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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Investigating Alternative Treatment Options Unfeasible for Local Ablation Therapy in Patients with Small Solitary Hepatocellular Carcinomas

Chang Hun Lee , In Hee Kim

Department of Internal Medicine, Jeonbuk National University Medical School and Research Institute of Clinical Medicine of Jeonbuk National University Hospital-Jeonbuk National University Medical School, Jeonju, Korea

Correspondence to: Chang Hun Lee
ORCID https://orcid.org/0000-0001-7244-8849
E-mail chleemd@jbnu.ac.kr

See “Chemoembolization versus Radiotherapy for Single Hepatocellular Carcinomas of ≤3 cm Unsuitable for Image-Guided Tumor Ablation” by Jihye Lim, et al. on page 125, Vol. 18, No. 1, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2024;18(1):5-6. https://doi.org/10.5009/gnl230559

Published online January 15, 2024, Published date January 15, 2024

Copyright © Gut and Liver.

Liver cancer ranks as the second leading cause of cancer-related mortality and stands as the seventh most common cancer globally, remaining an ongoing global health threat.1 Hepatocellular carcinomas (HCCs) measuring 3 cm or less, accounting for up to 30% of cases,2 are typically recommended for curative treatments such as resection, local ablation therapy (LAT), or liver transplantation in most guidelines.3-5 Where curative treatments are deemed unfeasible, transarterial chemoembolization (TACE) stands out as the leading alternative treatment option.4 On the other hand, most Asian guidelines recommend external beam radiation therapy as an alternative to surgical resection or locoregional therapy.5,6 Nevertheless, there is a notable lack of research on the next second-best treatment option when the tumor is inoperable, and LAT is also deemed unfeasible.

Lim, et al.7 presents a comprehensive evaluation of the therapeutic outcomes of chemoembolization and radiotherapy (RT) in small HCCs unsuitable for LAT after sonographic planning. They analyzed a total of 651 individuals with 801 nodules, of which 619 nodules were treatment-naïve. In the entire cohort, there was no significant difference in local tumor progression (LTP)-free survival and overall progression-free survival between LAT and RT. However, the TACE group demonstrated a significantly shorter duration for LTP-free and overall progression-free survivals. These results were consistent when focusing exclusively on treatment-naïve patients. In the sub-cohort of LAT-unsuitable nodules, after propensity score-based matching and inverse probability of treatment weighting, RT-treated nodules had a longer LTP-free survival than the TACE-treated nodules in both propensity score-based matching and inverse probability of treatment weighting pairs. Regarding overall survival, patient-based analysis was not affected by treatment modality. Therefore, the authors suggest that TACE and RT are equally effective options for single small HCCs found to be unsuitable for LAT.

In the context of small HCC, decision-making involves consideration of various factors, including tumor size (≤2 cm, 2–3 cm), candidacy for liver transplantation, hepatic reservoir function, performance status, tumor location, and socioeconomic considerations.2 Although radiofrequency ablation (RFA) serves as the best alternative modality for resection, there are still limitations that render RFA unsuitable in certain cases despite advances in technique. In Lim's study, the most common reason for the inability to perform RFA was invisibility, constituting more than half of the cases, consistent with findings from previous studies. In such cases, TACE emerges as a widely used alternative tool, and in Lim's study, 80% of patients deemed unsuitable for RFA underwent TACE. On the other hand, external beam radiation therapy is still not stated due to a lack of robust evidence in many international guidelines. Nevertheless, recent studies have demonstrated favorable outcomes for RT, specifically with stereotactic body radiation therapy and proton beam RT emerging as promising modalities. Stereotactic body radiation therapy has shown high local control and long-term survival in HCC patients unsuitable for standard locoregional treatments.8 Additionally, proton beam therapy has yielded significantly longer 2-year LTP-free survival for recurrent small HCCs compared to RFA.9 Lim’s study supports the notion that RT can be a favorable option alongside TACE for single small HCCs unfeasible for LAT. For future research, in light of recent results in radiation segmentectomy, there is an anticipated need for comparing the efficacy of TACE, RT, and radioembolization in the context of small HCCs.10 Additionally, considering potential cost variations among treatment modalities, there is a perceived necessity for future studies examining their cost-effectiveness.

The study by Lim et al. has several limitations. Firstly, being retrospective in nature, bias may have influenced the selection of each treatment. Notably, the RT group included many recurrent patients, and TACE patients often presented with lesions at the periphery. Researchers employed the propensity score-based matching and inverse probability of treatment weighting analyses to mitigate the bias. Secondly, the study involves a mix of treatment-naïve and recurrent patients. To address this issue, researchers provided supplementary data focusing solely on treatment-naïve patients, and the results were consistent with those of the overall group. Finally, in each group of LAT, TACE, and RT, various treatment methods are mixed, conclusive comparisons among each subtype could not be obtained.

Selecting the appropriate treatment modality is crucial to improve the prognosis for patients with HCC. In cases where RFA is unfeasible for inoperable single small HCCs (≤3 cm), both TACE and RT have demonstrated comparable outcomes in terms of LTP and overall survival. Determining the most suitable treatment modality can be achieved by considering their advantages and contraindications. Future large-scale prospective studies are essential to accumulate evidence on this matter and advance our understanding of the optimal treatment approaches.

No potential conflict of interest relevant to this article was reported.

  1. Choi S, Kim BK, Yon DK, et al. Global burden of primary liver cancer and its association with underlying aetiologies, sociodemographic status, and sex differences from 1990-2019: A DALY-based analysis of the Global Burden of Disease 2019 study. Clin Mol Hepatol 2023;29:433-452.
    Pubmed KoreaMed CrossRef
  2. Wu X, Lokken RP, Mehta N. Optimal treatment for small HCC (<3 cm): resection, liver transplantation, or locoregional therapy?. JHEP Rep 2023;5:100781.
    Pubmed KoreaMed CrossRef
  3. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-750.
    Pubmed CrossRef
  4. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681-693.
    Pubmed KoreaMed CrossRef
  5. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea Practice Guidelines for the management of hepatocellular carcinoma. Korean J Radiol 2022;23:1126-1240.
    Pubmed KoreaMed CrossRef
  6. Cho Y, Kim BH, Park JW. Overview of Asian clinical practice guidelines for the management of hepatocellular carcinoma: an Asian perspective comparison. Clin Mol Hepatol 2023;29:252-262.
    Pubmed KoreaMed CrossRef
  7. Lim J, Kim E, Kim S, et al. Chemoembolization versus radiotherapy for single hepatocellular carcinomas of ≤3 cm unsuitable for image-guided tumor ablation. Gut Liver 2024;18:125-134.
    Pubmed CrossRef
  8. Mathew AS, Atenafu EG, Owen D, et al. Long term outcomes of stereotactic body radiation therapy for hepatocellular carcinoma without macrovascular invasion. Eur J Cancer 2020;134:41-51.
    Pubmed KoreaMed CrossRef
  9. Kim TH, Koh YH, Kim BH, et al. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial. J Hepatol 2021;74:603-612.
    Pubmed CrossRef
  10. Kim E, Sher A, Abboud G, et al. Radiation segmentectomy for curative intent of unresectable very early to early stage hepatocellular carcinoma (RASER): a single-centre, single-arm study. Lancet Gastroenterol Hepatol 2022;7:843-850.
    Pubmed CrossRef

Article

Editorial

Gut and Liver 2024; 18(1): 5-6

Published online January 15, 2024 https://doi.org/10.5009/gnl230559

Copyright © Gut and Liver.

Investigating Alternative Treatment Options Unfeasible for Local Ablation Therapy in Patients with Small Solitary Hepatocellular Carcinomas

Chang Hun Lee , In Hee Kim

Department of Internal Medicine, Jeonbuk National University Medical School and Research Institute of Clinical Medicine of Jeonbuk National University Hospital-Jeonbuk National University Medical School, Jeonju, Korea

Correspondence to:Chang Hun Lee
ORCID https://orcid.org/0000-0001-7244-8849
E-mail chleemd@jbnu.ac.kr

See “Chemoembolization versus Radiotherapy for Single Hepatocellular Carcinomas of ≤3 cm Unsuitable for Image-Guided Tumor Ablation” by Jihye Lim, et al. on page 125, Vol. 18, No. 1, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

Liver cancer ranks as the second leading cause of cancer-related mortality and stands as the seventh most common cancer globally, remaining an ongoing global health threat.1 Hepatocellular carcinomas (HCCs) measuring 3 cm or less, accounting for up to 30% of cases,2 are typically recommended for curative treatments such as resection, local ablation therapy (LAT), or liver transplantation in most guidelines.3-5 Where curative treatments are deemed unfeasible, transarterial chemoembolization (TACE) stands out as the leading alternative treatment option.4 On the other hand, most Asian guidelines recommend external beam radiation therapy as an alternative to surgical resection or locoregional therapy.5,6 Nevertheless, there is a notable lack of research on the next second-best treatment option when the tumor is inoperable, and LAT is also deemed unfeasible.

Lim, et al.7 presents a comprehensive evaluation of the therapeutic outcomes of chemoembolization and radiotherapy (RT) in small HCCs unsuitable for LAT after sonographic planning. They analyzed a total of 651 individuals with 801 nodules, of which 619 nodules were treatment-naïve. In the entire cohort, there was no significant difference in local tumor progression (LTP)-free survival and overall progression-free survival between LAT and RT. However, the TACE group demonstrated a significantly shorter duration for LTP-free and overall progression-free survivals. These results were consistent when focusing exclusively on treatment-naïve patients. In the sub-cohort of LAT-unsuitable nodules, after propensity score-based matching and inverse probability of treatment weighting, RT-treated nodules had a longer LTP-free survival than the TACE-treated nodules in both propensity score-based matching and inverse probability of treatment weighting pairs. Regarding overall survival, patient-based analysis was not affected by treatment modality. Therefore, the authors suggest that TACE and RT are equally effective options for single small HCCs found to be unsuitable for LAT.

In the context of small HCC, decision-making involves consideration of various factors, including tumor size (≤2 cm, 2–3 cm), candidacy for liver transplantation, hepatic reservoir function, performance status, tumor location, and socioeconomic considerations.2 Although radiofrequency ablation (RFA) serves as the best alternative modality for resection, there are still limitations that render RFA unsuitable in certain cases despite advances in technique. In Lim's study, the most common reason for the inability to perform RFA was invisibility, constituting more than half of the cases, consistent with findings from previous studies. In such cases, TACE emerges as a widely used alternative tool, and in Lim's study, 80% of patients deemed unsuitable for RFA underwent TACE. On the other hand, external beam radiation therapy is still not stated due to a lack of robust evidence in many international guidelines. Nevertheless, recent studies have demonstrated favorable outcomes for RT, specifically with stereotactic body radiation therapy and proton beam RT emerging as promising modalities. Stereotactic body radiation therapy has shown high local control and long-term survival in HCC patients unsuitable for standard locoregional treatments.8 Additionally, proton beam therapy has yielded significantly longer 2-year LTP-free survival for recurrent small HCCs compared to RFA.9 Lim’s study supports the notion that RT can be a favorable option alongside TACE for single small HCCs unfeasible for LAT. For future research, in light of recent results in radiation segmentectomy, there is an anticipated need for comparing the efficacy of TACE, RT, and radioembolization in the context of small HCCs.10 Additionally, considering potential cost variations among treatment modalities, there is a perceived necessity for future studies examining their cost-effectiveness.

The study by Lim et al. has several limitations. Firstly, being retrospective in nature, bias may have influenced the selection of each treatment. Notably, the RT group included many recurrent patients, and TACE patients often presented with lesions at the periphery. Researchers employed the propensity score-based matching and inverse probability of treatment weighting analyses to mitigate the bias. Secondly, the study involves a mix of treatment-naïve and recurrent patients. To address this issue, researchers provided supplementary data focusing solely on treatment-naïve patients, and the results were consistent with those of the overall group. Finally, in each group of LAT, TACE, and RT, various treatment methods are mixed, conclusive comparisons among each subtype could not be obtained.

Selecting the appropriate treatment modality is crucial to improve the prognosis for patients with HCC. In cases where RFA is unfeasible for inoperable single small HCCs (≤3 cm), both TACE and RT have demonstrated comparable outcomes in terms of LTP and overall survival. Determining the most suitable treatment modality can be achieved by considering their advantages and contraindications. Future large-scale prospective studies are essential to accumulate evidence on this matter and advance our understanding of the optimal treatment approaches.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

  1. Choi S, Kim BK, Yon DK, et al. Global burden of primary liver cancer and its association with underlying aetiologies, sociodemographic status, and sex differences from 1990-2019: A DALY-based analysis of the Global Burden of Disease 2019 study. Clin Mol Hepatol 2023;29:433-452.
    Pubmed KoreaMed CrossRef
  2. Wu X, Lokken RP, Mehta N. Optimal treatment for small HCC (<3 cm): resection, liver transplantation, or locoregional therapy?. JHEP Rep 2023;5:100781.
    Pubmed KoreaMed CrossRef
  3. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-750.
    Pubmed CrossRef
  4. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681-693.
    Pubmed KoreaMed CrossRef
  5. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea Practice Guidelines for the management of hepatocellular carcinoma. Korean J Radiol 2022;23:1126-1240.
    Pubmed KoreaMed CrossRef
  6. Cho Y, Kim BH, Park JW. Overview of Asian clinical practice guidelines for the management of hepatocellular carcinoma: an Asian perspective comparison. Clin Mol Hepatol 2023;29:252-262.
    Pubmed KoreaMed CrossRef
  7. Lim J, Kim E, Kim S, et al. Chemoembolization versus radiotherapy for single hepatocellular carcinomas of ≤3 cm unsuitable for image-guided tumor ablation. Gut Liver 2024;18:125-134.
    Pubmed CrossRef
  8. Mathew AS, Atenafu EG, Owen D, et al. Long term outcomes of stereotactic body radiation therapy for hepatocellular carcinoma without macrovascular invasion. Eur J Cancer 2020;134:41-51.
    Pubmed KoreaMed CrossRef
  9. Kim TH, Koh YH, Kim BH, et al. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial. J Hepatol 2021;74:603-612.
    Pubmed CrossRef
  10. Kim E, Sher A, Abboud G, et al. Radiation segmentectomy for curative intent of unresectable very early to early stage hepatocellular carcinoma (RASER): a single-centre, single-arm study. Lancet Gastroenterol Hepatol 2022;7:843-850.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.1
January, 2024

pISSN 1976-2283
eISSN 2005-1212

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