Annals of Hepato-Biliary-Pancreatic Surgery (한국간담췌외과학회지)

The Korean Association of Hepato-Biliary-Pancreatic Surgery (한국간담췌외과학회)
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The impact of waiting time and delayed treatment on the outcomes of patients with hepatocellular carcinoma: A systematic review and meta-analysis

  • Received : 2023.07.17
  • Accepted : 2023.08.30
  • Published : 2024.02.29
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Abstract

Hepatocellular carcinoma (HCC) is the sixth most diagnosed cancer worldwide. Healthcare resource constraints may predispose treatment delays. We aim to review existing literature on whether delayed treatment results in worse outcomes in HCC. PubMed, Embase, The Cochrane Library, and Scopus were systematically searched from inception till December 2022. Primary outcomes were overall survival (OS) and disease-free survival (DFS). Secondary outcomes included post-treatment mortality, readmission rates, and complications. Fourteen studies with a total of 135,389 patients (delayed n = 25,516, no delay n = 109,873) were included. Age, incidence of male patients, Child-Pugh B cirrhosis, and Barcelona Clinic Liver Cancer Stage 0/A HCC were comparable between delayed and no delay groups. Tumor size was significantly smaller in delayed versus no delay group (mean difference, -0.70 cm; 95% confidence interval [CI]: -1.14, 0.26; p = 0.002). More patients received radiofrequency ablation in delayed versus no delay group (OR, 1.22; 95% CI: 1.16, 1.27; p < 0.0001). OS was comparable between delayed and no delay in HCC treatment (hazard ratio [HR], 1.13; 95% CI: 0.99, 1.29; p = 0.07). Comparable DFS between delayed and no delay groups (HR, 0.99; 95% CI: 0.75, 1.30; p = 0.95) was observed. Subgroup analysis of studies that defined treatment delay as > 90 days showed comparable OS in the delayed group (HR, 1.04; 95% CI: 0.93, 1.16; p = 0.51). OS and DFS for delayed treatment were non-inferior compared to no delay, but might be due to better tumor biology/smaller tumor size in the delayed group.

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References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 202171:209-249. 
  2. Liao YY, Ou J, Luo CP, Peng NF, Zhong JH. Does delayed treatment affect the survival of patients with hepatocellular carcinoma? Transl Cancer Res 2018;7:E14-E16.  https://doi.org/10.21037/tcr.2018.04.08
  3. Xu K, Watanabe-Galloway S, Rochling FA, Farazi PA, Monirul Islam KM, Wang H, et al. Surgical delay is associated with improved survival in hepatocellular carcinoma: results of the National Cancer Database. J Gastrointest Surg 2019;23:933-943.  https://doi.org/10.1007/s11605-018-3925-4
  4. Kabir T, Syn N, Ramkumar M, Yeo EYJ, Teo JY, Koh YX, et al. Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma: inverse probability of treatment weighting using propensity scores and propensity score adjustment. Surgery 2020;167:417-424.  https://doi.org/10.1016/j.surg.2019.09.022
  5. Tsilimigras DI, Hyer JM, Diaz A, Moris D, Bagante F, Ratti F, et al. Impact of time-to-surgery on outcomes of patients undergoing curative-intent liver resection for BCLC-0, A and B hepatocellular carcinoma. J Surg Oncol 2021;123:381-388.  https://doi.org/10.1002/jso.26297
  6. Rao A, Rich NE, Marrero JA, Yopp AC, Singal AG. Singal, diagnostic and therapeutic delays in patients with hepatocellular carcinoma. J Natl Compr Canc Netw 2021;19:1063-1071.  https://doi.org/10.6004/jnccn.2020.7689
  7. Govalan R, Luu M, Lauzon M, Kosari K, Ahn JC, Rich NE, et al. Therapeutic underuse and delay in hepatocellular carcinoma: prevalence, associated factors, and clinical impact. Hepatol Commun 2022;6:223-236.  https://doi.org/10.1002/hep4.1795
  8. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. 
  9. Lo CK, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers' to authors' assessments. BMC Med Res Methodol 2014;14:45. 
  10. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135. 
  11. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815-2834.  https://doi.org/10.1002/(SICI)1097-0258(19981230)17:24<2815::AID-SIM110>3.0.CO;2-8
  12. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. 
  13. Wagle NS, Park S, Washburn D, Ohsfeldt RL, Rich NE, Singal AG, et al. Racial, ethnic, and socioeconomic disparities in treatment delay among patients with hepatocellular carcinoma in the United States. Clin Gastroenterol Hepatol 2023;21:1281-1292.e10. 
  14. Singal AG, Waljee AK, Patel N, Chen EY, Tiro JA, Marrero JA, et al. Therapeutic delays lead to worse survival among patients with hepatocellular carcinoma. J Natl Compr Canc Netw 2013;11:1101-1108.  https://doi.org/10.6004/jnccn.2013.0131
  15. Tsai WC, Kung PT, Wang YH, Kuo WY, Li YH. Influence of the time interval from diagnosis to treatment on survival for early-stage liver cancer. PLoS One 2018;13:e0199532. 
  16. He Y, Liang T, Mo S, Chen Z, Zhao S, Zhou X, et al. Effect of timing of surgical resection of primary hepatocellular carcinoma on survival outcomes in elderly patients and prediction of clinical models. BMC Gastroenterol 2021;21:230. 
  17. Huo TI, Huang YH, Chiang JH, Wu JC, Lee PC, Chi CW, et al. Survival impact of delayed treatment in patients with hepatocellular carcinoma undergoing locoregional therapy: is there a lead-time bias? Scand J Gastroenterol 2007;42:485-492.  https://doi.org/10.1080/00365520600931402
  18. Lim C, Bhangui P, Salloum C, Gomez-Gavara C, Lahat E, Luciani A, et al. Impact of time to surgery in the outcome of patients with liver resection for BCLC 0-A stage hepatocellular carcinoma. J Hepatol 2018;68:100-108.  https://doi.org/10.1016/j.jhep.2017.09.017
  19. Ong DY, Lee ZY, Pua U. Impact of waiting time on hepatocellular carcinoma progression in patients undergoing curative tumour ablation. Quant Imaging Med Surg 2022;12:1499-1504.  https://doi.org/10.21037/qims-20-1411
  20. Brahmania M, Ahmed O, Kelley M, Wong D, Kowgier M, Khalili K, et al. Wait time for curative intent radio frequency ablation is associated with increased mortality in patients with early stage hepatocellular carcinoma. Ann Hepatol 2017;16:765-771.  https://doi.org/10.5604/01.3001.0010.2776
  21. Chen WT, Fernandes ML, Lin CC, Lin SM. Delay in treatment of early-stage hepatocellular carcinoma using radiofrequency ablation may impact survival of cirrhotic patients in a surveillance program. J Surg Oncol 2011;103:133-139.  https://doi.org/10.1002/jso.21797
  22. Singal AG, Patel NJ, Marrero JA, Tiro JA, Yopp A. 794 institution of a multidisciplinary liver tumor clinic reduces therapeutic delays for patients with hepatocellular carcinoma. Gastroenterology 2013;144:S961. 
  23. Hanna TP, King WD, Thibodeau S, Jalink M, Paulin GA, Harvey-Jones E, et al. Mortality due to cancer treatment delay: systematic review and meta-analysis. BMJ 2020;371:m4087. 
  24. Cone EB, Marchese M, Paciotti M, Nguyen DD, Nabi J, Cole AP, et al. Assessment of time-to-treatment initiation and survival in a cohort of patients with common cancers. JAMA Netw Open 2020;3:e2030072. 
  25. Nathani P, Gopal P, Rich N, Yopp A, Yokoo T, John B, et al. Hepatocellular carcinoma tumour volume doubling time: a systematic review and meta-analysis. Gut 2021;70:401-407.  https://doi.org/10.1136/gutjnl-2020-321040
  26. Jha RC, Zanello PA, Nguyen XM, Pehlivanova M, Johnson LB, Fishbein T, et al. Small hepatocellular carcinoma: MRI findings for predicting tumor growth rates. Acad Radiol 2014;21:1455-1464.  https://doi.org/10.1016/j.acra.2014.06.011
  27. An C, Choi YA, Choi D, Paik YH, Ahn SH, Kim MJ, et al. Growth rate of early-stage hepatocellular carcinoma in patients with chronic liver disease. Clin Mol Hepatol 2015;21:279-286.  https://doi.org/10.3350/cmh.2015.21.3.279
  28. Kim JK, Kim HD, Jun MJ, Yun SC, Shim JH, Lee HC, et al. Tumor volume doubling time as a dynamic prognostic marker for patients with hepatocellular carcinoma. Dig Dis Sci 2017;62:2923-2931.  https://doi.org/10.1007/s10620-017-4708-6
  29. Park MS. Early stage hepatocellular carcinoma in Koreans with chronic liver disease: tumor growth rate and 5-year survival. J Hepatol 2014;60:S534. 
  30. Rich NE, John BV, Parikh ND, Rowe I, Mehta N, Khatri G, et al. Hepatocellular carcinoma demonstrates heterogeneous growth patterns in a multicenter cohort of patients with cirrhosis. Hepatology 2020;72:1654-1665.  https://doi.org/10.1002/hep.31159
  31. Jones M, Fowler R. Immortal time bias in observational studies of time-to-event outcomes. J Crit Care 2016;36:195-199.  https://doi.org/10.1016/j.jcrc.2016.07.017
  32. Agarwal P, Moshier E, Ru M, Ohri N, Ennis R, Rosenzweig K, et al. Immortal time bias in observational studies of time-to-event outcomes: assessing effects of postmastectomy radiation therapy using the National Cancer Database. Cancer Control 2018;25:1073274818789355. 
  33. Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014;146:1691-1700.e3.  https://doi.org/10.1053/j.gastro.2014.02.032
  34. Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681-693.  https://doi.org/10.1016/j.jhep.2021.11.018
  35. Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019;380:1450-1462.  https://doi.org/10.1056/NEJMra1713263
  36. Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med 2014;11:e1001624. 
  37. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7:6. 
  38. Johnson BA, Waddimba AC, Ogola GO, Fleshman JW Jr, Preskitt JT. A systematic review and meta-analysis of surgery delays and survival in breast, lung and colon cancers: implication for surgical triage during the COVID-19 pandemic. Am J Surg 2021;222:311-318.  https://doi.org/10.1016/j.amjsurg.2020.12.015
  39. Wang B, Shelat VG, Chow JJL, Huey TCW, Low JK, Woon WWL, et al. Prehabilitation program improves outcomes of patients undergoing elective liver resection. J Surg Res 2020;251:119-125.  https://doi.org/10.1016/j.jss.2020.01.009
  40. Chan KS, Low JK, Shelat VG. Associated liver partition and portal vein ligation for staged hepatectomy: a review. Transl Gastroenterol Hepatol 2020;5:37. 
  41. Liang BY, Gu J, Xiong M, Zhang EL, Zhang ZY, Chen XP, et al. Tumor size may influence the prognosis of solitary hepatocellular carcinoma patients with cirrhosis and without macrovascular invasion after hepatectomy. Sci Rep 2021;11:16343. 
  42. Menahem B, Lubrano J, Duvoux C, Mulliri A, Alves A, Costentin C, et al. Liver transplantation versus liver resection for hepatocellular carcinoma in intention to treat: an attempt to perform an ideal meta- analysis. Liver Transpl 2017;23:836-844.  https://doi.org/10.1002/lt.24758
  43. Kamath PS, Kim WR; Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology 2007;45:797-805.  https://doi.org/10.1002/hep.21563
  44. Mehta N, Dodge JL, Hirose R, Roberts JP, Yao FY. Predictors of low risk for dropout from the liver transplant waiting list for hepatocellular carcinoma in long wait time regions: implications for organ allocation. Am J Transplant 2019;19:2210-2218.  https://doi.org/10.1111/ajt.15353
  45. Tan CHN, Yu Y, Tan YRN, Lim BLK, Iyer SG, Madhavan K, et al. Bridging therapies to liver transplantation for hepatocellular carcinoma: a bridge to nowhere? Ann Hepatobiliary Pancreat Surg 2018;22:27-35.  https://doi.org/10.14701/ahbps.2018.22.1.27
  46. Kwong AJ, Ebel NH, Kim WR, Lake JR, Smith JM, Schladt DP, et al. OPTN/SRTR 2020 annual data report: liver. Am J Transplant 2022;22 Suppl 2:204-309.  https://doi.org/10.1111/ajt.16978
  47. Kanwal F, Hernaez R, Liu Y, Taylor TJ, Rana A, Kramer JR, et al. Factors associated with access to and receipt of liver transplantation in veterans with end-stage liver disease. JAMA Inter Med 2021;181:949-959.  https://doi.org/10.1001/jamainternmed.2021.2051
  48. Klassen AC, Klassen DK, Brookmeyer R, Frank RG, Marconi K. Factors influencing waiting time and successful receipt of cadaveric liver transplant in the United States. 1990 to 1992. Med Care 1998;36:281-294.  https://doi.org/10.1097/00005650-199803000-00006
  49. Liver transplant: National University Hospital. Diseases & Conditions (n.d.). 2023 [cited 2023 April 6]. Available from: https://www.nuh.com.sg/Health-Information/Diseases-Conditions/Pages/Liver-Transplant.aspx. 
  50. Mehta N, Heimbach J, Lee D, Dodge JL, Harnois D, Burns J, et al. Wait time of less than 6 and greater than 18 months predicts hepatocellular carcinoma recurrence after liver transplantation: proposing a wait time "sweet spot." Transplantation 2017;101:2071-2078.  https://doi.org/10.1097/TP.0000000000001752
  51. Schlansky B, Chen Y, Scott DL, Austin D, Naugler WE. Waiting time predicts survival after liver transplantation for hepatocellular carcinoma: a cohort study using the United Network for Organ Sharing registry. Liver Transpl 2014;20:1045-1056.  https://doi.org/10.1002/lt.23917
  52. Halazun KJ, Patzer RE, Rana AA, Verna EC, Griesemer AD, Parsons RF, et al. Standing the test of time: outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment. Hepatology 2014;60:1957-1962.  https://doi.org/10.1002/hep.27272
  53. Roberts JP, Venook A, Kerlan R, Yao F. Hepatocellular carcinoma: ablate and wait versus rapid transplantation. Liver Transpl 2010;16:925-929.  https://doi.org/10.1002/lt.22103
  54. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 2015;19:223-238. https://doi.org/10.1016/j.cld.2015.01.001