there was a 6% reduction in HCV-related HCC mortality with current HCC screening practices (scenario 2), compared to without HCC screening (scenario 1): RR = 0.95 (CI95%: 0.91-0.98; P=0.0013, Figure 4A). Once again, increasing the rate of
access to HCC screening from 57% to 97% (scenario 3 vs. scenario 2) reduced mortality by 5%: RR = 0.95 (CI95%: 0.91-1.00; P= 0.045, Figure 4B). In contrast the efficacy of HCC screening, such as in clinical trial CHC 2000, significantly improved HCV-related HCC mortality (scenario 4 vs. scenario 2): RR = 0.91 (CI95%: 0.86-0.96; P=0.0002, Figure 4B). Finally, the influence of increasing access to screening and the effectiveness of HCC screening (scenario 5 vs. scenario 2) was even greater: RR = 0.80 (CI95%: 0.75-0.85; P< 0.0001, Figure 4B).
Figure 5 shows the most influential variables in the model. LE and risk of death at 5 years were most sensitive to the effectiveness of HCC screening and the rate of access to HCC screening. When comparing scenario 2 to scenario 1, a) LE increased by 7 to 25 months when varying the effectiveness of screening and by 4 to 14 months when varying the rate of access to screening (11 months in baseline analysis); b) HCV-related HCC mortality was reduced by 4% to 15% when varying the effectiveness of screening (6% in baseline analysis) and by 2% to 10% when varying the rate of access to screening (6% in baseline analysis). Moreover, a 20% rate of access to screening did not significantly impact LE (+4 months) and HCV-related HCC mortality at 5-year (-2%) (P=0.18) (Figure 6).
Therefore, for screening to be beneficial, the minimum rate of access to screening should be 34% with a 42%-effectiveness and the minimum effectiveness of screening should be 31% with a 57%-rate of access to screening. This interaction between the effectiveness and the rate of access to screening
is illustrated in Figure 7. It shows the minimum rate of access and effectiveness of HCC screening necessary for these variables. The results of additional sensitivity analyses are shown in Supplementary material (Supplementary Figures 3 to 5).
American and European guidelines on screening for HCC are a subject of debate (33-34) since some investigators consider that data from RCTs on the impact on survival are not reliable. However it is ethically impossible to perform RCTs to assess the impact of screening on survival with a design
that includes an arm without screening (21). The present study uses a model that provides more facts and less speculation on the survival benefit of HCC screening at diagnosis. All of the different scenarios showed that HCC screening led to a substantial increase in LE and decreased the risk of HCV-related HCC death in patients aware of their HCV status. Scenarios that include improving the effectiveness of HCC screening were the most efficient, with the greatest increase in LE of approximately 31 months for the scenario combining the efficacy of HCC screening with an increase in access to screening. Analysis of the different variations of rates of access to screening and effectiveness of screening show the impact of their interaction on mortality from HCC at 5 years. In France, as in other countries, screening for HCC is not standard in real clinical practice. It
should be noted that screening rates vary drastically according to the type of center and hospital with higher rates of screening for HCC in tertiary-care centers (35) or primary care practices (36) than those observed in the national registration database (27, 37).
Ideally the design of studies testing the benefits of screening on survival should: 1) only include patients with compensated cirrhosis; indeed, patients with decompensated cirrhosis are often not candidates for treatment; 2) provide appropriate therapeutic options to patients, especially
curative treatment for early stage disease; 3) integrate the limited availability of liver grafts; 4) take into account lead-time bias. Most studies have not fulfilled all of these prerequisites. Our study only evaluated patients with compensated cirrhosis. The proportion of HCV-related HCC patients with compensated cirrhosis in whom curative treatment was indicated increased from 14.4% in those without HCC screening to 25.0% with current HCC screening, to 40.0% with an efficacy of screening
corresponding to optimal HCC screening and 58.5% when the rate of access to screening was increased and the effectiveness of screening was improved. We also attributed a limited number of LT based on real-data (38). Finally, we took into account lead-time bias and also performed sensitivity analysis according to tumor growth, thus guaranteeing the reliability of results. However, these results cannot be extrapolated to other etiologies of cirrhosis, since part of the modeling data are lacking for non-HCV-related HCC.
At first glance, increasing the rate of access to screening appears to be an easy way to improve the outcome of patients with HCC. Our baseline assumption of a rate of access to screening of 57% may at first glance appear to be different from the rate of around 20% that has been reported
in the general population (27, 39). However, our study was limited to HCV patients with cirrhosis who were aware of their HCV status while in the global HCV population (aware or not of their virological status), the rate of access to screening access is markedly lower because patients who are not aware of their HCV status, are, by definition, not in an HCC screening program because their liver disease is undiagnosed. Our results show that a 20% rate of access to screening was not effective. Because this rate may reflect the rate of access in the general population with cirrhosis (27, 39), these results strongly suggest that public health policies should not only increase the rate of access to screening in patients aware of their liver disease but also the percentage of patients aware of their HCV status.
The influence of HCC screening on survival has been evaluated in two RCTs (10-11). The first study was inconclusive because a large proportion of diagnosed patients did not receive appropriate treatment (10). Although the second trial showed that HCC screening was beneficial, experts have
shown (34, 40) that there were methodological flaws and limitations in the study design (11). Other cost-effectiveness studies in patients with hepatitis C and cirrhosis concluded that US screening provided a benefit in survival (41-43). The main objective of that study was to identify the most cost effective HCC screening method. Conversely, the goal of our study was to evaluate the impact of US screening on survival in real-life and to test the influence of different strategies to improve current screening practices. As suggested in a prior study (44) our study showed that the effectiveness of HCC screening was the most important variable. Indeed, compared to currently existing practices of HCC screening practices, efficacy of HCC screening increased the number of patients diagnosed with early stage disease (87% vs. 42%) and reduced 5-year mortally by 9%. The efficacy of HCC screening described in RCTs (16-17) may be due to highly experienced operators and centers, standard quality US material, selection of patients and strict follow-up. Therefore, we strongly recommend that clinicians and policymakers target the effectiveness of US screening to improve survival in HCC patients.
As expected in a modeling approach, the present work had several limitations because of data from multiple sources and assumptions. The impact of these weaknesses seems to be limited since we focused on available and robust data from HCV patients. In addition, our study took into account lead-time bias. Moreover, we performed sensitivity analysis to assess the potential impact of uncertainties. The results of these sensitivity analyses did not modify the main conclusions of our study and confirmed the robustness of baseline assumptions.
In summary, the present study shows that US screening for HCC in compensated HCV-related cirrhosis improves survival, and emphasizes the importance of screening effectiveness. Policy makers and experts should recommend better training for US operators, standard quality US materials, better education of patients in terms of compliance, better quality follow-up and an improved multidisciplinary network to increase awareness of the benefits to survival of HCC screening in patients and for general practitioners.