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Original research
Hepatocellular carcinoma tumour volume doubling time: a systematic review and meta-analysis
  1. Piyush Nathani1,
  2. Purva Gopal2,
  3. Nicole Rich1,
  4. Adam Yopp3,
  5. Takeshi Yokoo4,
  6. Binu John5,
  7. Jorge Marrero1,
  8. Neehar Parikh6,
  9. Amit G Singal1
  1. 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  2. 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  3. 3 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  4. 4 Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  5. 5 Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VAMC, Richmond, Virginia, USA
  6. 6 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Amit G Singal, Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA; amit.singal{at}


Background Tumour growth patterns have important implications for surveillance intervals, prognostication and treatment decisions but have not been well described for hepatocellular carcinoma (HCC). The aim of our study was to characterise HCC doubling time and identify correlates for indolent and rapid growth patterns.

Methods We performed a systematic literature review of Medline and EMBASE databases from inception to December 2019 and national meeting abstracts from 2010 to 2018. We identified studies reporting HCC tumour growth or tumour volume doubling time (TVDT), without intervening treatment, and abstracted data to calculate TVDT and correlates of growth patterns (rapid defined as TVDT <3 months and indolent as TVDT >9 months). Pooled TVDT was calculated using a random-effects model.

Results We identified 20 studies, including 1374 HCC lesions in 1334 patients. The pooled TVDT was 4.6 months (95% CI 3.9 to 5.3 months I2=94%), with 35% classified as rapid, 27.4% intermediate and 37.6% indolent growth. In subgroup analysis, studies from Asia reported shorter TVDT than studies elsewhere (4.1 vs 5.8 months). The most consistent correlates of rapid tumour growth included hepatitis B aetiology, smaller tumour size (continuous), alpha fetoprotein doubling time and poor tumour differentiation. Studies were limited by small sample sizes, measurement bias and selection bias.

Conclusion TVDT of HCC is approximately 4–5 months; however, there is heterogeneity in tumour growth patterns, including more aggressive patterns in Asian hepatitis B-predominant populations. Identifying correlates of tumour growth patterns is important to better individualise HCC prognostication and treatment decisions.

  • hepatocellular carcinoma
  • meta-analysis
  • liver imaging

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  • NP and AGS are joint senior authors.

  • Twitter @PiyushNathani3, @NDP1001

  • Correction notice This article has been corrected since it published Online First. A typographical error has been corrected in the title.

  • Contributors AGS and PN had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design (AGS and NP); Acquisition of the data (PN); Analysis and interpretation of the data (PN); Drafting of the manuscript (PN); Critical revision of the manuscript for important intellectual content (all authors); Obtained funding (AGS); Administrative, technical, and material support (AGS); Study supervision (AGS).

  • Funding This work was conducted with support from NIH R01 MD012565 R01 CA222900 and R01 CA212008.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests NP serves as a consultant to Exelixis, Eli Lilly and Bristol-Myers Squibb. He has served on advisory boards for Eisai, Wako Diagnostics and Bayer and has received institutional research funding from Bayer and Exact Sciences. AGS has served on advisory boards or as a consultant for Gilead, Abbvie, Bayer, Genentech, Eisai, Exelixis, Bristol Meyers Squibb, Wako Diagnostics, Exact Sciences, Roche, Glycotest, and TARGET Pharmasolutions.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information. The data supporting this systematic review and meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available in the manuscript and the supplementary files. Additional data can be requested from the corresponding author.

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