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Surveillance for Hepatocellular Carcinoma: Local vs Non-local Ultrasound

This study investigates the effectiveness of surveillance for hepatocellular carcinoma (HCC) using "local" or "non-local" ultrasound screenings. The aim is to evaluate the impact on patient survival and compare the two approaches.

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Surveillance for Hepatocellular Carcinoma: Local vs Non-local Ultrasound

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  1. Surveillance for hepatocellular carcinoma promotes cancer diagnosis at early stages and improves survival employing both, “local” or “non-local” ultrasound. • Authors: Federico Piñero1,11,12, Fernando Rubinstein15, Sebastián Marciano2, Nora Fernández5, Jorge Silva10, Yanina Zambelo8, Margarita Anders4, Alina Zerega9, Ezequiel Ridruejo1,3, Carlos Miguez6, Beatriz Ameigeiras14, Claudia D’Amico13, Luis Gaite7, Carla Bermúdez2, Carlos Rosales10, Gustavo Romero6, Lucas McCormack4, Virginia Reggiardo8, Luis Colombato5, Adrián Gadano2 and Marcelo Silva1 • 1. Hospital Universitario Austral, Universidad Austral, Facultad de Medicina, Argentina. 2. Hospital Italiano from Buenos Aires. Sección Hepatología, Departamento de Investigación.3.Centro de EducaciónMédica e InvestigacionesClínicas Norberto Quirno (CEMIC).4.Hospital Alemán from Buenos Aires.5.Hospital Británico from Buenos Aires.6.Hospital Udaondo, Buenos Aires.7.Clínicade Nefrología from Santa Fe.8.Hospital del Centenario, Rosario, Santa Fe.9.Hospital Privado from Córdoba.10.Hospital G Rawson, San Juan.11.Sanatorio Trinidad San Isidro. Buenos Aires.12. ClínicaPrivada San Fernando. Buenos Aires.13.Centro EspecialidadesMedicasAmbulatorias (CEMA), Mar del Plata, Buenos Aires.14.Hospital Ramos Mejía, Ciudad de Buenos Aires. • 15. Institutode EfectividadClínica y Sanitaria (IECS).

  2. Introduction. • Surveillance for HCC is mandatory in patients with cirrhosis irrespective of etiology and in all patients with chronic hepatitis B infection (HBV). • Biannual ultrasound (US) is recommended as the clinical screening tool for HCC; highly specific, although not enough sensitive. Ultrasound sensitivity has several threats. In the first place, it depends on the operator. • That is the very reason why international guidelines recommend that expert sonographers should perform US screening. • In the daily practice, trained US experts in specialized centers usually perform HCC screening, while in tertiary centers a generalist sonographer performs it. Heimbach J, Kulik LM, Finn R, Sirlin CB, Abecassis M, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358-380. Méndez-Sánchez N, Ridruejo E. Latin American Association for the Study of the Liver (LAASL) Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Annals of Hepatology 2014;13(1):S4-40. Zhang B-H, Yang B-H, Tang Z-Y. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res ClinOncol. 2004;130(7):417-22. Chen J-G, Parkin DM, Chen Q-G, Lu J-H, Shen Q-J, Zhang B-C, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen. 2003;10:204–209. SingalA, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Alimentary Pharmacology & Therapeutics. 2009;30:37–47.

  3. Aim. • To the best of our knowledge, the effectiveness of US performed in specialized centers or "local US" compared with non-specialized or "non-local" centers has not been previously evaluated. • Therefore, our aim was to evaluate the adjusted treatment effect (ATE) of surveillance on patient survival and compare the effect of localvsnon-local US screening upon survival in the daily practice.

  4. Methods. • This was a dual cohort study conducted between January 1 2009 and January 1 2016 in 14 different regional hospitals from Argentina. Cohort 1 or retrospective (2009-September 2014). Cohort 2 or prospective: September 2 2014-January 2016. • Criteria for inclusion: newly diagnosed HCC as recommended by international guidelines. • Patients were categorized as receiving surveillance for HCC if at least 2 consecutive US were performed every 6 months as recommended by international guidelines. • The site where the last ultrasound (US) was performed was categorized as “local” if this US was done in the same hospital by experienced operators or “non-local or external” if it was not done in the local center by non-experienced operators. • Tumor burden was classified according to Barcelona Clinic Liver Cancer criteria (BCLC) at HCC diagnosis.Serum alpha-fetoprotein (AFP) levels at HCC diagnosis: ≤100 ng/ml, 101-1000 ng/ml and >1000 ng/ml. Heimbach J, Kulik LM, Finn R, Sirlin CB, Abecassis M, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358-380. Méndez-Sánchez N, Ridruejo E. Latin American Association for the Study of the Liver (LAASL) Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Annals of Hepatology 2014;13(1):S4-40. Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul J-L, Schirmacher P, Vilgrain V. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2018

  5. Study End-Points. • Primary end-point: 5-year overall survival*. • Secondaryend-points: • Surveillancefailure: surveillance failure was defined as HCC diagnosis not meeting BCLC 0-A stages. • *For survival analysis: Patient follow-up was defined as date of HCC diagnosis or first date on medical record at the site where the patient was seen for HCC, whichever was earlier, until death or end of study. • All procedures followed were in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Elm von E, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–1457.

  6. Statistical Analysis. • Survival analysis: multivariate Cox regression with hazard ratios (HR) and 95% CI. Kaplan Meier survival curves were compared using the log-rank test. Proportional hazards assumption and Harrell’s c-statistic index. • Multiple logistic regression analysis*: associated variables with surveillance. Odds Ratios (OR) and its corresponding 95% CIs. Calibration and discrimination power: Hosmer-Lemeshow test and receiving operator curve (ROC). • Propensity score matching (PS), to adjust for group differences and reduce confounding bias. Probability of being screened as a function of different variables and used that score as a single matching covariate. Variables included in the model were those included in the final logistic regression model*. • Finally, in order to estimate the adjusted average treatment effect (ATE) of this intervention in the context of an observational study, we used inverse probability weighting (IPW) as a strategy for causal inference. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Statist Med 2013;33:1242–58. doi:10.1111/j.1541-0420.2005.00356.x.

  7. Results.

  8. Surveillancepromoted HCC diagnosis at BCLC 0-A stages. P<0.0001

  9. Surveillancepromotedbetteroverallsurvival.

  10. Baseline variables associated with HCC surveillance. Logistic Regression Analysis, Odds Ratios (OR).

  11. Propensity Score Matching (PS). Inverse Probability Weighting (IPW). The adjusted HR of surveillance was 0.53 (CI 0.38;0.73). Finally, we estimated the adjusted treatment effect (ATE) using inverse probability weighting (IPW), which showed that surveillance added 9.4 months to baseline survival (subject not under surveillance). Patients under surveillance had a significantly longer overall survival when compared with those without surveillance [25.2 months (CI 20.1;30.3) versus 15.8 months (CI 11.6;20.1) (P<0.0001)], even adjusted for BCLC 0-A stages.

  12. Patients’ characteristics with localversus non-local surveillance.

  13. Survival effect according to localversus non-local surveillance. Patients under non-local US were less frequently under surveillance when compared to those with local US (44.5% vs. 100%; P<0.0001). The effect upon survival in patients whom surveillance was correctly done was not significantly different either with local or non-local US [HR 0.74 (CI 0.49;1.13)] Rates of surveillance failure were similar between local or non-local US (32% vs. 26.3%; P=0.25).

  14. Conclusions. • As expected, routine surveillance was more likely to detect HCC at BCLC stages 0-A. • After adjusting for the PS and BCLC stage, surveillance was associated with a mortality relative risk reduction of 47% (CI 27%;62%). • Surveillance ATE showed a significant longer overall survival when compared with those without surveillance. • This survival benefit effect might be probably due to a high probability of receiving curative treatments among patients under surveillance. • Routine surveillance for HCC in the daily practice improved survival either with local or non-local US and this effect persisted after controlling for stage at diagnosis.

  15. Agradecimientos. SebastiánMarciano, Nora Fernández, Jorge Silva, YaninaZambelo, Margarita Anders, AlinaZerega, EzequielRidruejo, Carlos Miguez, Beatriz Ameigeiras, Claudia D’Amico, Luis Gaite, Carla Bermúdez, Carlos Rosales, Gustavo Romero, Lucas McCormack, Virginia Reggiardo, Luis Colombato, AdriánGadano Fernando Rubinstein Marcelo Silva

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