Hepatocellular carcinoma — open questions¶
Last curated: 2026-10-25
Stable IDs are retained when questions are revised. Tier 1 questions could change practice and are designable now; Tier 2 questions require more assay, cohort, or mechanistic development.
Tier 1 — practice-changing and designable today¶
OQ-1 — Does contemporary HCC surveillance reduce mortality outside chronic HBV?¶
The sole large positive randomized trial enrolled 18,816 HBV-infected Shanghai adults and reported a mortality rate ratio of 0.63 despite 58% adherence (Zhang 2004, PMID 15042359). Observational meta-analysis supports early detection, curative treatment, and survival but remains vulnerable to bias and heterogeneity (Singal 2022, PMID 35139400), while systematic review rated mortality evidence very low strength (Kansagara 2014, PMID 24934699). A pragmatic randomized strategy trial in nonviral cirrhosis remains designable.
OQ-2 — Which non-cirrhotic MASLD subgroup should undergo surveillance?¶
Average incidence (~0.1–1.3 per 1,000 patient-years) is too low for blanket surveillance, but risk concentrates by age, sex, diabetes, and fibrosis (Huang 2021, PMID 33349658). In 30,414 veterans, HCC risk rose 18% per 5-kPa liver-stiffness increment, while an individual-patient/aggregate meta-analysis of 379,194 non-cirrhotic patients found that non-invasive tests enrich risk without yet validating an actionable universal threshold (John 2026, PMID 40810411; Siriwong 2025, PMID 39919008). A 2026 decision-curve analysis of nine clinical risk scores in 853,131 veterans with non-cirrhotic steatotic liver disease found minimal net benefit for HCC-surveillance selection. At a 0.25% 10-year risk threshold, the best score (SAFE) yielded 1.6 additional true positives per 1,000 (Mezzacappa 2026, PMID 42766290). aMAP discriminates in UK Biobank SLD (C-index 0.80), but 15-year cumulative incidence was 1.43% in the aMAP-high group and 5.35% in a refined aMAP >64 validation subgroup—still low if treated as an annual surveillance-threshold problem (Xu 2026, PMID 42904608). Direct HCC-risk scoring may therefore be the wrong first step, and cirrhosis or stiffness detection the right one. The decisive study is a prospective two-stage design: lock/calibrate an eligibility rule, then randomize surveillance within the above-threshold stratum and measure late-stage HCC, false-positive procedures, cost, and mortality.
OQ-3 — Should poor ultrasound visualization trigger abbreviated MRI?¶
Ultrasound detects only ~47% of early HCC in meta-analysis (Tzartzeva 2018, PMID 29425931). In paired NAFLD-cirrhosis data, severe visualization limitation occurred in 35% with ultrasound versus 19% with abbreviated MRI, and obesity increased the odds of severe ultrasound limitation (OR 5.1, 95% CI 1.1–23.1) (Huang 2022, PMID 35229334). Active MRI-versus-ultrasound studies (NCT06658782; NCT07010588) should prespecify a VIS-C-triggered strategy, interval cancers, false referrals, decompensation, and cost—not sensitivity alone.
OQ-4 — Can blood panels improve surveillance outcomes, not only AUC?¶
Case-control performance is no longer enough. In phase-3 cohorts, HES V2.0 exceeded GALAD true-positive rate by 7.2% at a fixed 10% false-positive rate, yet external HEDS validation gave both algorithms AUROC 0.79 with different threshold profiles (El-Serag 2025, PMID 38899967; El-Serag 2026, PMID 41043723). A prospective head-to-head accuracy comparison with ultrasound is now reported. In ALTUS (2,293 paired participants; 27 early-stage HCCs), early-stage sensitivity was 66.7% for a multitarget blood test versus 22.2% for ultrasound, but blood-test specificity was 81.8% against a prespecified 82% target (ultrasound 98.6%) (John 2026, PMID 42800682; NCT05064553). A ~18% false-positive rate makes the recall budget the binding constraint, not sensitivity. A randomized replacement/augmentation trial should fix the false-positive budget, specify recall imaging, and measure late-stage incidence and treatment eligibility.
OQ-5 — At what post-HCV-cure risk can surveillance safely stop?¶
After sustained response, pooled HCC occurrence remains 2.47 per 100 person-years with cirrhosis versus 0.85 without (Lv 2024, PMID 38965190). Two pieces now exist separately. A microsimulation found twice-yearly surveillance cost-effective after cure through age 70 in cirrhosis and age 60 in advanced fibrosis (Mueller 2022, PMID 35157959). In 3,067 post-SVR cirrhotic patients, a competing-risk analysis found that current FIB-4/APRI values carried risk information but their slopes did not, and it could not identify anyone safe to stop (Nahon 2025, PMID 40020929). A 2026 AGA Clinical Practice Update addresses stopping surveillance in older adults through life expectancy and fitness for treatment, not through post-cure risk (Das 2026, PMID 42820904). A dynamic model incorporating fibrosis regression, age, diabetes, and competing death could support randomized discontinuation/non-inferiority testing (see D2).
OQ-6 — Which BCLC B phenotype should receive systemic therapy before TACE?¶
BCLC 2022 acknowledges heterogeneous transplantable, TACE-suitable, and diffuse intermediate disease (Reig 2022, PMID 34801630). EMERALD-1 and LEAP-012 improve PFS with TACE-systemic combinations (Sangro 2025, PMID 39798579; Kudo 2025, PMID 39798578). LEAP-012 final OS, posted to ClinicalTrials.gov on 2026-09-03, shows no survival difference: median 40.4 versus 40.8 months, HR 0.98 (95% CI 0.76–1.26) (NCT04246177). This is not yet peer-reviewed and EMERALD-1 OS is unreported. A 4.6-month median PFS gain that leaves OS unchanged sharpens the question. One untested explanation is that adding systemic therapy to TACE front-loads treatment that control-arm patients receive later, at progression; post-progression therapy data would be needed to test it. A 2026 HCC-Live expert consensus recommends systemic therapy as the comparator for larger-burden and locally advanced disease, with PFS and OS as primary outcomes linked by alpha-recycling (Yarchoan 2026, PMID 42785981). A three-arm platform—selective TACE, contemporary systemic therapy, and combination—should stratify by up-to-seven burden, ALBI, distribution, and planned selectivity, with OS, time to decompensation, and quality-adjusted survival as co-key outcomes.
2026-10-25 follow-up: Abstract-level results are now incorporated. TORCH (two Chinese centres; TACE then RFA versus TACE) reported PFS 17.7 versus 7.3 months (HR 0.47, 0.34–0.65) and OS 88.6 versus 35.1 months (HR 0.50, 0.34–0.73) (Lyu 2026, PMID 42530948). EMERALD-3 reported STRIDE plus lenvatinib plus TACE PFS 13.0 versus 9.8 months (HR 0.70, 0.57–0.86) and OS 39.5 versus 34.7 months (HR 0.84, 0.65–1.09; p=0.18); an October erratum exists and its text was still unreadable (Kudo 2026, PMID 42636832; PMID 42805209). EMERALD-3 therefore joins LEAP-012 as a TACE-plus-systemic program whose PFS gain has not become a significant OS gain. TORCH answers a different question (ablation after TACE). Open full text and the EMERALD-3 correction remain due.
OQ-7 — What is the optimal stopping rule for repeated TACE?¶
Repeated incomplete response and liver-function decline predict diminishing benefit, yet “TACE refractoriness” definitions vary. Japanese criteria use at least two consecutive inadequate responses after technical reassessment, while European “untreatable progression” also emphasizes invasion, spread, performance, and liver reserve (Kudo 2014, PMID 25427730; Raoul 2014, PMID 24945002). A prospective stopping rule should be tested against clinician judgment and jointly model viable-tumor response, selectivity, bilirubin/ALBI change, and the opportunity cost of delaying systemic therapy.
OQ-8 — Which first-line immunotherapy combination should be chosen?¶
Atezolizumab-bevacizumab, tremelimumab-durvalumab, nivolumab-ipilimumab, and regionally available combinations were tested against sorafenib or TKIs, not one another (Finn 2020, PMID 32402160; Abou-Alfa 2022, PMID 38319892; Yau 2025, PMID 40349714; Qin 2023, PMID 37499670). A targeted PubMed search on 2026-08-30 found no randomized direct comparison among the active combinations. A pragmatic head-to-head trial stratified by bleeding risk and etiology would change practice.
OQ-9 — What is the best sequence after first-line IO combination failure?¶
Regorafenib, cabozantinib, and ramucirumab phase 3 evidence was largely generated after sorafenib (Bruix 2017, PMID 27932229; Abou-Alfa 2018, PMID 29972759; Zhu 2019, PMID 30665869). New post-IO comparisons remain observational: LEVIATHAN reported adjusted advantages for lenvatinib over sorafenib, and a 1,663-patient reconstructed-data meta-analysis found heterogeneous TKI outcomes with residual confounding (Lombardi 2025, PMID 41321927; Akkus 2026, PMID 42128139). Pooled individual-patient data from three prospective Asian single-arm second-line trials (117 patients) gave median PFS 4.2 and OS 10.6 months; macrovascular invasion, not prior IO response, was the only independent OS factor (HR 3.55, 95% CI 1.89–6.67) (Chan 2026, PMID 42800536). PubMed searches on 2026-08-30 and 2026-10-11 identified no prospective randomized post-IO sequence trial; IMbrave251 (NCT04770896) is active, not recruiting, with no posted results.
OQ-10 — Does MASLD/MASH etiology modify checkpoint benefit?¶
Mechanistic and pooled subgroup work suggests impaired antitumor surveillance in NASH-HCC (Pfister 2021, PMID 33762733), but “nonviral” is heterogeneous and subgroup comparisons are underpowered. An umbrella review of 15 meta-analyses found the PD-(L)1 plus antiangiogenic OS benefit larger in HBV (HR 0.64, 95% CI 0.55–0.74) than in nonviral HCC (HR 0.91, 0.75–1.11), with an interaction P = 0.02 for OS. Overlap between the source meta-analyses was very high (CCA 44.4%) (Petrelli 2026, PMID 41794163). An individual-patient-data network meta-analysis of first-line regimens has a published protocol (Luo 2026, PMID 41988192). Prospective individual-patient randomized interaction testing is still needed before etiology guides treatment.
OQ-11 — Does adjuvant immunotherapy improve cure rather than delay recurrence?¶
IMbrave050 initially improved recurrence-free survival after high-risk resection/ablation, but the 2026 update found that benefit was not sustained (RFS HR 0.90, 95% CI 0.72–1.12); OS remained immature and numerically unfavorable (HR 1.26, 95% CI 0.85–1.87), so the benefit–risk profile did not support adjuvant atezolizumab-bevacizumab (Qin 2023, PMID 37871608; Yopp 2026, PMID 41580093). KEYNOTE-937 registry results, posted 2026-04-24, are also null: adjuvant pembrolizumab RFS HR 1.06 (95% CI 0.88–1.26), OS HR 1.08 (0.81–1.43), 959 randomized; no PubMed primary was retrieved on 2026-10-25 (NCT03867084). A 332-patient phase-3 adjuvant-TACE trial was negative overall (RFS HR 0.88, 95% CI 0.62–1.24), whereas a selected 280-patient HBV/high-risk trial was positive (HR 0.68), showing that “high risk” is biologically heterogeneous (Ma 2025, PMID 39808820; Wang 2018, PMID 29420221). Perioperative camrelizumab-rivoceranib in CARES-009 improved EFS versus surgery alone (42.1 vs 19.4 months; HR 0.59, 0.41–0.85) in a Chinese CNLC Ib–IIIa population, with 38% grade ≥3 treatment-related events and two neoadjuvant treatment-related deaths (Wang 2025, PMID 41125112; NCT04521153). That is a perioperative package, not an adjuvant-only result. Future trials should distinguish early metastatic recurrence from late new primaries, separate perioperative from adjuvant-only designs, and require durable RFS plus mature OS or patient-important net benefit.
OQ-12 — How should transplant selection balance morphology, biology, and equity?¶
Milan provides transparency; Metroticket 2.0 improves continuous prediction using AFP, number, and size (Mazzaferro 1996, PMID 8594428; Mazzaferro 2018, PMID 28989060). In a post hoc analysis of 485 SiLVER trial patients classified on explant pathology, Milan, UCSF, Up-to-7 and Metroticket 2.0 all discriminated modestly and similarly (OS C-index 0.55–0.57), while Up-to-7 admitted 83.9% versus Milan's 65.6% (Kupke 2026, PMID 42669573). Allocation simulations should quantify graft utility and disparate access before replacing categorical rules.
OQ-13 — How far beyond standard limits can successful downstaging select transplant candidates?¶
XXL randomized evidence and MERITS-LT support transplant after sustained response in selected patients, but upper entry limits and required observation time vary (Mazzaferro 2020, PMID 32615109; Mehta 2021, PMID 34331914).
OQ-14 — Can checkpoint therapy be integrated safely before liver transplantation?¶
Checkpoint exposure can precipitate graft rejection. An individual-patient meta-analysis found 24 rejections among 91 exposed recipients (26.4%), while an international 119-recipient cohort found rejection in 20.2%; washout <30 days had OR 21.3 and 30–50 days OR 9.48 versus >50 days (Rezaee-Zavareh 2025, PMID 38996924; Moeckli 2025, PMID 40042053). A 416-recipient propensity-matched Chinese cohort initially beyond Milan associated ICI-based downstaging with better post-transplant OS (HR 0.63, 95% CI 0.43–0.92) but doubled 90-day acute rejection (16.3% vs 8.2%). Patients who never reached transplant were not included (Ong 2026, PMID 42821267). The question is no longer only whether ICIs are safe before transplant; it is whether better tumour control outweighs a twofold rejection risk, judged from listing rather than from transplant. A prospective protocol must record agent, dose, last exposure, receptor-occupancy/immune assays, donor type, immunosuppression, rejection histology, graft loss, recurrence, and the denominator who never reaches transplant.
OQ-15 — How should Child-Pugh B systemic therapy be tested?¶
Pivotal trials largely enrolled Child-Pugh A. Child-Pugh B combines mildly abnormal laboratories, prior or active decompensation, and heterogeneous portal hypertension, making uncontrolled outcomes hard to interpret. The phase IIIb SIERRA study gave single-arm STRIDE to 44 Child-Pugh B7/B8 patients: grade 3/4 possibly related adverse events within 6 months occurred in 18.2% and objective response in 6.8% (Chan 2026, PMID 42838226; NCT05883644). The study shows tolerability but, with no comparator, not benefit. A dedicated platform should stratify B7 versus B8/9, active versus historical ascites/encephalopathy, ALBI, and tumor burden; use starting-dose rules; and jointly adjudicate cancer progression, treatment toxicity, decompensation, non-cancer death, symptoms, and quality of life.
OQ-16 — Which intervention closes the surveillance-to-curative-treatment equity gap?¶
US meta-analysis found lower early-stage detection and worse survival for Black patients; SEER-Medicare showed lower curative-treatment receipt, especially in high-poverty neighborhoods (Rich 2022, PMID 33387668; Wagle 2022, PMID 34796703). Cluster-randomized navigation/registry interventions should measure stage and curative therapy, not orders alone.
The London implementation cohort now supplies a UK service-delivery baseline, but does not test an intervention (Qurashi 2026, PMID 42866364). A pragmatic intervention should keep specialist-referral failures in its denominator rather than analysing only patients already in follow-up.
OQ-17 — Does early integrated palliative care improve HCC outcomes?¶
Qualitative studies show symptom, information, and caregiver burden, while intervention evidence remains thin (Hansen 2015, PMID 25122134; Hansen 2017, PMID 28820518). A pilot randomized intervention enrolled 57 of 109 approached patients and retained 52, establishing feasibility but not definitive benefit (Verma 2023, PMID 36149682). A multicentre trial should trigger at advanced disease or first decompensation and test symptom burden, quality of life, goal-concordant treatment, acute-care use, caregiver outcomes, and survival without treating lower anticancer intensity as failure.
Tier 2 — enabling biology, tools, and future designs¶
OQ-18 — Can dominant HCC drivers be exploited therapeutically?¶
TERT, CTNNB1, and TP53 dominate the exome landscape but remain undrugged; “actionable” alterations rarely translate into HCC matches (Schulze 2015, PMID 25822088; Harding 2019, PMID 30373752). Synthetic-lethal and state-directed screens need liver-specific toxicity constraints.
OQ-19 — Is Wnt/CTNNB1 a predictive biomarker for specific IO regimens?¶
β-catenin activation drives immune exclusion and anti-PD-1 resistance in models and retrospective correlates (Ruiz de Galarreta 2019, PMID 31186238). Post hoc phase-3 analyses now exist. In CheckMate 459, nivolumab beat sorafenib only in Wnt-unaltered tumors (OS HR 0.66, 95% CI 0.47–0.91), partly because sorafenib did better in Wnt-mutated tumors (Neely 2026, PMID 42762856). In IMbrave150, a high mutated-β-catenin signature showed no significant atezolizumab-bevacizumab gain over sorafenib (Lehrich 2024, PMID 39583094). Both use sorafenib as the comparator, so neither ranks immune regimens. Prospective randomized treatment-by-marker interaction is needed; mutation alone may not equal pathway state.
OQ-20 — Can spatial immune architecture be reduced to a deployable assay?¶
Single-cell work identifies heterogeneous malignant, macrophage, T-cell, and tertiary-lymphoid states (Lu 2022, PMID 35933472). A clinically useful assay must survive sampling, platform, spatial, and temporal heterogeneity.
OQ-21 — Can ctDNA define minimal residual disease after local cure?¶
MRD studies are assay-diverse and observational (Galli 2025, PMID 40058162). A 2026 meta-analysis of 12 cohorts (880 patients) found postoperative ctDNA detection associated with RFS HR 4.95 (95% CI 2.77–8.83; low certainty, I² = 79%) and concluded routine use is not supported (Abdelrahim 2026, PMID 42715861). A locked assay should stratify recurrence early enough to support randomized ctDNA-guided adjuvant intervention. NCT07350824, previously cited here as that vehicle, is registered as NON_RANDOMIZED, with active-monitoring and adjuvant-PD-1 cohorts, and is not yet recruiting (registry checked 2026-10-11). It therefore cannot answer the question.
OQ-22 — What causes early versus late post-resection recurrence?¶
Micrometastatic recurrence and new primary HCC require different prevention. Multi-region tumor/adjacent-liver phylogenetics plus longitudinal ctDNA could distinguish them and refine adjuvant endpoints.
OQ-23 — Can personalized TARE dosimetry be standardized?¶
DOSISPHERE-01 shows dose planning changes response and survival, while comparative TARE literature mixes dosimetry approaches (Garin 2021, PMID 33166497; Brown 2023, PMID 35943116). Cross-platform absorbed-dose standards and liver-toxicity models are needed.
OQ-24 — What biomarker separates immune hepatitis from decompensation or progression?¶
All can raise liver tests during checkpoint therapy. Serial immune, viral, imaging, and tissue studies need adjudicated diagnoses to prevent both delayed immunosuppression and inappropriate steroid exposure.
OQ-25 — Can risk scores predict net surveillance benefit rather than cancer incidence?¶
Existing HBV models vary in transportability, and most omit competing death and treatment eligibility (Wu 2021, PMID 33667678). Utility models should combine HCC risk, detection performance, curative access, and non-HCC mortality.
2026-10-18 follow-up: The new head-to-head THRI/aMAP cohort merits full-text assessment before informing deferral thresholds (Moussa 2026, PMID 42686444). Check competing-risk methods, calibration and missed cancers, then distinguish low predicted incidence from proven safety of stopping surveillance. No new stopping rule is adopted from its abstract.
2026-10-25 follow-up: THCC-RI (THRI) was externally validated in the prospective HEDS cirrhosis-surveillance cohort: 1,560 patients, 114 HCC, C-index 0.77 (0.64–0.85); high versus medium risk HR 3.5 (2.4–5.1). Discrimination was more stable than aMAP beyond three years. The authors state that implementation still requires further research; the abstract does not report a low-risk incidence that would support stopping surveillance (Kanwal 2026, PMID 41672261). Full text was not open this session.
OQ-26 — How should patient preferences enter treatment allocation algorithms?¶
Interviews report clinician-led decisions despite variable goals; preference studies show tradeoffs among route, efficacy, and burden (Wörns 2024, PMID 39052152; Chiba 2019, PMID 31118587). A preference-elicitation tool needs evidence that it improves concordance without delaying care.
Dots not yet connected¶
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| D1 | Average non-cirrhotic NAFLD incidence is ~0.1–1.3 per 1,000 patient-years (Huang 2021, PMID 33349658), while 30,414 veterans with MASLD included a subgroup without cirrhosis or clinically significant portal hypertension but with diabetes and liver stiffness ≥10 kPa whose HCC incidence was 0.46 per 100 person-years (95% CI 0.29–0.78) (John 2026, PMID 40810411) | In 54 prospectively imaged patients with NAFLD cirrhosis, severe visualization limitation occurred in 35% on ultrasound versus 19% on abbreviated MRI; obesity predicted severe ultrasound limitation (OR 5.1, 95% CI 1.1–23.1) (Huang 2022, PMID 35229334). In a cirrhosis meta-analysis, ultrasound sensitivity for early HCC was 47% (95% CI 33%–61%) (Tzartzeva 2018, PMID 29425931) | The cited risk estimate selects a non-cirrhotic MASLD subgroup, whereas the cited modality-performance estimates come from cirrhosis. Targeted PubMed searches S1 (3 records) and S2 (21 records) on 2026-10-07 did not identify a prospective visualization or modality-comparison study within a risk-selected non-cirrhotic MASLD subgroup; a retrospective UK stage-at-diagnosis study is adjacent but does not measure visualization (PMID 40337094). Patient selection and test selection therefore still need joint evaluation | OQ-2, OQ-3 |
| D2 | In 3,067 patients with cirrhosis after HCV cure, current FIB-4/APRI values carried HCC risk information after accounting for competing death, but their slopes added no information when current values were included; the authors could not identify patients safe to stop surveillance (Nahon 2025, PMID 40020929) | A post-cure microsimulation found twice-yearly surveillance cost-effective through age 70 in cirrhosis and age 60 in stable advanced fibrosis (Mueller 2022, PMID 35157959); a separate model estimated a 0.7-per-100-person-years incidence threshold at $100,000 per QALY (Chhatwal 2024, PMID 37302445) | The economic stopping ages and threshold have not been converted into a validated stopping decision using a person's repeatedly measured risk and competing mortality. The Nahon cohort explicitly cautions against stopping on improved non-invasive tests; the Mueller and Chhatwal models do not supply that longitudinal decision rule | OQ-5, OQ-25 |
| D3 | In an HCC mouse model, β-catenin activation impaired dendritic-cell recruitment and anti-PD-1 response (Ruiz de Galarreta 2019, PMID 31186238); among 31 checkpoint-treated patients in a separate cohort, disease control was 0% with activating Wnt/β-catenin alterations versus 53% without (Harding 2019, PMID 30373752) | Exploratory CheckMate 459 tissue analyses found an OS advantage for nivolumab over sorafenib in Wnt/β-catenin-unaltered tumors (HR 0.66, 95% CI 0.47–0.91) (Neely 2026, PMID 42762856). A high mutated-β-catenin gene-signature score in IMbrave150 was associated with no significant OS or PFS gain for atezolizumab-bevacizumab over sorafenib (Lehrich 2024, PMID 39583094) | The mechanistic and exploratory clinical signals are related but do not establish a prospective treatment-by-marker interaction or select among current first-line immune combinations. Both cited trial biomarker analyses are post hoc and compare an immune regimen with sorafenib, not immune regimens with one another | OQ-8, OQ-19 |
| D5 | In 88 resected patients, postoperative tumor-informed ctDNA MRD status was the strongest measured recurrence factor (HR 2.162, 95% CI 1.09–4.30) (Hu 2025, PMID 39526910). A 2025 review of 91 MRD studies reported 50%–80% sensitivity and up to 94% specificity for ctDNA/CTCs; at its search cutoff, none of 17 ongoing studies assigned treatment by biomarker (Galli 2025, PMID 40058162) | Unselected adjuvant atezolizumab-bevacizumab caused grade 3–4 adverse events in 41% versus 13% (Qin 2023, PMID 37871608); its early RFS HR of 0.72 (adjusted 95% CI 0.53–0.98) was not sustained (updated HR 0.90, 95% CI 0.72–1.12), and OS remained immature (HR 1.26, 95% CI 0.85–1.87) (Yopp 2026, PMID 41580093) | Prognostic MRD testing has not shown that assigning adjuvant therapy by MRD improves outcomes. On 2026-10-07, PubMed S5 returned 3 reviews and ClinicalTrials.gov S6 returned 12 studies, none assigning randomized adjuvant treatment by MRD status: NCT07350824 is non-randomized, NCT07379489 is observational, and NCT05482516 is a single-arm GI-cancer pilot (11 enrolled). A separate recruiting trial randomizes ctDNA monitoring versus standard follow-up, not adjuvant treatment (NCT07001085) | OQ-11, OQ-21 |
| D6 | DOSISPHERE-01 randomized 60 patients with locally advanced HCC and an index lesion ≥7 cm; among 56 treated and evaluable patients (28 per arm), personalized TARE dosimetry targeting ≥205 Gy to the index lesion produced objective response in 71% versus 36% with standard 120 ± 20 Gy to the perfused lobe (Garin 2021, PMID 33166497) | Adding durvalumab-bevacizumab to TACE gave PFS 15.0 versus 8.2 months (HR 0.77, 95% CI 0.61–0.98) (EMERALD-1; Sangro 2025, PMID 39798579). Adding lenvatinib-pembrolizumab to TACE gave PFS 14.6 versus 10.0 months (HR 0.66, 95% CI 0.51–0.84), while interim OS was not significant (HR 0.80, 95% CI 0.57–1.11) (LEAP-012; Kudo 2025, PMID 39798578); registry-posted final OS was HR 0.98 (95% CI 0.76–1.26) (NCT04246177, results posted 2026-09-03) | The two combination trials used TACE rather than dose-planned TARE. Targeted PubMed S7 returned 2 reviews, and a ClinicalTrials.gov search of randomized TARE studies (S8, 36 records) found no completed dosimetry-planned TARE versus systemic-first comparison. Two identified BCLC B locoregional-versus-systemic trials terminated after poor accrual: REPLACE (NCT04777851; 45 enrolled) and NCT05537402 (1 enrolled); neither registry record specifies dosimetry | OQ-6, OQ-23 |
| D9 | Black patients had lower odds of early-stage HCC than White patients (OR 0.66, 95% CI 0.54–0.78; 35 studies, 563,097 patients) (Rich 2022, PMID 33387668); in SEER-Medicare, Black patients in high-poverty neighborhoods had lower odds of curative treatment (OR 0.64, 95% CI 0.49–0.84) and worse survival (HR 1.13, 95% CI 1.02–1.25) (Wagle 2022, PMID 34796703) | Organized surveillance programmes increased ultrasound uptake (OR 6.00, 95% CI 3.35–10.77; 9 studies, 4,550 patients) (Ramai 2023, PMID 34999648) | The disparity is measured at stage and treatment, but the intervention's clear benefit is process uptake. Outreach plus navigation increased surveillance to 23.3% versus 7.3% in one trial without a difference in early-stage proportion among detected cancers (Singal 2019, PMID 30070379). In the later 2,872-person trial, screening-process completion rose to 6.6% versus 3.3% (Singal 2024, PMID 38839269), but early-stage proportion among 125 HCC cases did not significantly improve (64.2% versus 79.3%; P=0.06) (Singal 2025, PMID 39288308). Targeted PubMed searches S10 (12 records) and D9stage (5 records) on 2026-10-07 found no randomized report establishing an outreach effect on curative treatment, survival, or the Black–White gap | OQ-16, OQ-1 |
| D10 | In 39 interviews with 13 family caregivers of patients with terminal HCC, caregivers reported feeling unprepared and struggling to distinguish HCC-related from cirrhosis-related symptoms (Hansen 2017, PMID 28820518). A pilot randomized palliative-care study enrolled 57 of 109 approached patients and measured quality of life and symptoms (Verma 2023, PMID 36149682) | Among 640 patients endoscoped before atezolizumab-bevacizumab, 45 (7.0%) developed variceal bleeding; cumulative incidence was 7.4% at 12 months, and main portal-vein invasion was associated with bleeding (SHR 3.49, 95% CI 1.63–7.44). No patient died from variceal bleeding in this cohort (Park 2025, PMID 39871662) | The caregiver interviews document uncertainty about symptom attribution, while the treatment cohort documents a specific acute complication; neither shows that caregivers missed bleeding signs. A caregiver education and escalation intervention could test recognition, time to presentation, and acute-care use. PubMed S11 found 0 records with caregiver-intervention and acute-care terms on 2026-10-07; a broader caregiver-intervention query returned 15 titles and no matching HCC trial | OQ-17, OQ-26 |
| D13 | In a phase 3 prospective-specimen, blinded-evaluation cohort of 2,331 patients with cirrhosis (125 developed HCC), HES V2.0 improved HCC detection sensitivity over GALAD at a fixed 10% false-positive rate in several assessment windows (El-Serag 2025, PMID 38899967) | Among 655 veterans with cirrhosis who were eventually diagnosed with HCC, 46.9% had a diagnostic delay of more than 60 days after a guideline-defined red flag; this is a case-only delay estimate, not a recall-failure rate for all abnormal screens (Choi 2021, PMID 32693047) | Better blood-panel accuracy and timely diagnostic follow-up are different parts of the surveillance pathway. A prospective end-to-end evaluation should measure whether adding the panel, together with tracked follow-up of positive findings, increases completed diagnosis and curative treatment. The cited studies separately measure detection performance and delay; neither tests that combined pathway | OQ-4, OQ-16 |
| D15 | In a discrete-choice experiment, 200 US patients with unresectable HCC valued 10 additional months of maintained daily function as much as or more than 10 additional months of OS (Li 2023, PMID 36900262); 150 European patients were willing to trade OS to avoid diarrhea and hypertension risk (Lo 2021, PMID 34313150) | First-line phase 3 trials prioritized OS and/or PFS: IMbrave150 had co-primary OS and PFS (Finn 2020, PMID 32402160), HIMALAYA and CheckMate 9DW had primary OS (Abou-Alfa 2022, PMID 38319892; Yau 2025, PMID 40349714), and CARES-310 had primary PFS and OS (Qin 2023, PMID 37499670) | Composite treatment rankings exist, but the two located analyses did not use patient-elicited weights: ESIRA selected a 0.7:0.3 efficacy-to-safety ratio by sensitivity analysis (Li 2026, PMID 41634252), while a TOPSIS network meta-analysis used entropy weights (Nie 2026, PMID 42250662). Targeted PubMed S13 (25 records) on 2026-10-07 did not identify a trial or synthesis using patients' function-versus-survival tradeoffs to rank these regimens | OQ-8, OQ-26 |
“Powers” names the open questions that become more tractable if the junction is studied; it does not imply that no relevant study exists anywhere, only that the two evidence bodies remain unintegrated in this build.
Row IDs are stable. The 2026-10-07 independent audit restored D2, D3 and D13. D4, D7, D8, D11, D12 and D14 remain removed; the deletion audit is in LOG.md.