Dear Editor,
We sincerely appreciate Professor Lee’s thoughtful and comprehensive response to our letter entitled “Beyond diagnostic accuracy: economic and clinical considerations for NC-MRI in Late HCC recurrence surveillance.” [
1-
3] Four key considerations were addressed for the clinical application of non-contrast magnetic resonance imaging (NCMRI): individual recurrence risk, the relative cost and examination time compared with contrast-enhanced multiphasic computed tomography (CECT), the availability of medical resources to ensure high-quality imaging, and patient adherence to surveillance. These factors are essential for advancing the clinical use of NC-MRI. Furthermore, a more profound comprehension of the oncological attributes of hepatocellular carcinoma (HCC), the sites of recurrence, alternative monitoring methodologies, and the management subsequent to recurrence can facilitate the formulation of more precise individualized monitoring strategies, enhance the efficient allocation of medical resources, and elevate the quality of life for patients.
Currently, there are no effective treatment strategies to reduce postoperative recurrence, which underscores the importance of relying on efficient surveillance. Although several phase 3 randomized controlled trials (RCTs) have shown that postoperative adjuvant treatments, such as cytokine-induced killer cells, transarterial chemoembolization (TACE), and hepatic arterial infusion chemotherapy, can help reduce the risk of HCC recurrence following curative treatment [
4-
7], the reliability of these studies remains uncertain. Conversely, the global multicenter phase 3 IMbrave050 study demonstrated that postoperative adjuvant atezolizumab plus bevacizumab does not reduce the risk of recurrence [
8]. At present, in addition to postoperative adjuvant therapies, numerous clinical trials are underway to investigate neoadjuvant, adjuvant, and combined neoadjuvant + adjuvant treatments. These trials aim to mitigate the risk of recurrence for HCC patients subsequent to curative treatment. Prior to the emergence of effective strategies for reducing postoperative recurrence, however, high-efficiency surveillance remains the most critical approach.
We concur with the Lee team’s perspective that routine monitoring for extrahepatic recurrence is not justified, given the relatively low incidence of extrahepatic recurrence and the lack of alignment with health economic efficiencies [
1,
8]. We conducted a secondary analysis of a previous meta-analysis [
9], revealing pooled extrahepatic recurrence rates of 5.98% for surgical resection and 5.81% for ablation (
Fig. 1). Additionally, we reviewed the extrahepatic recurrence rates at our center for patients with BCLC stage 0–A HCC undergoing resection or ablation from 2010 to 2020, which were 0.6% and 0.8%, respectively (
Fig. 1). These findings suggest that while monitoring recurrent lesions solely with abdominal NC-MRI or CECT may not be perfect, it should be considered cost-effective for post-treatment surveillance.
In addition to CT and MRI imaging, various methods, such as tissue biomarkers and liquid biopsy technologies, have been developed in recent years to predict the risk of HCC recurrence post-curative treatment. Regarding tissue biomarkers, a recent study identified GULP1 as a key gene by analyzing three genomic datasets. In tissue samples from HCC patients after surgical resection, GULP1 protein levels demonstrated a significantly better ability to predict recurrence after curative treatment compared to alpha-fetoprotein (AFP) [
10]. Another study performed a whole-genome DNA methylation analysis on pre-surgical HCC tissue samples and identified a novel methylation signature. This signature outperformed traditional prognostic indicators, such as AFP, protein induced by vitamin K absence-II (PIVKA-II), and the Milan criteria, in predicting the risk of postoperative recurrence [
11]. In the context of liquid biopsy, the detection and quantification of circulating tumor DNA (ctDNA) mutations prior to ablation have been correlated with heightened mortality rates and an elevated risk of recurrence [
12]. Consequently, the proactive employment of recurrence risk prediction methods could aid in the identification of HCC patients who are at a high risk of recurrence, thereby facilitating more frequent surveillance and early intervention, which may represent a potential avenue for future development.
Finally, it is crucial to select the appropriate treatment for recurrent HCC following curative-intent treatment. In the study conducted by the Lee team [
1], among the 21 patients experiencing intrahepatic recurrent HCC, 12 underwent local ablative therapy, 3 received stereotactic body radiotherapy, 6 were treated with TACE, and 1 patient with lymph node metastasis was administered a combination of atezolizumab and bevacizumab as systemic therapy. This year, two RCTs from our institution have potentially offered significant guidance on the management of recurrent HCC. The first phase 3 RCT compared the efficacy of TACE combined with radiofrequency ablation (RFA) versus surgical resection for small recurrent HCC (single lesion ≤5 cm or ≤3 lesions, each ≤3 cm). The results showed no significant differences in overall survival (OS) and recurrence-free survival rates between the two groups, but TACE combined with RFA was associated with a lower complication rate [
13]. The second phase 3 RCT compared stereotactic body radiation therapy (SBRT) with RFA for single recurrent HCC lesions ≤5 cm. SBRT demonstrated superior local progression-free survival compared to RFA, with similar OS and safety profiles [
14]. In summary, selecting the right treatment for recurrent HCC after initial curative-intent therapy is vital, as demonstrated by the Lee team’s study and recent RCTs from our institution, which revealed that minimally invasive interventional therapies, such as TACE combined with RFA and SBRT, offer effective management options with comparable OS and favorable safety profiles for recurrent HCC.
In conclusion, the execution of neoadjuvant and postoperative adjuvant therapies for the purpose of early intervention to mitigate recurrence remains under investigation. The development of efficient HCC recurrence surveillance techniques, including the utilization of high-sensitivity diagnostic tools such as NC-MRI for early diagnosis, continues to be a crucial focus.
FOOTNOTES
-
Authors’ contributions
Qi-Feng Chen, Sui-Xing Zhong and Xiong-Ying Jiang wrote the manuscript; Ming Zhao revised the manuscript. Qi-Feng Chen, Sui-Xing Zhong, Xiong-Ying Jiang and Ming Zhao approved the final manuscript. Ming Zhao is the guarantor.
-
Acknowledgements
Supported by the National Natural Science Foundation of China (No. 82402403 and 82072022), and the Guangdong Basic and Applied Basic Research Foundation (No. 2025A1515011330).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.Comparison of recurrence patterns between surgical resection and ablation for hepatocellular carcinoma within the Milan criteria. RCTs, randomized controlled trials; Non-RCTs, non-randomized controlled trials; SYSUCC, Sun Yat-sen University Cancer Center.
Abbreviations
contrast-enhanced multiphasic computed tomography
non-contrast magnetic resonance imaging
randomized controlled trial
stereotactic body radiation therapy
transarterial chemoembolization
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