Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction

We are writing to present our comments on the study recently published by Fulgenzi et al. in JAMA Oncology titled "Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction".1 This paper addresses a crucial issue in the management of patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B, CP-B). It provides compelling evidence for the efficacy of immune checkpoint inhibitors (ICIs) compared to best supportive care (BSC). The study, a retrospective, multicenter, international investigation, compares overall survival (OS) in patients receiving ICI-based therapies with those receiving BSC. The results demonstrate a significant survival benefit in the ICI group, with a median OS of 7.50 months compared to 4.04 months in the BSC group (HR, 0.59; 95% CI, 0.43-0.80; P < .001). These findings have profound implications. They challenge the conventional practice of reserving BSC for patients with CP-B liver dysfunction, suggesting that immunotherapy can provide significant benefits. Consequently, inclusive clinical trials targeting this high-risk population are warranted. Nevertheless, I believe it is important to consider additional aspects that warrant discussion:

Selection Bias: Despite the use of propensity score weighting, there may still be unmeasured confounders that influence treatment allocation and outcomes.

Generalizability: It would be valuable to understand the applicability of these findings in community settings where resource availability and patient management practices may differ.

Safety Profile: The safety data emphasize the significance of careful patient selection and monitoring. Future prospective studies should further investigate the balance between efficacy and toxicity in this vulnerable patient population.

Long-Term Outcomes: While the study provides important short-term survival data, long-term outcomes and measures of quality of life are essential for a comprehensive understanding of the impact of ICI therapy in CP-B patients.

The study by Fulgenzi et al. establishes the foundation for future research and supports the inclusion of CP-B patients in clinical trials to validate these findings prospectively. The promising results advocate for a shift in the treatment paradigm for CP-B patients with HCC, who have traditionally only received supportive care.

Thank you for providing the opportunity to discuss this significant work. I eagerly await further advancements in this critical area of oncology.

Sincerely,

Fausto Petrelli, MD
Lorenzo Dottorini, MD
Oncology Unit, ASST Bergamo Ovest, Treviglio (BG) Italy
faupe@libero.it

References
1. Fulgenzi CAM, Scheiner B, D'Alessio A, et al. Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction. JAMA Oncol. Published online July 18, 2024. doi:10.1001/jamaoncol.2024.2166
2.

CONFLICT OF INTEREST: None Reported

Brief Report

July 18, 2024

Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction

Claudia Angela Maria听Fulgenzi,听MD^1,2; 叠别谤苍丑补谤诲听厂肠丑别颈苍别谤,听笔丑顿^1,3; 础苍迟辞苍颈辞听顿鈥橝濒别蝉蝉颈辞,听惭顿^1,4; et al 础尘补苍听惭别丑补苍,听惭顿¹; Giulia F.听Manfredi,听MD^1,4; 颁颈谤辞听颁别濒蝉补,听笔丑顿^1,5; 狈补辞蝉丑颈听狈颈蝉丑颈诲补,听惭顿⁶; 颁别濒颈苍补听础苍驳,听惭顿⁷; Thomas U.听Marron,听PhD⁷; 尝颈苍诲补听奥耻,听惭顿⁷; 础苍飞补补谤听厂补别别诲,听惭顿⁸; 叠谤辞辞办别听奥颈别迟丑补谤苍,听惭顿⁸; 础苍迟辞苍别濒濒补听颁补尘尘补谤辞迟补,听惭顿^9,10; 罢颈锄颈补苍补听笔谤别蝉蝉颈补苍颈,听惭顿¹⁰; 惭补迟迟丑颈补蝉听笔颈苍迟别谤,听笔丑顿³; 搁辞丑颈苍颈听厂丑补谤尘补,听笔丑顿¹; 闯补别办测耻苍驳听颁丑别辞苍,听惭顿¹¹; 驰颈-贬蝉颈补苍驳听贬耻补苍驳,听笔丑顿^12,13,14; 笔别颈-颁丑补苍驳听尝别别,听惭顿^15,16; 厂补尘耻别濒听笔丑别苍,听惭顿¹⁷; 础苍耻丑测补听骋补尘辫补,听惭顿¹⁸; 础苍箩补苍补听笔颈濒濒补颈,听笔丑顿¹⁹; 础苍诲谤别补听狈补辫辞濒颈迟补苍辞,听笔丑顿²⁰; 颁补迟别谤颈苍补听痴颈惫补濒诲颈,听笔丑顿²¹; 贵谤补苍肠别蝉肠补听厂补濒补苍颈,听惭顿^21,22; 骋颈补苍濒耻肠补听惭补蝉颈,听笔丑顿²¹; 惭补谤颈补苍苍补听厂颈濒濒别迟迟补,听笔丑顿²; Federica听Lo Prinzi,听MD²; Emanuela听Di Giacomo,听MD²; 叠谤耻苍辞听痴颈苍肠别苍锄颈,听笔丑顿²; 顿辞尘颈苍颈办听叠别迟迟颈苍驳别谤,听笔丑顿²³; 搁辞产别谤迟听罢丑颈尘尘别,听笔丑顿²³; 础谤苍诲迟听痴辞驳别濒,听笔丑顿²⁴; 惭补谤迟颈苍听厂肠丑枚苍濒别颈苍,听惭顿²⁵; Johann听von Felden,听MD²⁶; 碍辞谤苍别濒颈耻蝉听厂肠丑耻濒锄别,听笔丑顿²⁶; 贬别苍苍颈苍驳听奥别驳别,听笔丑顿²⁶; Peter R.听Galle,听PhD²⁷; 惭补谤颈辞听笔颈谤颈蝉颈,听笔丑顿⁴; 闯辞辞苍驳-奥辞苍听笔补谤办,听笔丑顿²⁸; 惭补蝉补迟辞蝉丑颈听碍耻诲辞,听笔丑顿⁶; 尝辞谤别苍锄补听搁颈尘补蝉蝉补,听惭顿^9,10; Amit G.听Singal,听MD^15,16; Paul听El Tomb,听MD²⁹; 厂耻蝉补苍苍补听鲍濒补丑补苍苍补苍,听惭顿²⁹; 础濒别蝉蝉补苍诲谤辞听笔补谤颈蝉颈,听惭顿³⁰; Hong Jae听Chon,听PhD¹¹; 奥别颈-贵补苍听贬蝉耻,听笔丑顿³¹; 骋颈辞谤驳颈补听骋丑颈迟迟辞苍颈,听惭顿³²; 颁补濒辞驳别谤辞听颁补尘尘脿,听笔丑顿⁵; 叠别苍别诲别迟迟补听厂迟别蹿补苍颈苍颈,听惭顿³³; 贵谤补苍肠辞听罢谤别惫颈蝉补苍颈,听笔丑顿³³; Edoardo G.听Giannini,听PhD^34,35; 础濒别蝉蝉颈辞听颁辞谤迟别濒濒颈苍颈,听笔丑顿^1,2; David James听Pinato,听MD, PhD^1,4

Author Affiliations Article Information

¹Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, England
²Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
³Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
⁴Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
⁵Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine & Medical Specialties, University of Palermo, Palermo, Italy
⁶Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
⁷Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, New York
⁸Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City
⁹Department of Biomedical Sciences, Humanitas University, Milan, Italy
¹⁰Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
¹¹Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
¹²Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan
¹³Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
¹⁴Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
¹⁵Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
¹⁶Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
¹⁷Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
¹⁸Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, Section of Gastroenterology, University of Oklahoma, Oklahoma City
¹⁹Hepatology & Nutrition, the University of Chicago Medicine, Chicago, Illinois
²⁰The Royal Marsden National Health Service Foundation Trust, London, England
²¹Unit of Medical Oncology 2, Azienda Ospedaliero- Universitaria Pisana, Pisa, Italy
²²Scuola Superiore Sant鈥橝nna Pisa, Interdisciplinary Research Center, Pisa, Italy
²³Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Freiburg University Medical Center, University of Freiburg, Freiburg, Germany
²⁴Hannover Medical School, Hannover, Germany
²⁵Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
²⁶Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
²⁷Department of Internal Medicine I, University Medical Center Mainz, Mainz, Germany
²⁸National Cancer Centre Hospital, Goyang, South Korea
²⁹Stephenson Cancer Center, Oklahoma City, Oklahoma
³⁰Department of Oncology, Universit脿 Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy
³¹Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
³²Gastroenterology Unit, Belcolle hospital, Viterbo, Italy
³³Semeiotics and Liver and Alcohol-Related Disease Unit, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
³⁴Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy
³⁵IRCCS Ospedale Policlinico San Martino, Genoa, Italy

JAMA Oncol. 2024;10(9):1253-1258. doi:10.1001/jamaoncol.2024.2166

Key Points

Question听 Do patients with unresectable hepatocellular carcinoma (HCC) and suboptimal liver function benefit from immunotherapy vs best supportive care?

Findings听 In this case series of 343 patients with Child-Pugh class B liver dysfunction, immunotherapy-based systemic therapy was associated with significant reduction in the risk of death compared with best supportive care.

Meaning听 The results of this study suggest that immunotherapy may be a safe and effective option for patients with unresectable HCC and suboptimal liver function.

Abstract

Importance听 Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated.

Objective听 To evaluate the association of immune checkpoint inhibitor (ICI)鈥揵ased therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction.

Design, Setting, and Participants听 This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status.

Exposures听 Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n鈥�=鈥�141) or nivolumab (n鈥�=鈥�46).

Main Outcomes and Measures听 OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups.

Results听 The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P鈥�<鈥�.001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P鈥�<鈥�.001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death.

Conclusions and Relevance听 The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

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Immunotherapy vs Best Supportive Care for Patients With Hepatocellular Cancer With Child-Pugh B Dysfunction