Hepatocellular carcinoma (HCC) progresses at highly variable rates. It is widely believed that active treatment should begin as soon as possible after diagnosis. This may not always occur for various reasons, and it remains unclear whether such delays shorten overall survival.
In a recent issue of the Journal of Hepatology, Lim and coworkers (1) addressed this question for patients diagnosed with single HCC at very early or early stages. Their prospective analysis of 100 patients during follow-up extending 33 months from diagnosis showed that patients who underwent resection ≥3 months after diagnosis had similar oncological and long-term outcomes as patients who underwent resection <3 months after diagnosis. While we applaud the authors for tackling this important question, we wish to highlight the need for caution when interpreting their data and drawing conclusions for clinical practice.
One potential issue is the generalizability of their findings. Their patients showed median tumor size of 3.4 (range, 2.2–5.7) cm at diagnosis and 3.5 (range, 2.5–6.2) cm at resection. Thus, few patients had large HCC (>5 cm) or huge HCC (≥10 cm), and tumors had grown by only ~0.1 cm in the interval from diagnosis to surgery. In addition, the difference in median delay until surgery between the “≥3 months” and “<3 months” patient groups was only 2.8 months (4.6 vs. 1.8 months). This reflects the fact that 29 of 50 patients (58%) in the “≥3 months” group experienced delays of 3–5 months. These issues raise concern about whether the results of Lim et al. can be extrapolated to other patient populations. Another question is whether the apparent lack of effect of delayed surgery extends to the long term, since 15 of 50 patients (30%) in the “≥3 months” group were enrolled after 2015, making follow-up too short to calculate long-term survival.
Our own analysis of literature indexed in PubMed identified several studies involving patients with HCC diagnosed at various stages that come to the opposite conclusion as Lim et al. (Table 1). Those studies conclude that patients initiating treatment >3 months after diagnosis (4,5), 2 months after diagnosis (3), or even 5 weeks after diagnosis (2) have significantly lower overall and disease-free survival (2) than patients starting treatment earlier.
Just as with other cancers (6), delayed treatment is likely to influence outcomes for patients with HCC. Since life expectancy for many HCC patients without any positive treatment is shorter than 12 months, delaying treatment for more than 3 months often allows substantial tumor growth (7), which is a mortality risk factor in single HCC (8) and is associated with greater incidence of microvascular invasion. In one study, for example, 25% of patients with tumors <2 cm had microvascular invasion, compared to 31% of patients with tumors >2–4 cm and 50% of patients with tumors >4 cm (9).
The question addressed by Lim et al. is timely: nearly 30% of HCC patients in Europe and the USA initiate treatment more than 3 months after diagnosis (4). These delays can allow tumor growth and increase risk of microvascular invasion, reducing overall survival. Timely delivery of treatment to HCC patients should be improved, especially for those with disease in intermediate or advanced stages (10).
Funding: This work was supported by the Graduate Course Construction Project of Guangxi Medical University (YJSA2017014), the Foundation Ability Enhancement Project for Young Teachers in Guangxi Universities (2018KY0122), and the National Natural Science Foundation of China (81560460/H1602).
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Lim C, Bhangui P, Salloum C, 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;68:100-8. [Crossref] [PubMed]
- Chen WT, Fernandes ML, Lin CC, et al. 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;103:133-9. [Crossref] [PubMed]
- Huo TI, Huang YH, Chiang JH, 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;42:485-92. [Crossref] [PubMed]
- Singal AG, Waljee AK, Patel N, et al. Therapeutic delays lead to worse survival among patients with hepatocellular carcinoma. J Natl Compr Canc Netw 2013;11:1101-8. [Crossref] [PubMed]
- Croome KP, Chudzinski R, Hanto DW. Increasing time delay from presentation until surgical referral for hepatobiliary malignancies. HPB (Oxford) 2010;12:644-8. [Crossref] [PubMed]
- Richards MA, Westcombe AM, Love SB, et al. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet 1999;353:1119-26. [Crossref] [PubMed]
- Patel N, Yopp AC, Singal AG. Diagnostic delays are common among patients with hepatocellular carcinoma. J Natl Compr Canc Netw 2015;13:543-9. [Crossref] [PubMed]
- Zhong JH, Pan LH, Wang YY, et al. Optimizing stage of single large hepatocellular carcinoma: A study with subgroup analysis by tumor diameter. Medicine (Baltimore) 2017;96:e6608. [Crossref] [PubMed]
- Esnaola NF, Lauwers GY, Mirza NQ, et al. Predictors of microvascular invasion in patients with hepatocellular carcinoma who are candidates for orthotopic liver transplantation. J Gastrointest Surg 2002;6:224-32; discussion 32. [Crossref] [PubMed]
- Mittal S, Kanwal F, Ying J, et al. Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: A United States cohort. J Hepatol 2016;65:1148-54. [Crossref] [PubMed]