Highlight
– A Bayesian network meta-analysis of nine phase 3 trials (n=6,425) assessed time to deterioration in patient-reported health-related quality of life (HR-QoL) across first-line systemic therapies for unresectable or advanced hepatocellular carcinoma (HCC).
– Atezolizumab plus bevacizumab ranked highest by SUCRA for preservation of global health/QoL and several HCC-specific symptoms; when integrated with overall survival, it provided the best combined profile across evaluated items.
– The results support integrating HR-QoL into first-line treatment selection and call for standardized PRO collection and head-to-head comparisons where possible.
Background
Advanced hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Over the past decade, first-line systemic therapy options have expanded beyond sorafenib to include tyrosine kinase inhibitors (TKIs) such as lenvatinib, and multiple immune-based combinations (for example, atezolizumab plus bevacizumab and durvalumab plus tremelimumab). Overall survival (OS) remains the primary endpoint in registrational trials, but health-related quality of life (HR-QoL) and symptom control are essential patient-centered outcomes that directly affect daily functioning, tolerability and treatment value.
Study design
The study by Celsa et al. (JAMA Oncology, Oct 2025) performed a systematic review and Bayesian network meta-analysis of phase 3 randomized clinical trials comparing TKI monotherapies and immune checkpoint inhibitor-based regimens in first-line unresectable/advanced HCC. The literature search covered MEDLINE, CENTRAL and Scopus through November 2024 and included conference abstracts from main oncology meetings (2020–2024).
Inclusion criteria required phase 3 randomized trials with first-line HCC populations that reported time to deterioration (TTD) of HR-QoL domains measured by the EORTC QLQ-C30 and disease-specific HCC18 module. Two reviewers independently selected studies and extracted data. Risk of bias was assessed with the Cochrane tool; a Bayesian network meta-analysis used sorafenib as the common comparator. Treatment ranking for HR-QoL items was expressed as surface under the cumulative ranking (SUCRA). The authors also integrated HR-QoL rankings with OS to evaluate combined patient-centered benefit.
Key findings
Nine randomized clinical trials reporting HR-QoL met inclusion criteria, contributing outcomes on seven QoL items across 6,425 patients. The principal findings were:
– Atezolizumab plus bevacizumab had the highest probability of reducing deterioration in global health status/QoL (SUCRA 85%), abdominal swelling (95%), jaundice (89%), and pain (86%) compared with other available first-line options in the network.
– When the authors integrated HR-QoL SUCRA rankings with overall survival across treatments, atezolizumab plus bevacizumab consistently outperformed other regimens across all evaluated QoL items, yielding the most favorable combined profile.
Interpretation of SUCRA rankings
SUCRA provides a probabilistic ranking that summarizes the likelihood that a given treatment is the best (or among the best) for a specific outcome. In this analysis, atezolizumab plus bevacizumab’s high SUCRA values indicate that among the evaluated regimens it most consistently delayed deterioration in global QoL and common HCC symptoms reported on the QLQ-C30/HCC18 instruments.
Clinical and safety context
These HR-QoL advantages should be interpreted alongside the known efficacy and safety profiles. Atezolizumab plus bevacizumab demonstrated OS and progression-free survival (PFS) benefits over sorafenib in the IMbrave150 trial (Finn et al., NEJM 2020), which helped establish it as a standard first-line option. However, bevacizumab is associated with bleeding risk (notably from esophageal varices), and careful pre-treatment endoscopic evaluation is recommended. Immune-related adverse events may also affect QoL and must be managed proactively.
Strengths
– The analysis integrates patient-reported outcomes (PROs) with survival, offering a patient-centered synthesis beyond OS alone.
– Use of a Bayesian network allowed indirect comparisons across many regimens despite an absence of head‑to‑head trials for several combinations.
– Focus on time to deterioration (TTD) captures both onset and durability of HR-QoL changes and aligns with clinically meaningful patient experience.
Limitations and considerations
– Heterogeneity in trial populations and PRO collection: Differences in baseline characteristics (for example, etiology of liver disease, geographic distribution), timing and frequency of QoL assessments, and handling of missing PRO data can bias indirect comparisons.
– Trial eligibility: Most trials enrolled patients with Child-Pugh A liver function and excluded patients with untreated high‑risk varices; therefore, findings may not generalize to patients with more advanced liver dysfunction or those with uncontrolled variceal bleeding risk.
– Unblinded trials and differential patient/physician expectations may influence subjective PRO reporting, although TTD metrics mitigate some bias by focusing on sustained deterioration events.
– Granularity of results: SUCRA gives relative ranking probabilities but does not provide absolute magnitude of benefit in patient-level units (for example, median TTD or hazard ratios for QoL deterioration in the meta-analysis text were not reproduced here). Clinicians should interpret rankings alongside absolute effect sizes reported in individual trials.
– Integration with OS: The method of combining SUCRA for HR-QoL with survival metrics is reasonable for exploratory, patient-centered synthesis but is not a replacement for formal quality-adjusted survival (for example, Q-TWiST) analyses that require utility weights and patient-level data.
Clinical implications
For clinicians counseling patients with unresectable or advanced HCC, these findings reinforce the value of considering HR-QoL outcomes when choosing first-line therapy. Atezolizumab plus bevacizumab appears to offer the most favorable balance between extending survival and preserving quality of life among currently available options, according to the integrated network meta-analysis.
However, individual patient factors must guide therapy selection: comorbidities, liver function (Child-Pugh status), risk of bleeding, comedications, autoimmune disease history, and patient preferences regarding route of administration, frequency of visits and toxicity trade-offs. For patients at high risk of bleeding or with contraindications to anti-VEGF therapy, alternative immunotherapy combinations (for example, durvalumab plus tremelimumab) or TKIs may remain appropriate.
Research and policy priorities
– Standardize PRO collection: Future registrational trials should harmonize instruments, assessment schedules and missing data handling to permit more robust cross-trial comparisons and meta-analyses.
– Head-to-head trials and real-world evidence: Direct comparisons of leading immunotherapy combinations, as well as real-world studies that include patients with Child-Pugh B cirrhosis and those with comorbidities frequently excluded from trials, are needed to confirm generalizability.
– Quality-adjusted survival: Incorporating utility-based, quality-adjusted survival metrics (for example, Q-TWiST or QALYs) into trial reporting would provide more directly interpretable combined survival and QoL estimates for health technology assessment and shared decision-making.
– PRO-guided care: Trials testing PRO-driven symptom management interventions and integration of PROs into routine clinical workflows could further improve patient-centered outcomes.
Expert commentary
Integrating HR-QoL with survival reflects a more patient-centered metric palette for therapeutic value assessment. The findings by Celsa et al. align with prior trial-level observations from IMbrave150 and the evolving immunotherapy landscape that favors combinations which both prolong survival and reduce symptom burden. Clinicians should continue to weigh safety profiles (particularly bleeding risk with anti‑VEGF agents) and patient-level priorities in therapy selection. Guidelines increasingly recognize the importance of PROs; this network meta-analysis provides useful comparative evidence but should complement—not replace—individualized care planning.
Conclusion
This Bayesian network meta-analysis integrating HR-QoL deterioration and survival across first-line systemic therapies for unresectable or advanced HCC found that atezolizumab plus bevacizumab most consistently preserved QoL and yielded the most favorable combined benefit when survival was considered. The study highlights the importance of routinely incorporating PROs into trial endpoints and clinical decision-making. Future work should harmonize PRO methods, explore quality-adjusted survival metrics and expand evidence in underrepresented patient subgroups.
Funding and trial registration
Funding and trial-level registration information should be checked in the original publication (Celsa et al., JAMA Oncology 2025) and in the registries for individual trials. Examples of pivotal trial registrations include IMbrave150 (NCT03434379) and REFLECT (NCT01761266).
References
1) Celsa C, Di Maria G, Lombardi P, et al. Integrating Quality of Life and Survival in Systemic Therapy for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis. JAMA Oncol. 2025 Oct 1;11(10):1160-1168. doi: 10.1001/jamaoncol.2025.2470 IF: 20.1 Q1 .
2) Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi:10.1056/NEJMoa1915745 IF: 78.5 Q1 .
3) Kudo M, Finn RS, Qin S, et al. Lenvatinib versus Sorafenib in First‑Line Treatment of Patients With Unresectable Hepatocellular Carcinoma: REFLECT Trial. N Engl J Med. 2018;379(24):2347-2358. doi:10.1056/NEJMoa1717007 .
4) Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ‑C30: a quality‑of‑life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376.
5) Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomized trials. BMJ. 2011;343:d5928.
6) Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple‑treatment meta‑analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163-171.
7) European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: Management of hepatocellular carcinoma (2018) and subsequent guideline updates. (For guidance on management and the role of systemic therapy.)
