Perioperative camrelizumab plus rivoceranib in resectable hepatocellular carcinoma: translating CARES-009 outcomes into a new therapeutic paradigm

Abstract

Background:

Hepatocellular carcinoma (HCC) is one of the most common causes of malignancy, and recurrence rates are 50–70% even with curative resection, which indicates the necessity to employ an efficient perioperative systemic treatment.

Aim:

To conclude, regarding the mechanistic rationale and clinical evidence for perioperative camrelizumab (PD-1 inhibitor) and rivoceranib (VEGFR2 inhibitor) in resectable HCC, it is crucial to review CARES-009 and related information to inform clinical practice and research priorities.

Results:

Camrelizumab overturns T-cell exhaustion, whereas rivoceranib normalizes tumor vasculature and alleviates hypoxia, creating immuno-angiogenic synergy. In CARES-009, perioperative camrelizumab combined with rivoceranib was superior to surgery for event-free survival and primary pathological response in intermediate/high-risk resectable HCC. The favorable antitumor activity and favorable safety profile are supported by evidence from CARES-310 and other immunotherapy-TKI trials in advanced HCC. Translational research demonstrates that immune-angiogenic signatures and circulating tumor DNA can be used to risk-stratify. However, existing evidence is scarce due to poor overall survival outcomes, cohorts mostly driven by hepatitis B virus, and various regional differences in costs and access to drugs.

Conclusion:

Perioperative camrelizumab plus rivoceranib is a biologically rational and clinically promising agent that can be used to decrease recurrence in high-risk patients who have undergone resection of HCC. Nevertheless, these should be routinely introduced once mature survival, biomarker, real-world, and economic data are available. Once again, current use is best utilized in clinical trials or structured registry models.

Introduction

Hepatocellular carcinoma (HCC) remains a major global health challenge, contributing substantially to cancer-related morbidity and mortality worldwide^[1^]. Although early-stage HCC can be treated with curative-intent resection, postoperative recurrence rates remain unacceptably high, significantly diminishing long-term survival prospects^[2^]. This persistent risk underscores the need for effective perioperative systemic strategies to reduce recurrence and improve durable outcomes^[3^]. Building on this overarching concern, it is essential to contextualize the global burden of HCC and the patterns of recurrence that shape the need for perioperative interventions. Primary liver cancer is a rapidly increasing global health problem, with age-standardized incidence rates rising markedly between 1990 and 2021 – from approximately 345 912 to over 739 299 cases^[4^]. The highest incidence continues to occur in East Asia and sub-Saharan Africa, driven by chronic hepatitis B and C infections, metabolic dysfunction-associated steatotic liver disease, and other chronic liver disorders^[5^]. Despite advances in surgical techniques, recurrence after resection remains high, with studies reporting 5-year recurrence rates of 50–70%^[6^]. This risk is particularly pronounced during the first year postoperatively, when the hazard rate peaks at nearly 21.7%, and although it gradually declines, it persists beyond 5 years^[7^]. These epidemiological realities underscore the need for therapeutic strategies that address early and late recurrence, prompting further consideration of why surgery alone remains insufficient. Even with improved surgical precision and perioperative care, a substantial proportion of patients with resectable HCC experience disease recurrence, exposing the limitations of surgery as monotherapy^[2^]. Recurrence frequently stems from microscopic residual disease, intrahepatic micrometastases, or de novo tumor development in cirrhotic livers – reflecting the complex biology of HCC^[8^]. Traditional adjuvant approaches, including chemotherapy and local ablative modalities, have shown limited efficacy in reducing recurrence or improving overall survival (OS)^[9^]. In contrast, immunotherapy and targeted therapies offer promising avenues, particularly in the perioperative setting, where modifying the tumor immune microenvironment (TME) before or after resection may meaningfully reduce recurrence risk^[10,11^]. Given these therapeutic gaps and evolving strategies, it is necessary to define the objective framework guiding this review.

HIGHLIGHTS

• Review explores perioperative camrelizumab–rivoceranib in resectable hepatocellular carcinoma.

• Combination reverses T-cell exhaustion, normalizes vasculature, and enhances immunity.

• Cares-009 shows better event-free survival and pathological response than surgery.

• Safety favorable but data immature; evidence mainly from hepatitis B virus-driven Asian cohorts.

• Use best confined to trials until global, biomarker, and economic data mature.

Aim and objective of the review

This review aims to synthesize the mechanistic rationale and clinical evidence supporting the use of perioperative camrelizumab (a PD-1 inhibitor) and rivoceranib (a VEGFR2 inhibitor) in resectable HCC, with emphasis on translating findings from the CARES-009 trial into clinical practice. Specifically, the review will:

1. Examine the mechanistic basis underlying combined PD-1 inhibition and VEGFR2 blockade in the perioperative phase.

2. Review clinical data – including CARES-009 and related trials – focusing on efficacy and safety outcomes.

3. Integrate these findings into the broader context of current perioperative immunotherapy and targeted-therapy paradigms to identify directions for clinical implementation and future research.

To understand the therapeutic synergy of this combination, it is essential to first outline the underlying mechanistic framework.

Methods

This narrative review is based on previously published literature. To ensure methodological transparency and rigor, the literature search and data synthesis were conducted in alignment with the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. A comprehensive literature search was performed across major electronic databases, including PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, from database inception up to March 2026. The search strategy utilized a combination of Medical Subject Headings (MeSH) and free-text keywords combined with Boolean operators to capture the full breadth of the topic.

The primary search string utilized was: (“Hepatocellular carcinoma” OR “HCC” OR “liver cancer”) AND (“Camrelizumab” OR “SHR-1210” OR “anti-PD-1” OR “immune checkpoint inhibitor”) AND (“Rivoceranib” OR “Apatinib” OR “anti-VEGFR2” OR “tyrosine kinase inhibitor”) AND (“Perioperative” OR “Neoadjuvant” OR “Adjuvant” OR “Resectable” OR “Recurrence”).

To capture the most recent and highly relevant data not yet fully published in peer-reviewed journals, a supplementary manual search was conducted covering recent major oncology conference proceedings, specifically the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (up to 2025). Furthermore, the reference lists of included primary articles, meta-analyses, and systematic reviews were hand-searched to identify any additional relevant studies. To maintain the focus and quality of the review, specific inclusion and exclusion criteria were applied during the study selection process.

Inclusion criteria:

• Study types: Randomized controlled trials (e.g., phase II/III trials), prospective and retrospective cohort studies, and significant translational/biomarker studies evaluating the combination of camrelizumab and rivoceranib (or apatinib).

• Population: Adult patients diagnosed with resectable or advanced HCC.

• Outcomes: Studies reporting on event-free survival (EFS), OS, primary/major pathological response (MPR), recurrence rates, safety/tolerability [immune-related adverse events (irAEs)], and cost-effectiveness [incremental cost-effectiveness ratios (ICERs)].

• Language: Articles published in the English language.

Exclusion criteria:

• Study types: Single-case reports, editorials, unverified preprints, and non-systematic reviews that did not contribute original data or novel mechanistic insights.

• Relevance: Studies focusing solely on other malignancies without direct translational relevance to the HCC TME.

• Data integrity: In vitro or animal studies that did not directly support the clinical rationale of combined PD-1 and VEGFR2 blockade in human HCC models.

Two independent researchers screened the titles and abstracts of the retrieved records to eliminate duplicates and irrelevant studies. Full-text articles of potentially relevant studies were subsequently reviewed against the predefined inclusion criteria. Discrepancies were resolved through consensus or consultation with a third reviewer. Extracted data were synthesized narratively, focusing on the mechanistic rationale, clinical efficacy, safety (with an emphasis on translating CARES-009 trial outcomes), translational biomarker perspectives, surgical considerations, and global health economic impacts.

Discussion

Mechanistic framework

TME and recurrence biology

The TME plays a fundamental role in HCC progression and postoperative recurrence^[12,13^]. Chronic liver inflammation fosters an immunosuppressive TME enriched with regulatory T cells, myeloid-derived suppressor cells, and exhausted CD8⁺ T cells^[13^]. This environment facilitates immune evasion and increases the likelihood of recurrence, with recurrence rates exceeding 70% within 5 years among high-risk patients^[13^]. Additionally, angiogenic signaling, particularly via VEGF, drives abnormal vasculature, hypoxia, and further immunosuppression^[14^]. Within this immunosuppressive landscape, PD-1 blockade emerges as a key strategy to restore antitumor immunity.

PD-1 blockade and immune restoration (Camrelizumab)

Camrelizumab, a humanized monoclonal antibody targeting PD-1, restores antitumor immunity by preventing PD-1–PD-L1 interaction^[15,16^]. This blockade reactivates exhausted T cells, enhances cytotoxic function, and promotes increased effector T-cell infiltration into the TME^[16,17^]. These effects are particularly relevant in virally mediated HCC, where PD-L1 expression is frequently upregulated^[15,16^]. Complementing immune restoration, VEGFR2 inhibition provides additional therapeutic benefit by modulating tumor vasculature.

VEGFR2 inhibition and vascular normalization (Rivoceranib)

Rivoceranib selectively inhibits VEGFR2, thereby normalizing abnormal tumor vasculature^[14,17^]. This process reduces vessel permeability, alleviates tumor hypoxia, and improves drug delivery. Concurrently, VEGFR2 inhibition decreases pro-angiogenic signals and modifies cellular adhesion pathways, further reshaping the TME^[17^]. Together, these mechanisms form the basis for a synergistic immuno-angiogenic interaction.

Immuno-angiogenic synergy and translational evidence

Combined PD-1 blockade and VEGFR2 inhibition enhances antitumor activity by integrating immune activation with vascular normalization^[12,14,15,17,18^]. Preclinical HCC models show increased CD8⁺ T-cell infiltration, reduced MDSCs, and reprogramming of the TME toward an immunostimulatory phenotype^[12,17,18^]. Biomarker and translational studies further support this synergy by favorably modulating immune-activation genes and angiogenic markers^[18^]. In vivo models consistently demonstrate superior tumor regression with combination therapy compared to monotherapy^[17^]. With mechanistic synergy established, the next step is to evaluate clinical data assessing this combination in resectable and advanced HCC (Fig. 1).

Figure 1.

Synergistic immune-modulating effects of camrelizumab plus rivoceranib in HCC.

Clinical evidence

CARES-009 trial design and efficacy outcomes

The CARES-009 study was a randomized, open-label phase III trial evaluating perioperative camrelizumab plus rivoceranib versus surgery alone in patients with resectable HCC at intermediate or high risk of recurrence^[19^]. Patients received two cycles of neoadjuvant therapy, followed by resection and up to 1 year of adjuvant treatment. The trial met its primary endpoint, demonstrating a significant improvement in EFS, with a hazard ratio of 0.52 (95% CI 0.39–0.69; P < 0.0001)^[19^]. Notably, primary pathological response (MPR) rates were significantly higher in the treatment arm (24.5%) than in the control arm (5.9%), reflecting vigorous antitumor activity^[19^]. These findings are further supported by results from related trials evaluating the same drug combination in more advanced disease settings.

CARES-310 and related immunotherapy–TKI studies

In advanced HCC, the phase III CARES-310 trial compared camrelizumab plus rivoceranib with sorafenib as first-line therapy^[20,21^]. Updated OS data presented in January 2025 at ASCO GI showed a median OS of 23.8 months for the combination versus 15.2 months with sorafenib (HR 0.62), with similar benefit across viral and non-viral subgroups^[20^]. Post hoc analyses supported treatment efficacy regardless of underlying etiology^[20^]. Additional network meta-analyses consistently ranked the camrelizumab–rivoceranib combination among the most effective immunotherapy–TKI–TKI regimens for advanced HCC^[22,23^]. Despite these favorable outcomes, regulatory approval has been complicated by manufacturing-related issues, leading to a second FDA complete response letter (CRL) in March 2025^[22,23^]. When viewed alongside comparable perioperative immunotherapy trials, the performance of the camrelizumab–rivoceranib regimen provides meaningful context for positioning CARES-009 within the current therapeutic landscape.

Comparison with other perioperative immunotherapy trials

Across the broader perioperative landscape, CARES-009 demonstrates competitive efficacy. For instance, the IMbrave050 trial, which evaluated adjuvant atezolizumab plus bevacizumab, showed an improvement in recurrence-free survival among high-risk patients following resection (HR 0.72). However, this benefit diminished with longer follow-up^[24,25^]. Similarly, the phase II NeoLEAP-HCC trial investigated perioperative pembrolizumab plus lenvatinib, reporting MPR rates of up to 42% and favorable functional outcomes in updates from 2024 to 2025^[26^]. Meta-analyses of neoadjuvant immune checkpoint inhibitor studies have generally reported overall response rates of 20–30%, whereas CARES-009 has achieved more favorable EFS outcomes than adjuvant-only approaches such as IMbrave050^[27–29^]. While efficacy signals are encouraging, the clinical adoption of any perioperative strategy also depends on an acceptable safety profile and perioperative tolerability.

Safety and perioperative tolerability

The combination of camrelizumab and rivoceranib has shown a manageable safety profile, consistent with known toxicities of PD-1 inhibitors and VEGFR2-TKIs. IrAEs – including rash and thyroid dysfunction – occur in approximately 30–40% of patients and are generally controllable with standard immunomodulatory measures^[18,23^]. In the perioperative context, safety outcomes have been reassuring: postoperative complications, such as wound-healing delays, appear less common than with TKI monotherapy, likely due to vascular normalization^[14^]. In CARES-009, treatment-related serious adverse events occurred in 12% of patients, compared with 4% in the control arm; importantly, these did not lead to increased surgical delays^[19^]. Population-level data from CARES-310 also showed maintained quality of life, with irAEs largely reversible using guideline-recommended management strategies^[13,16,23^]. Building on these clinical outcomes, the next section evaluates the methodological strengths and limitations of the CARES-009 trial to determine its robustness and potential impact on clinical practice (Fig. 2).

Figure 2.

Synergistic immune and vascular modulation in HCC.

Critical Appraisal of CARES-009

Methodological strengths

The CARES-009 trial incorporates several methodological strengths that enhance its internal validity and clinical relevance. First, the biological rationale for combining camrelizumab and rivoceranib is supported by robust preclinical and advanced-disease clinical evidence. Previous trials, including CARES-310, demonstrated improved survival and disease control with the same combination in unresectable HCC, suggesting strong mechanistic synergy between VEGFR2 inhibition and PD-1 blockade^[19,26,30^]. This provides a compelling foundation for evaluating the regimen earlier in the disease course, when surgical intervention remains feasible, and the potential for cure is higher.

A significant strength of CARES-009 is its integrated perioperative design. The use of both neoadjuvant and adjuvant therapy offers a dual opportunity to influence tumor biology: neoadjuvant therapy enhances immune activation, modulates the tumor microenvironment, and may facilitate surgical resection; adjuvant therapy targets residual microscopic disease to reduce recurrence risk^[31,32^]. This design allows for comprehensive assessment of both clinical endpoints – such as EFS – and biological endpoints, including pathological response and immune infiltration patterns within resected tissue. Primary pathological response (MPR), in particular, serves as an early surrogate marker associated with reduced recurrence risk in several solid tumor types.

Additionally, the combination’s mechanism-driven synergy enhances the biological plausibility of the trial’s outcomes. VEGFR2 inhibition decreases hypoxia and normalizes vascular architecture, thereby enhancing T-cell infiltration and potentiating the effects of PD-1 blockade^[31^]. Safety data from advanced HCC trials further reinforce confidence in the regimen’s suitability for perioperative use, particularly given the need to maintain adequate postoperative liver function^[32,33^]. Collectively, these strengths establish CARES-009 as a well-designed, scientifically grounded trial capable of informing future clinical practice. Despite these strengths, several limitations must be acknowledged, particularly concerning data maturity, generalizability, and methodological variability.

Key limitations

One of the most critical limitations of CARES-009 is the lack of a complete peer-reviewed publication; currently available data are primarily derived from conference presentations, registries, and interim analyses. The absence of mature OS data and reliance on earlier endpoints – such as EFS and MPR – introduces a risk of overinterpretation^[19,26^]. Furthermore, if any single-arm components or historical controls were used in exploratory analyses, these may introduce selection or performance bias. Even in randomized settings, incomplete reporting of stratification factors – such as performance status or extent of underlying liver disease – may compromise interpretability.

Another key limitation concerns external validity. As with many HCC trials, CARES-009 predominantly enrolled patients from Asian centers where hepatitis B virus (HBV) infection is the primary etiology, and patients were younger, with better liver function and fewer comorbidities^[26,32,33^]. These factors limit the applicability of results to Western populations, where metabolic dysfunction-associated steatotic liver disease, hepatitis C, and older age predominate. Similar concerns were raised in CARES-310, which included a high proportion of HBV-positive patients from China^[26^]. Therefore, caution is required before generalizing the findings globally.

A further methodological concern relates to pathological response assessment. Definitions of MPR and pCR remain inconsistent across trials, and the absence of centralized pathology review can contribute to interobserver variability^[34^]. Additionally, the duration of follow-up in currently available reports may not adequately capture late recurrences or long-term liver-specific morbidity. Finally, without direct comparisons against other perioperative immunotherapy regimens – such as anti-PD-1 plus bevacizumab or pembrolizumab–lenvatinib combinations – comparative effectiveness remains uncertain^[32,33^]. These limitations highlight the importance of evaluating how well the CARES-009 population and trial conditions mirror real-world clinical practice, which is essential for determining its broader applicability.

External validity and clinical applicability

The external validity of CARES-009 depends on its relevance to routine clinical practice, where patients often present with more complex disease and comorbidity profiles than those included in clinical trials. Patients in CARES-009 generally had good performance status, preserved liver function, and clearly resectable disease – conditions that represent an idealized patient population rather than typical real-world cohorts^[32,33^]. In practice, many patients are older, have multifocal HCC, exhibit significant portal hypertension, or possess comorbid conditions that may limit tolerance to neoadjuvant therapy.

Successful implementation of neoadjuvant–adjuvant therapy also demands high-level multidisciplinary coordination involving surgeons, oncologists, hepatologists, and radiologists. Challenges include timing systemic treatment relative to surgery, monitoring response, and ensuring the liver remnant remains adequate for postoperative recovery. These logistical and infrastructure requirements may limit adoption in centers without established multidisciplinary tumor boards or experience with perioperative immunotherapy^[35^].

Cost, regulatory approval, and resource availability further influence applicability. Although camrelizumab and rivoceranib are available in China, global access remains uneven, and cost-effectiveness varies across healthcare systems. Moreover, the ongoing regulatory complexities affecting this drug combination in advanced disease – such as the FDA’s CRL – suggest that adoption in the perioperative setting may face similar delays^[36,37^]. Patient selection also requires refinement, as individuals at the highest risk of recurrence may stand to benefit the most, though validated risk-stratification tools remain limited. Beyond clinical and biological considerations, the regulatory landscape will also shape the integration of perioperative camrelizumab plus rivoceranib into standard care.

Regulatory and policy implications

Favorable perioperative outcomes have accelerated regulatory approvals for immunotherapies in other tumor types, such as lung and esophageal cancer, where pathological response serves as a surrogate endpoint. A similar pathway could theoretically apply to resectable HCC. However, because camrelizumab–rivoceranib is a dual-agent regimen administered in a surgically sensitive population, regulatory agencies may require more extensive OS data and long-term safety monitoring before approval^[32,35^].

The regimen has already undergone regulatory evaluation in unresectable HCC, but the FDA’s CRL highlighting manufacturing issues^[35,36^] illustrates that non-clinical factors may affect approval timelines. Health-technology assessment bodies and reimbursement committees will also require real-world cost-effectiveness analyses that model reductions in recurrence rates, surgical outcomes, and quality-adjusted life years (QALYs) gained^[37^]. Until these data mature, guideline committees such as EASL and AASLD are likely to recommend use primarily within clinical trials or structured registry settings. Having evaluated methodological strengths and limitations, the review now shifts toward biomarker and translational insights that may refine patient selection and therapeutic personalization.

Biomarker and translational perspectives

Predictive biomarkers of response

The success of perioperative immuno-angiogenic therapy in resectable HCC will depend heavily on biomarker-driven patient selection and response monitoring. Conventional biomarkers such as PD-L1 expression, tumor mutational burden, microsatellite instability, and checkpoint ligand expression have shown limited predictive utility in HCC, primarily due to inconsistent thresholds and biological heterogeneity^[32^]. Consequently, there is growing interest in developing integrated biomarkers that reflect the combined immune, vascular, and residual disease dynamics unique to HCC.

Given the mechanistic interplay between PD-1 blockade and VEGFR2 inhibition, several candidates warrant attention. These include baseline tumor immune infiltration profiles – such as densities of CD8⁺ T cells, dendritic cells, and regulatory T cells – as well as angiogenic markers like VEGF-A levels, VEGFR2 expression, microvascular density, and pericyte coverage^[31–33^]. Hypoxia-related markers, including HIF-1α and CA-IX, also hold promise given their relevance to vascular normalization. Additionally, composite immune-vascular gene signatures, such as those related to endothelial activation, antigen presentation, and myeloid suppression, may offer more nuanced predictive power.

Early perioperative studies using camrelizumab plus apatinib showed that higher baseline dendritic cell infiltration and specific immune gene signatures correlated with an MPR^[34^]. These findings highlight the potential to integrate biomarker-driven stratification into future therapeutic algorithms. While tumor-tissue biomarkers guide initial treatment planning, circulating biomarkers provide a dynamic window into treatment response and residual disease burden.

Circulating tumor DNA and minimal residual disease

Minimal residual disease (MRD) plays a pivotal role in early recurrence after HCC resection, with micrometastatic tumor foci driving relapse in more than 60% of cases within two years^[30,38^]. Circulating tumor DNA (ctDNA) has emerged as a powerful non-invasive tool for MRD detection, outperforming traditional biomarkers such as AFP in sensitivity and prognostic accuracy.

For example, Xu et al developed a 13-gene plasma ctDNA panel that accurately predicted early postoperative relapse and identified patients at high risk for recurrence^[30^]. Tumor-naïve multi-omics ctDNA assays have also shown strong prognostic performance in early-stage liver cancer^[39–41^]. Several comprehensive reviews now support ctDNA as a promising biomarker for MRD detection, treatment monitoring, and recurrence prediction in HCC^[38,42^].

In the perioperative setting, serial ctDNA sampling – before neoadjuvant therapy, immediately before resection, and early after surgery – may enable dynamic risk stratification. Persistent ctDNA before resection could suggest suboptimal neoadjuvant response and may prompt reassessment of surgical timing. Likewise, positive ctDNA after resection may identify patients who require intensified adjuvant therapy or extended immunotherapy duration^[30,38,42^]. Early studies in liver-resection cohorts have demonstrated the feasibility and predictive value of such longitudinal ctDNA profiling^[42^]. Beyond circulating biomarkers, resected tumor specimens offer a unique biological window into treatment response and resistance mechanisms.

Pathological response and immune profiling

Analysis of resected tumor tissue following neoadjuvant therapy provides critical insight into the biological effects of immuno-angiogenic treatment. Complete and MPRs have been linked with favorable outcomes in several malignancies and have increasingly gained relevance in HCC^[34,43^]. In trials evaluating perioperative camrelizumab combined with apatinib, patients achieving MPR exhibited higher baseline mutational loads, stronger immune activation signatures, and improved relapse-free survival^[34^].

Deep immunophenotyping of resected HCC tissue has revealed meaningful patterns associated with therapeutic response. These include increased infiltration of CD8⁺ T cells, presence of tertiary lymphoid structures, higher dendritic-cell activity, reduced regulatory T-cell density, and improved vascular normalization markers. Additionally, profiling of hypoxia-related and angiogenesis-related pathways offers valuable clues to resistance and may guide post-operative tailoring of adjuvant therapy^[41,43^]. Although individual biomarker categories provide important insights, integrating multimodal data can enable more precise and personalized perioperative management.

Integration of multi-omics approaches

To advance toward precision perioperative therapy in resectable HCC, multi-omics integration is essential. Systems-biology models combining genomic, transcriptomic, proteomic, metabolomic, imaging, and liquid-biopsy data allow comprehensive characterization of the tumor-immune-vascular ecosystem^[38–41^]. Such approaches can identify distinct biological phenotypes – for example, “immune-hot,” “immune-cold,” “angiogenic,” or “myeloid-suppressed” – that may differentially respond to immuno-angiogenic therapy.

For instance, angiogenic-immune gene signatures have shown utility in stratifying patients likely to respond to combination therapy versus those with inherent resistance, such as tumors with active Wnt/β-catenin signaling^[31^]. Future adaptive trial designs may incorporate biomarker-based treatment arms, where ctDNA-positive patients receive extended adjuvant therapy, immune-cold patients receive intensified combination regimens, and immune-hot responders undergo treatment de-escalation^[36–39^].

By integrating tumor biology, immune status, vascular characteristics, and MRD dynamics, multi-omics frameworks can guide personalized perioperative strategies. For example, patients with high angiogenic gene expression, low CD8⁺ T-cell infiltration, and persistent pre-resection ctDNA may benefit from intensified immunotherapeutic or anti-VEGF antibody therapy. Conversely, immune-hot tumors with negative ctDNA may be candidates for shorter treatment duration, minimizing toxicity without compromising efficacy^[38,39^]. These biomarker-driven insights set the stage for understanding how systemic therapy interacts with surgical decision-making and perioperative outcomes, which is addressed in the next section.

Surgical and perioperative considerations

Impact on resectability and timing

The CARES-009 trial demonstrated that perioperative therapy with camrelizumab and rivoceranib significantly improved EFS in patients with resectable HCC at intermediate or high risk of recurrence, with a median EFS of 42.1 months compared with 19.4 months in the surgery-alone cohort (hazard ratio 0.59, 95% CI 0.41–0.85; P = 0.004)^[12^]. These findings suggest that neoadjuvant immuno-angiogenic therapy can effectively target occult micrometastatic disease and optimize surgical outcomes by reducing early disease propagation.

Integrating two cycles of neoadjuvant camrelizumab plus rivoceranib necessitates precise coordination of surgical timing. In CARES-009, patients received camrelizumab biweekly and daily rivoceranib before surgery, followed by prolonged adjuvant therapy^[12^]. This approach requires surgeons to carefully navigate the balance between allowing sufficient time for treatment-induced tumor modulation and avoiding undue delay that might permit tumor progression, hepatic decompensation, or loss of resectability. As highlighted by Zhang et al, effective implementation depends on rigorous surveillance during the neoadjuvant period, including interval imaging, liver function monitoring, and AFP assessments to ensure timely operative intervention^[44^].

Management of immune-related and vascular adverse events

Perioperative use of camrelizumab and rivoceranib introduces specific safety considerations, particularly regarding hepatotoxicity, immune-mediated events, and VEGFR2 inhibitor-associated vascular toxicity. In CARES-009, grade ≥3 treatment-related adverse events occurred in 38% of patients, with hepatotoxicity, renal injury, and treatment-related deaths (two cases) reported during the preoperative phase^[12^]. These events necessitate vigilant preoperative evaluation of hepatic reserve, renal function, and cardiovascular status.

During neoadjuvant therapy, routine laboratory assessments – including liver function tests, serum creatinine, complete blood counts, thyroid function, and blood pressure measurements – are essential. Hypertension, a known consequence of VEGFR2 inhibition, may require antihypertensive therapy or dose modification of rivoceranib. Immune-related hepatotoxicity is managed according to established algorithms, typically involving prompt interruption of therapy and initiation of corticosteroids in collaboration with hepatology and oncology teams.

Given the perioperative risks associated with immune activation, the timing of surgery relative to the resolution of irAEs requires careful consideration. Severe toxicity may necessitate delaying surgery until adequate hepatic recovery and steroid tapering have been achieved to ensure operative safety.

Multidisciplinary coordination and workflow optimization

Translation of the CARES-009 regimen into clinical practice requires a structured, multidisciplinary workflow. Effective perioperative management of resectable HCC hinges on coordination among hepatobiliary surgeons, medical oncologists, hepatologists, radiologists, anesthesiologists, and clinical nursing teams. Multidisciplinary tumor boards play a central role in assessing candidacy for neoadjuvant therapy, determining the optimal sequencing of interventions, and coordinating preoperative imaging and postoperative care.

Evidence indicates that multidisciplinary tumor boards (MDT)-based evaluation improves decision-making, enables standardized surveillance milestones, and optimizes patient selection for perioperative therapy^[45^]. Innovations such as deep-learning–enhanced intraoperative ultrasound offer potential advantages by improving visualization of vascular anatomy during resection after systemic therapy^[46^].

Overall, successful integration of perioperative camrelizumab plus rivoceranib requires a harmonized care model that supports treatment planning, toxicity management, surgical timing, and long-term surveillance.

Global and economic perspectives

Cost-effectiveness and resource allocation

While the CARES-009 trial focuses primarily on clinical efficacy, broader implementation of perioperative camrelizumab plus rivoceranib requires careful economic evaluation. Cost-effectiveness analyses conducted in the context of unresectable HCC – particularly those informed by CARES-310 data – have demonstrated substantial regional variation. In China, ICERs of approximately US$30 410 per QALY fall within commonly accepted willingness-to-pay thresholds^[47^]. Additional analyses in medium- and high-income provinces in China show even more favorable ICERs, around US$9150 per QALY^[37^].

Conversely, cost-utility modeling in the United States has yielded ICER estimates near US$272 853 per QALY, far exceeding standard cost-effectiveness thresholds unless major reductions in drug pricing are achieved^[24^]. These findings underscore that resource allocation decisions are highly context-dependent and will be influenced by national drug pricing policies, reimbursement frameworks, and health-system capacity to support costly perioperative immunotherapy regimens.

Thus, widespread adoption of this strategy will require not only clinical validation but also robust economic assessments tailored to local healthcare financing structures.

Drug accessibility and infrastructure challenges

Access to camrelizumab and rivoceranib remains highly uneven worldwide. Although both agents are approved and widely used in China, regulatory clearance in most countries is pending, creating significant disparities in availability^[48^]. Even in settings where regulatory approval is granted, infrastructural constraints – such as limited infusion capacity, inadequate laboratory monitoring systems, and shortages of trained oncology personnel – pose barriers to safe and effective use, particularly in low- and middle-income countries (LMICs).

Financial toxicity is also a significant concern. A recent meta-analysis indicates that over half of cancer patients in LMICs face substantial economic hardship attributable to treatment costs^[49^]. In the context of perioperative HCC management, these challenges are further amplified by the high costs of surgery, prolonged monitoring, and management of immune-related or vascular toxicities. Limited health insurance coverage, out-of-pocket payments, and inadequate social protection frameworks exacerbate disparities in access^[50^].

Regional disparities in implementation

Significant regional and socioeconomic differences will shape the uptake of perioperative camrelizumab plus rivoceranib. While Chinese cost-effectiveness analyses appear favorable – even in lower-income regions^[37^] – most countries lack context-specific pharmacoeconomic evaluations. Variability in healthcare infrastructure, availability of multidisciplinary teams, surgical expertise, and postoperative monitoring capabilities can lead to inequities in outcomes and eligibility for treatment.

Generalizability is further limited by the demographic profile of the CARES-009 cohort, which was composed almost entirely of Han Chinese patients (~99%)^[12^]. This restricts certainty regarding applicability to populations with different ethnicities, comorbidity patterns, or etiologic distributions (e.g., HCV-associated HCC or metabolic-dysfunction–associated steatotic liver disease prevalent in Western regions).

These disparities highlight the need for additional clinical and real-world data across diverse populations, as well as region-specific policy development. Moreover, economic analyses from China and the United States indicate that drug pricing remains a dominant driver of cost-effectiveness^[24^], suggesting that globally equitable implementation will require coordinated efforts among manufacturers, national regulators, and healthcare payers to ensure affordability and adequate system capacity.

Future research directions

Biomarker-driven adaptive perioperative trial models

The encouraging findings from CARES-009 underscore the importance of refining patient selection and individualizing therapy in resectable HCC. Future clinical research should prioritize the development of biomarker-driven adaptive trial designs that enable dynamic stratification based on predictive indicators of response. While PD-L1 expression has demonstrated some predictive utility in advanced HCC^[51^], its role in the perioperative setting remains inconsistent. Additional biomarkers – including circulating free DNA, ctDNA, cytokine signatures, and dendritic-cell infiltration – have shown potential relevance, particularly in studies examining camrelizumab plus apatinib^[52^].

To operationalize biomarker-driven care, future trials should incorporate systematic biospecimen collection at predefined perioperative time points and use adaptive statistical frameworks – such as Bayesian adaptive randomization – to allocate patients based on the likelihood of benefit. This approach may enhance therapeutic precision, minimize exposure to ineffective therapy, and optimize outcomes in resectable HCC.

ctDNA-guided therapy adaptation strategies

ctDNA represents a powerful, minimally invasive tool for monitoring therapeutic response and detecting MRD. ctDNA kinetics – particularly early quantitative declines – have been associated with favorable responses to immune checkpoint inhibitors, whereas rising ctDNA levels may indicate resistance or early relapse^[53^]. Studies in non-small cell lung cancer have shown high concordance between ctDNA responses and pathological outcomes following neoadjuvant immunotherapy, suggesting similar applicability in HCC^[54^].

Evidence from randomized trials in other solid tumors indicates that ctDNA-guided adjuvant therapy can safely reduce overtreatment without compromising survival^[55^]. Applying such strategies to the perioperative immuno-angiogenic setting could allow real-time adjustment of therapy intensity, escalation for patients with persistent MRD, or de-escalation for those with rapid ctDNA clearance. Integration of longitudinal ctDNA modeling with clinical endpoints may further enhance decision-making and trial efficiency.

Optimization of treatment duration and sequencing

Optimizing the duration and sequencing of perioperative camrelizumab plus rivoceranib is an essential next step. Evidence suggests that the timing of neoadjuvant therapy influences the magnitude of antitumor immunity, with shorter intervals potentially maximizing immune priming while minimizing toxicity^[56^]. Comparative analyses indicate that perioperative immunotherapy may offer superior OS compared with purely neoadjuvant or adjuvant approaches due to the continuous immune modulation across surgical phases^[57^].

Sequencing of VEGF pathway inhibition relative to immunotherapy is particularly important. Retrospective data in NSCLC demonstrate that administering anti-VEGF therapy before ICIs may shorten response duration, whereas anti-VEGF therapy administered after ICIs may enhance outcomes^[58,59^]. Although CARES-009 employed neoadjuvant combination therapy followed by prolonged adjuvant treatment, the optimal duration, spacing, and sequence of immuno-angiogenic therapy in resectable HCC remain undefined. Future randomized or adaptive trials are needed to clarify these parameters.

Real-world and long-term outcome studies

Real-world data are essential for understanding the long-term efficacy, safety, and feasibility of perioperative immunotherapeutic agents outside controlled trial settings. Observational studies of adjuvant PD-1 inhibitors following HCC resection suggest time-dependent benefits, with modulation of recurrence risk varying across patient subgroups^[60^]. Similarly, real-world evidence from combination strategies such as TACE plus camrelizumab and apatinib has demonstrated improvements in OS, progression-free survival, and objective response rates compared with TACE alone, particularly in advanced disease settings^[61^].

Although interim results from CARES-009 highlight superior EFS, OS data remain immature. To support broad implementation, long-term outcomes must be evaluated alongside cost-effectiveness in real-world populations, ensuring that clinical benefit justifies resource utilization – especially in regions with constrained healthcare budgets.

Clinical integration

Evidence-based patient selection

Effective integration of perioperative camrelizumab plus rivoceranib into clinical practice requires clear patient selection criteria grounded in tumor biology, hepatic reserve, and performance status. Data from CARES-009 indicate that patients with early- to intermediate-stage, resectable HCC, preserved liver function (Child–Pugh A), and good performance status (ECOG 0–1) derive the most significant benefit from this combination therapy^[12^]. Patients with substantial tumor burden may also benefit through downstaging, reduced micrometastatic dissemination, and improved recurrence-free outcomes^[62^].

Biological factors further refine selection. Tumors exhibiting PD-L1 expression, aggressive radiologic features, or immunologically active phenotypes may demonstrate enhanced responsiveness to immuno-angiogenic therapy^[63^]. Conversely, patients with autoimmune disorders, uncontrolled hypertension, significant cardiovascular disease, or a history of severe irAEs represent poor candidates and warrant individualized risk–benefit assessment^[64^].

Assessment of hepatic functional reserve and portal hypertension is critical, as patients with clinically significant portal hypertension or impaired synthetic function face heightened perioperative risks^[65^]. Overall, perioperative camrelizumab plus rivoceranib is most appropriate for biologically aggressive yet surgically resectable HCC in patients who are medically fit for immunotherapy and targeted therapy.

Monitoring and follow-up protocols

Structured monitoring is essential throughout the neoadjuvant and adjuvant phases to ensure therapeutic efficacy and prevent serious complications. During neoadjuvant therapy, patients should undergo clinical and laboratory evaluations every 2–3 weeks, including liver function tests, renal function tests, complete blood counts, thyroid function tests, and blood pressure monitoring^[66^]. Radiologic reassessment with contrast-enhanced CT or MRI after 4–6 weeks allows evaluation of treatment response and verification of continued resectability^[67^].

IrAEs – such as hepatitis, colitis, or pneumonitis – require early identification and management in accordance with established immunotoxicity guidelines^[68^]. Rivoceranib-associated hypertension and proteinuria necessitate routine blood pressure checks and urinalysis, with timely dose adjustments to maintain safety^[69^].

During the adjuvant phase, surveillance imaging is recommended every 3 months in the first year and every 6 months thereafter^[63^]. Given that immuno-angiogenic therapy may modulate long-term immune and angiogenic pathways, patients require prolonged monitoring for delayed immune-related events, cardiovascular complications, or disease recurrence^[64^].

Incorporation into multidisciplinary management pathways

Successful implementation of perioperative camrelizumab plus rivoceranib depends on robust multidisciplinary coordination. MDTs are central to evaluating eligibility, balancing risks, and determining therapy sequences relative to surgical planning^[12^]. Collaboration among hepatobiliary surgeons, medical oncologists, hepatologists, radiologists, and anesthesiologists ensures consistency in decision-making and optimizes patient outcomes.

In the neoadjuvant setting, oncologists and surgeons must coordinate closely to time resection appropriately and avoid delays stemming from toxicity or underrecognized progression. Radiologists play a critical role in providing standardized imaging assessments, while pathologists contribute insights into immune infiltration, microvascular invasion, and pathological response, which can inform postoperative planning^[67^].

Following surgery, integration continues through structured adjuvant therapy administration, toxicity surveillance, and long-term follow-up led by oncology teams with hepatology input^[64^]. Clinical pharmacists and specialized nursing teams further enhance safety by optimizing drug management, monitoring adverse effects, and providing patient education^[69^].

Conclusion

Significant improvements in EFS and pathological response in CARES-009 demonstrate that perioperative camrelizumab + rivoceranib offers a clinically attractive, scientifically supported approach to reduce recurrence in resectable HCC. Evidence from advanced-disease trials and mechanistic synergy suggests its efficacy. However, low generalizability beyond predominantly HBV-positive Asian cohorts, significant regional economic disparities, and immature OS statistics prevent further adoption. The regimen is best used in clinical trials until these data are obtained. Future integration will depend on mature outcomes, biomarker-driven patient selection, and real-world validation.

TITAN Guidelines: This manuscript is in compliant to TITAN Guidelines, 2025, declaring no use of AI^[70^].

Ethical approval

Not applicable. This study is a narrative review based solely on previously published literature.

Consent

Not applicable. This study is a narrative review based solely on previously published literature. This study does not contain any data from individual persons.

Sources of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

A.A. and U.A. conceived the idea, led the literature review, and drafted the initial manuscript. M.J., M.J., Z.M., and F.N.H. assisted in manuscript writing and critical revision. M.J. designed the figures, and S.S. contributed to compiling the entire study and revision. M.K.: Supervision, project administration, writing – review and editing, and final revision. All authors read and approved the final manuscript.

Conflicts of interest disclosure

The authors declare that they have no competing interests.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Muddassir Khalid.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

This narrative review is based on previously published literature. No new data were generated or analyzed in this study. Therefore, data sharing does not apply to this article.

Clinical trial number/code availability

Not applicable.