Does delayed treatment affect the survival of patients with hepatocellular carcinoma?

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.

Table 1 Studies indexed in PubMed on the effects of delayed treatment on survival of HCC patients
Full table

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).

Acknowledgments

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

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).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.04.08). The authors have no conflicts of interest to declare.

Ethical statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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