Evaluating patient-reported outcomes in randomized controlled trials of targeted therapy and/or immunotherapy for liver cancer: a scoping review.

Introduction

Liver cancer is a serious public health issue worldwide, with extremely high incidence and mortality rates. It is the sixth most frequently diagnosed cancer and the third leading cause of cancer death ( 1 ). The early symptoms of liver cancer are often insidious, but the disease progress is rapid. Consequently, the majority of patients are diagnosed at the intermediate or advanced stage, and have already lost the opportunity for surgical resection ( 2 ). For these patients, systemic therapy plays an important role in prolonging survival and improving quality of life (QoL) ( 3 ). In systemic therapy, molecular targeted therapy has become a key treatment for liver cancer since 2007 ( 4 – 7 ). Moreover, the programs based on immunotherapy have been acknowledged as the first-line treatment for patients with advanced-stage liver cancer ( 8 ). Notably, the first successful research (IMbrave150) in 2020, which combined immunotherapy with targeted therapy, marked the beginning of a new era of combination treatment in liver cancer ( 7 ).

In the past, the evaluation of therapeutic efficacy in tumors mainly focused on the objective indicators, such as mortality and the incidence of complications ( 9 ). With the application of patient-reported outcomes (PROs), the focus of clinical research has shifted from prolonging patient survival to improving patients’ multidimensional health status ( 10 ). PROs are defined as any report on the patient’s health status that come directly from the patient, without interpretation by clinicians or other healthcare providers ( 11 ). It complemented the disease-centered outcomes. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the U.S. Food and Drug Administration (FDA) have emphasized that PRO should be an essential metric in evaluating clinical efficacy and reporting clinical trials ( 12 ). The assessment of PRO should be integrated into routine clinical assessment ( 13 ). Patient-reported outcome measures (PROMs) are standardized instruments used to assess PRO. In clinical practice, PROMs can enable dynamic monitoring of treatment responses and facilitate communication between clinicians and patients ( 14 , 15 ). Integrating PROMs into routine care is crucial for accurately capturing the disease burden and refining management strategies ( 16 ).

However, current evidence indicated that the reporting quality of PRO in randomized controlled trials (RCTs) was suboptimal ( 17 ). PRO reports often exhibited differing levels of bias risk ( 18 ). To improve the reporting quality of PRO, the International Society for Quality of Life Research (ISOQOL) published the Consolidated Standards of Reporting Trials Extension for Patient-Reported Outcomes (CONSORT-PRO) in 2013 ( 19 ). Some researchers have employed this reporting standard to evaluate the reporting quality of PRO in RCTs related to advanced soft tissue sarcoma ( 20 ), metastatic colorectal cancer ( 21 ), and hematologic malignancies ( 22 ). However, these results showed that the reporting quality of PRO items was poor. High-quality PRO reporting is crucial for improving the overall quality of healthcare, which enables clinicians and patients to make wise treatment decisions based on the results of PRO. Moreover, no study has systematically evaluated the reporting quality of PRO in the RCTs of targeted therapy and/or immunotherapy for liver cancer. Therefore, our study aimed to evaluate the reporting quality and application of PRO in RCTs of targeted and/or immunotherapy for liver cancer to provide evidence for the deep implementation of PROs in future research and clinical practice.

Methods

This review was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines ( 23 ).

Inclusion criteria and exclusion criteria

The inclusion criteria were as follows: (a) Adult patients diagnosed with liver cancer; (b) Patients treated with targeted therapy and/or immunotherapy; (c) RCTs reporting the results of PROs; (d) Studies published in English or Chinese.

The following studies were excluded: (a) The PROMs were not specified. (b) The full text was unavailable.

Search strategy

A systematic literature search was performed independently by two researchers (R.L. and W.J.Y.) in six electronic databases (PubMed, Embase, Web of Science, CNKI, Wangfang and VIP) from their inception to April 17, 2025. We employed a search strategy that combined Medical Subject Headings (MeSH) and free-text terms to retrieve literature. The complete search strategies for all databases are provided in Supplementary Appendix 1 .

Data selection

All retrieved studies were imported into EndNote (Version 20.0) for duplicate removal. Two researchers (R.L. and Z.Y.Y.) independently screened studies by reading the title and abstract. For potentially relevant articles, the two reviewers evaluated the full text independently. Any disagreement during the screening process was resolved through discussion or consultation with a third researcher (S.C.X.).

Data extraction

Two reviewers (R.L. and L.S.J.) independently extracted the data by the standardized data extraction form. The extracted data included article title, publication year, study location, treatment regimen, adverse events, PRO, PROMs and so on. Any disagreement was resolved by discussion between the two individuals or consultation with a third researcher (S.C.X.).

The assessment of the reporting quality of PRO

We (R.L. and L.Y.T) used the CONSORT 2010 and CONSORT-PRO checklists to assess the reporting quality of the included trials. CONSORT 2010 has 25 core items, while CONSORT-PRO incorporates 5 supplementary items. CONSORT-PRO is a supplement to the CONSORT 2010, intending to improve the transparency and completeness of PRO reported in RCTs. We independently scored the items of the CONSORT-PRO according to the existing scoring criteria ( 24 , 25 ). The maximum raw total score of CONSORT-PRO adherence was 15 for trials with a PRO as the primary outcome and 14 for trials with a PRO as the secondary outcome. Finally, we converted raw item adherence scores of the CONSORT-PRO to percentages for further analysis. Adherence was classified as good when the study’s adherence score reached or exceeded 80% of the total score, as moderate when the score ranged from 50% to 79% of the total score, and as poor when the score fell below 50% of the total score ( 25 ).

Ethics

Ethical approval was not required for this study as it utilized only publicly available data.

Results

Study selection

A total of 1,908 papers were identified from the initial search. After removing duplicates and articles that did not meet the pre-defined inclusion criteria, 64 studies that reported PROs were included in this review. The selection process of studies was presented in Figure 1 .

Study characteristics

Sixty-four included trials were published between 2009 and 2025. Fifty studies were conducted in China, while the remaining studies originated from France (n = 4), Spain (n = 2), Germany (n = 2), the United States (n = 2), the United Kingdom (n = 1), Singapore (n = 1), Switzerland (n = 1), and Italy (n = 1). The majority of studies (n = 48) were published in China, the others were published in English. According to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonized guideline E8 (R1) (ICH E8(R1)) framework ( 26 ), 14 studies were confirmatory studies (Type C, 21.9%), which were phase III trials or large-scale registration trials intended to support drug licensing or establish definitive efficacy. Thirty-one studies were exploratory studies (Type E, 48.4%), defined as phase I/II trials or small-scale efficacy studies aiming at exploring preliminary efficacy or estimating doses. The remaining 19 studies (29.7%) were categorized as “Other” (Type O), including nursing interventions studies, traditional Chinese medicine studies and supportive care assessment studies that did not meet the conventional staging criteria for clinical trial phases (see Table 1 ).

Sixty-four trials involved 8,494 participants, ranging from 40 to 1171 with an average of 133 per trial. 74.58% participants were male. Of the included trials, 62 were double-arm trials and 2 were triple-arm trials. In the observation group of the double-arm trials, 7 studies applied single therapy and 55 studies applied combination therapy. In the control arm, 40 studies adopted single therapy and 22 employed combination therapy. The combination regimens included the combinations of different drugs within the same treatment modality. It also involved combinations across different treatment modalities, and the integration of the aforementioned combination regimens with supportive care. Among 50 trials focusing on targeted therapy, sorafenib was used the most frequently, followed by lenvatinib and bevacizumab. Immunotherapy was employed in 32 trials, with Cytokine-Induced Killer (CIK) cell therapy being the most frequently used, followed by sintilimab and atezolizumab. Only 15 studies (15/64) designated PROs as the primary outcome, while the majority (49/64) utilized PROs as the secondary outcome (see Table 1 ).

The application of PROs and PROMs

Of the included studies, 27 PROMs referring to 17 relevant domains of PRO were observed. Eight symptomatic adverse events (sleep quality, pain, anxiety, depression, dermatology, hand-foot skin reaction, negative emotions and cognitive function) were reported. Ten PRO reports in the nursing field documented 16 PROMs covering 12 domains and 54 reports in the medical field employed 17 PROMs addressing 10 domains. The core domain of PRO primarily included the broad QoL (54/64), as well as single-domain symptoms or specific functioning (19/64). The broad PROMs for QoL are categorized into generic and specific measures. The frequently used generic assessment instruments for QoL were the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (25/64) and the Short Form-36 Health Survey (SF-36) (12/64). The EORTC QLQ-C30 is a cancer-specific measure covering the domains of functional, symptom burden, and global health ( 27 ). The SF-36 is a generic measure with eight health dimensions, including physical functioning and social role functioning ( 28 ) (see Tables 1 , 2 ).

The frequently employed disease-specific instruments for QoL were the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Hepatocellular Carcinoma 18 (EORTC QLQ-HCC18) (8/64) and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) (7/64). The EORTC QLQ-HCC18 is a supplementary module to the EORTC QLQ-C30, specifically designed for assessing QoL in liver cancer patients. The FACT-Hep is a disease-specific module of the Functional Assessment of Cancer Therapy-General (FACT-G) scale designed to assess the specific QoL in liver cancer patients. They are frequently used with generic measures like the QLQ-C30 or EuroQol Five Dimensions Questionnaire (EQ-5D) ( 29 ). Besides, the Quality-of-Life Questionnaire for Liver Cancer (QOL-LC) ( 30 ) has been primarily used in studies conducted in Asia. In particular, the Dermatology Life Quality Index (DLQI) ( 31 ) was applied to assess skin reaction-related QoL in liver cancer patients, while the Hand-Foot Quality of Life questionnaire (HF-QoL) ( 32 ) was used to evaluate the impact of drug-induced hand-foot skin reactions on QoL.

The frequently utilized instruments for assessing single-domain symptoms or specific functioning were the Pittsburgh Sleep Quality Index (PSQI) ( 34 ) (6/64), the Visual Analogue Scale (VAS) ( 35 ) (5/64), the Self-Rating Anxiety Scale (SAS) ( 36 ) (4/64), and the Self-Rating Depression Scale (SDS) ( 37 ) (4/64). The PSQI was used to assess sleep quality, the VAS for pain, the SAS for anxiety, and the SDS for depression. In nursing research, the Self-Care Ability Evaluation Scale (ESCA) ( 33 ) was frequently used to assess patients’ self-care ability (2/64).

Among the 64 included studies, the most frequently used PROM was the EORTC QLQ-C30 which was employed in 25 studies (39.1%), followed by the SF-36 which was used in 12 studies (18.8%). The disease-specific instruments of the EORTC QLQ-HCC18 was applied in 8 studies (12.5%), and the FACT-Hep was utilized in 7 studies (10.9%) (see Table 2 , Figure 2 ). The most frequently used PROM was the EORTC QLQ-C30 (15/50) in Chinese studies, followed by the SF-36 (12/50). The most commonly used PROMs instrument was also the EORTC QLQ-C30 (10/14), followed by the EORTC HCC-18 (7/14) in non-Chinese studies (see Table 1 ). Last but not least, 40 studies employed a single PROM, while 24 studies utilized multiple PROMs. Among studies using multiple PROMs, the predominant combination patterns were the use of a generic QoL instrument alongside a single-domain PROM (9/24) and the combination of a generic with a disease-specific QoL instrument (10/24) (see Table 1 ).

The reporting quality of PRO

The reporting quality of PROs in the included studies was assessed based on the CONSORT 2010 and the CONSORT-PRO (see Table 3 ). The results showed that only 7.8% of studies clearly defined PROs as primary or secondary outcomes in their abstracts, 92.2% did not describe the methods for handling missing PRO data and 90.6% did not report PRO at the domain level. Within the CONSORT-PRO items, reporting adherence was good in 4 items (Item 13ai, Item 13aii, Item 16, Item 22), moderate in 4 (Item P1b partially addressed, Item P6ai, Item 15, Item 17ai), and poor in another 12 items. In contrast, items P7a (how sample size was determined) and P12a (statistical approach for dealing with missing data) were the most often neglected items in the reports.

The mean score of the CONSORT-PRO adherence was 6.2 (ranging from 3 to 14) in all included studies. Most studies did not report or incompletely reported the items (see Table 4 ). Besides, the mean score of the CONSORT-PRO adherence was 7.5 (ranging from 3 to 14) for confirmatory studies, 5.8 (ranging from 4 to 9) for exploratory studies, and 6.0 (ranging from 3 to 9) for other studies. Confirmatory studies demonstrated higher CONSORT-PRO adherence scores than both exploratory and other studies. Notable variability in the quality of PRO reporting was observed among confirmatory studies (scores ranging from 3 to 14), of which 28.6% had scores of ≥10 and 42.9% had scores of ≤5. The mean score of the CONSORT-PRO adherence was 5.9 (ranging from 4 to 9) for studies conducted in China and 7.4 (ranging from 3 to 14) for non-Chinese studies (see Table 3 ). The Chinese studies showed lower CONSORT-PRO adherence scores than other non-Chinese studies. Of the 64 included studies, only 3 studies demonstrated a good level of CONSORT-PRO adherence, 9 exhibited a moderate level of compliance, and the remaining 52 showed a poor level of CONSORT-PRO adherence (see Figure 3 ).

Discussion

This scoping review included 64 RCTs focusing on targeted therapy and/or immunotherapy for liver cancer. The publication time of the included literature demonstrated a phased increase. Except for one study published in 2009, 18 studies (28.1%) were published between 2014 and 2020, and 45 studies (70.3%) were published from 2021 to 2025. Over the last five years, the use of PROs in RCTs of targeted therapy and/or immunotherapy for liver cancer has markedly risen. This trend may be related to the key technological breakthroughs and changes in systemic treatment for liver cancer ( 4 , 7 , 34 ). In addition, the publication of the 2013 CONSORT-PRO guideline provided a framework for standardizing the use of PROs in research ( 19 , 35 ), which has heightened researchers’ attention to PROs. Notably, the majority of studies (78.1%) were conducted in China, which might be associated with the substantial population of liver cancer patients in China and prevailing policy preferences ( 36 , 37 ). Besides, this geographical distribution may also be related to our search strategy, which covered both international and Chinese databases and was restricted to English and Chinese publications.

Among the 64 studies, only 15 (23.4%) defined PROs as the primary outcome, while 49 (76.6%) classified PROs as a secondary outcome. This result indicated that PROs were often utilized as supplementary outcomes in current RCTs of targeted therapy and/or immunotherapy. This research design may underestimate the value of PROs in assessing treatment tolerability and patient experience ( 38 ). Previous research has shown that while combining targeted therapy and immunotherapy can prolong survival, it may also intensify symptom burden ( 14 ). PRO data are essential for balancing treatment efficacy against toxicity and optimizing therapeutic outcomes. Furthermore, the PRO data also has its own independent prognostic value ( 39 ). Some researchers argued that the PROs at baseline or during the early stage of treatment were significantly associated with patients’ survival period ( 40 , 41 ). Therefore, it is crucial to attach the value of PROs in research within the patient-centered care environment.

The included studies covered 27 PROMs about 17 relevant domains. QoL was the most frequently evaluated domain. The EORTC QLQ-C30, a generic tool designed for a broad cancer population, was the most often used PROM for assessing QoL in liver cancer patients. However, this tool fails to comprehensively capture liver cancer-specific symptoms, such as ascites, hepatic pain, jaundice, abdominal distension, etc. The identification of liver cancer-specific symptoms is primarily dependent on the QLQ-HCC18, the FACT-Hep, or other single-domain tools ( 42 ). However, only 8 studies concurrently employed both the EORTC QLQ-C30 and the QLQ-HCC18 or the FACT-G and the FACT-Hep. The use of single-domain tools was also limited. Furthermore, previous studies have reported that liver cancer patients receiving targeted therapy and/or immunotherapy often experienced multiple adverse symptoms ( 43 , 44 ). So, we considered that the assessment of PROs in the included studies might be insufficient to fully capture the symptom burden in this patient population. While using multiple PROMs often increases the reported burden of patients ( 45 ). Recent research has shown that computerized adaptive testing (CAT) can alleviate the response burden of patients and improve the quality of PRO data ( 46 ). So, the application of CAT for the electronic and personalized management of PRO data is crucial in future research directions. In particular, the exclusive use of generic instruments in confirmatory studies is prone to missing disease-specific symptom information. Therefore, we do not recommend using generic tools as the primary measurement tools for collecting PRO data. An ideal PROM should simultaneously assess both disease-specific symptoms and overall health-related quality of life, while also possessing sound psychometric properties. Thus, we suggest prioritizing the use of disease-specific assessment tools; specifically, the EORTC QLQ-C30 should be used in conjunction with the QLQ-HCC18 module to address the limitations of generic tools in specific disease assessment.

Prior studies have shown that adverse events significantly influence patients’ QoL ( 47 , 48 ). Basch et al. further emphasized the importance of QoL and proposed that more attention should be paid to dynamically tracking the symptomatic outcomes ( 49 ). However, there were relatively few evaluations of symptoms, such as sleep, pain, and hand-foot skin reactions, in the included studies. The scarcity in symptomatic outcomes assessment can be partly attributed to the existing healthcare model. In clinical practice, the reporting of these symptomatic adverse events primarily relies on physicians according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. However, the accurate capture of common symptomatic adverse events depends on the direct reporting of patients. Yip’s research ( 50 ) has also shown that there are significant differences between the symptoms reported by patients and those recorded by medical staff. Physician-driven reporting of symptomatic adverse events often underestimates the incidence and severity of such events ( 51 ). The symptoms self-reported by patients are usually earlier, more frequent and more severe. Moreover, existing studies have found that liver cancer patients receiving targeted therapy and/or immunotherapy often experienced multiple adverse symptoms ( 43 , 44 ). However, most researchers have only employed general tools to assess the overall QoL, which may overlook the disease-specific symptoms and treatment-specific symptoms in those receiving targeted therapy and/or immunotherapy. Al-Naesan ( 52 ) noted that generic instruments of QoL often lacked sufficient sensitivity to capture such specific symptoms. The lack of standardized and validated tools for different treatment modalities or diseases, or the inadequate use of such tools, may limit the overall quality of assessment. Therefore, future research should prioritize the development and validation of PRO tools for liver cancer patients who received targeted therapy and/or immunotherapy. These tools are critical to sensitively detect treatment-related adverse events and provide a reliable evidence base for clinical management.

Notably, the studies focusing on nursing intervention assessed a wider range of PROs, including anxiety, depression, and sleep quality and QoL, self-care ability, medication adherence, and overall well-being. In these studies, the purpose of assessing PROs was to evaluate the efficiency of non-pharmacological interventions, and then to improve patients’ experience and daily functioning. However, PROs in nursing research often failed to establish robust associations with clinical endpoints such as overall survival or tumor response rate. Furthermore, the integration of PROs with objective clinical data, including laboratory parameters and imaging findings, remained insufficient. Consequently, the value of nursing interventions may be difficult to quantify and fully acknowledged by clinicians and policymakers, and the translation of PRO findings into specific clinical nursing guidelines becomes complex. In medical research, PROs were primarily used to assess treatment efficacy and safety or to facilitate new drug registration. Whereas the potential of these PRO results to guide the development of personalized clinical care management strategies has not been fully exploited. Therefore, we advocate for the integration of PRO assessments led by nursing experts into large-scale medical RCTs, and to develop a collaborative framework that encompasses medical treatment evaluation, nursing symptom management, and patient experience ( 53 ). Future PRO research should adopt a multidisciplinary collaborative approach from the design stage, thereby strengthening the application of PRO evidence in clinical practice for patients with liver cancer.

PROs are essential for obtaining patients’ information that clinicians may not consistently monitor. However, our study revealed that the mean CONSORT-PRO adherence score of the included studies was only 6.2 (3–14). The overall adherence to the CONSORT-PRO checklist was poor in included RCTs on targeted therapy and/or immunotherapy for liver cancer. Similar findings were observed in RCTs for systemic treatment of late-stage soft tissue sarcomas in adults ( 20 ), locally recurrent rectal cancer ( 54 ), and multiple myeloma ( 55 ). What’s more, Kyte’s study indicated that 38% to 80% of trial protocols inadequately addressed or did not report PRO according to the CONSORT-PRO extension ( 56 ). This means that among the studies that reported PROs, low-quality PRO reporting may underestimate the value of PROs. Incomplete reporting may mask a potential risk of treatment, compromising the potential benefits for patients, clinicians, and healthcare institutions. Therefore, we recommend that future studies strictly adhere to the CONSORT-PRO guidelines for reporting PROs and cite it in their papers ( 57 ).

In addition, our study found that the mean CONSORT-PRO adherence score was higher for confirmatory studies (7.5) than for exploratory studies (5.8) and other studies (6.1). Confirmatory studies are typically intended to support drug marketing authorization and thus need to provide adequate benefit-risk evaluation evidence for regulatory agencies. Moreover, in recent years, regulatory institutes such as the FDA have explicitly required sponsors to include PRO data in drug approvals ( 58 ). Such regulatory pressure has prompted trial investigators to collect, analyze, and report PRO data more rigorously, thereby improving the CONSORT-PRO adherence of confirmatory studies. From a trial design perspective, confirmatory studies usually have larger sample sizes, longer follow-up periods, and more robust designs, with greater resources to implement PRO assessments. Finally, according to the ICH E8(R1) guideline, confirmatory studies need to prospectively focus on quality across all research aspects from the protocol design stage, including PRO-related hypotheses, instrument selection, data collection, and handling of missing data. This prospective design planning gives confirmatory trials an advantage in the completeness of PRO reporting. However, we observed significant variability in the quality of PRO reporting among confirmatory studies. The mean score of CONSORT-PRO adherence was ≥10 in 28.6% of confirmatory trials and ≤5 in 42.9% of confirmatory trials. The primary issues contributing to low-quality PRO reporting included failure to report methods for handling missing data, lack of pre-specified PRO hypotheses, and failure to present domain-level results in PRO data. Therefore, there remains a need to continue promoting the CONSORT-PRO guidelines and enforcing the regulatory in confirmatory studies.

In contrast, exploratory studies (such as phase I/II or small-sample efficacy studies) primarily aim to assess the preliminary efficacy of targeted therapy and/or immunotherapy, determine drug dosages, and evaluate safety. In these studies, PROs are often predefined as secondary or exploratory endpoints rather than core primary outcomes. Consequently, researchers invest relatively limited attention and resources in PRO collection and reporting. This research objectives directly lower the quality of PRO reporting.

Studies classified as “Other” (nursing intervention studies, traditional Chinese medicine studies, and supportive care studies, et al.) often fall outside the regulatory framework for drug approval. Researchers in these fields have limited awareness and application of PRO reporting guidelines, which results in poor reporting quality. Notably, in nursing intervention studies and supportive care studies, PROs are frequently used as primary outcome measures. Therefore, improving the quality of PRO reporting in these studies is critically important. Only high-quality PRO reports can enhance the credibility of evidence on nursing intervention and effectively guide clinical practice.

In the reporting of PROs among the included studies, we have observed that 92.2% of the studies did not clearly specify whether PROs were a primary or secondary outcome in their abstracts (item P1b). This omission reduced the retrieval efficiency for readers and hindered further data analysis ( 59 ). 90.6% of the studies failed to fully state the hypothesis and domains related to PRO in the background (item P2b), which perhaps increase the risk of selective reporting in their reports. Khan et al. have observed the same findings ( 60 ).

Besides, we also found that the transparency of the PRO reports in the methodological part of the included trials was poor. Maring et al. even disclosed that many RCTs registered on clinicaltrials.gov regarding targeted therapy and/or immunotherapy for liver cancer patients reported PROs in their research protocols, but failed to report PROs in subsequent papers ( 21 ). According to the CONSORT-PRO extension (Item P6a), studies should report the validity and reliability of PROMs and a brief rationale for selecting the PROMs in trials. While just over 50% of the 64 studies provided or cited evidence on the validity and reliability of the PROMs. Most studies did not explain the reason for selecting PROMs. Specifically, we also observed regional preferences in the use of PROMs. For example, the SF-36 was used only in studies conducted in China. However, in these studies, researchers only cited the evidence for the validity of the PROMs without providing a brief rationale for selecting PROMs. This difference may be related to our search strategy, which only included studies published in Chinese or English in Chinese and English databases. It is also worth noting that adherence scores were lower in Chinese studies than in non-Chinese studies. We think that this is related to the predominance of non-confirmatory studies in Chinese studies and insufficient regulatory oversight of PROs. In the future, Chinese researchers should give full consideration to the reporting standards for PROs. Furthermore, only 9.4% of the studies explicitly described the method of collecting PRO data (item P6aiii). Different collection methods may affect the results and introduce potential biases ( 20 ). More than 90% of the studies failed to describe the handling methods for missing PRO data (Item P12a). This omission could raise a risk of selective outcome reporting. Missing PRO data due to disease progression or treatment discontinuation can introduce potential bias. Transparent reporting of the magnitude and reasons for missing data at each time point is crucial for clinicians to evaluate the potential bias of the PRO results. Notably, the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium has published the guidelines, which provide recommendations on standardized statistical terminology and managing methods of missing PRO data ( 57 ). So, we advise that future RCTs using PRO as outcomes adhere to the guidelines for handling data.

Finally, the results and discussion section of PRO reports revealed some limitations. Specifically, 84.4% of studies reported only the total scores of PROMs, without fully presenting data or effect sizes for individual dimensions (Item 17a). The absence of data in dimensions impeded the development of detailed clinical decision-making at the domain-specific level. Failing to report effect sizes may cause readers to misinterpret the statistical or clinical significance of the research, weakening the persuasiveness of the results. Moreover, 90.6% of the studies completely omitted the evaluation of the limitations of the PROMs. while 75.0% did not discuss the generalizability or influence on clinical practice of the PRO results (Item P20/21). Most studies predominantly concentrated on describing PRO data, without a critical analysis of the PROMs’ suitability, sensitivity, or the coverage of dimensions. Future RCTs on targeted therapy and/or immunotherapy for liver cancer should analyze the limitations of PROMs in the discussion section, as recommended by guidelines. At the same time, it is advised to establish PRO databases for liver cancer patients to record regional discrepancies in responses to the same measures, thereby facilitating cross-cultural validation of these instruments. Regulatory authorities should draw on international experience to incorporate the assessment of PROMs into the approval requirements of clinical trials. Particularly for the innovative tools developed locally, evidence of equivalence to gold standard tools must be provided.

Limitation

In our scoping review, we conducted a systematic search and used the CONSORT-PRO checklist and the CONSORT 2010 standards to score the adherence of PRO reporting. However, there were still some limitations. Firstly, we only retrieved relevant RCTs in six databases. The limited databases may have resulted in the omission of some potential RCTs. Secondly, we only considered papers published in Chinese or English and excluded potentially eligible studies in other languages. Therefore, the majority of studies in this review originated from China (78.1%). Given that regional differences may exist in study design as well as in the selection and application of PROMs, this distribution may affect the generalizability of our findings. Therefore, caution is needed when extrapolating the results to other regions. Future systematic reviews should expand the scope of languages and databases to confirm the international applicability of these findings. Finally, we adhered the internationally recognized ICH E8(R1) framework to classify the types of included studies. However, we could not definitively determine whether some of the included nursing intervention trials and traditional Chinese medicine studies reported PRO should be classified as conventional confirmatory or exploratory studies. These studies were assigned to an “Other” category. The adoption of this “Other” classification strategy may have influenced the final results, and thus the findings of this study should be interpreted with caution. Future research is encouraged to report detailed study objectives and design more rigorously, so as to enable accurate stratification of study types and enhance the precision of the evidence.

Conclusions

We systematically evaluated the reporting quality of PRO in 64 RCTs of targeted therapy and/or immunotherapy for liver cancer. The results showed that the PROs reported in the included studies were highly concentrated on QoL. The most commonly used tool was the general EORTC QLQ-C30. The reporting of specific symptoms associated with targeted and/or immunotherapy, as well as liver cancer−specific symptoms, was inadequate. The application of disease-specific or treatment-specific PROMs was also used less frequently. Meanwhile, we also found that the integration of PROs with clinical endpoints was suboptimal in nursing-focused RCTs, and PRO data from medical studies were seldom used to guide nursing care practice. More importantly, the overall adherence scores to CONSORT-PRO of the included studies were low. Although confirmatory studies demonstrated higher scores than exploratory studies and other types of studies, there was considerable variation within this category. Common limitations included failure to clarify the role of PROs in abstracts, inadequate articulation of the hypothesis and domains about PRO in the background, low methodological transparency, particularly the handling methods for missing data, and incomplete interpretation of results. These issues undermine the interpretability of the findings and introduce potential bias into the research. In conclusion, future studies should prioritize the use of validated, standard disease-specific assessment tools to compensate for the limitations of generic instruments and strengthen the evaluation of treatment-related adverse events. Secondly, we advocate for the establishment of a collaborative framework that integrates medical, nursing, and patient perspectives, so that PRO data can effectively guide clinical decision−making and nursing practice. Furthermore, we also recommend that future studies, particularly confirmatory studies and nursing intervention or supportive care studies where PROs serve as primary outcomes, strictly adhere to the CONSORT−PRO guideline to enhance methodological transparency and reporting quality of PROs. Finally, all results obtained in this review are based solely on the 64 included studies, and future research should expand the search scope to enhance the generalizability of the evidence.

Glossary

patient-reported outcomes

International Society for Pharmacoeconomics and Outcomes Research

U.S. Food and Drug Administration

Patient-reported outcome measures

randomized controlled trials

International Society for Quality of Life Research

Consolidated Standards of Reporting Trials Extension for Patient-Reported Outcomes

quality of life

Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews

China National Knowledge Infrastructure

Cytokine-Induced Killer

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire

Short Form-36 Health Survey

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Hepatocellular Carcinoma 18

Functional Assessment of Cancer Therapy-Hepatobiliary

Functional Assessment of Cancer Therapy-General

EuroQol Five Dimensions Questionnaire

Quality-of-Life Questionnaire for Liver Cancer

Dermatology Life Quality Index

Hand-Foot Quality of Life questionnaire

Pittsburgh Sleep Quality Index

Visual Analogue Scale

Self-Rating Anxiety Scale

Self-Rating Depression Scale

Self-Care Ability Evaluation Scale

Dysfunctional Beliefs and Attitudes on Sleep

Numerical Rating Scale

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Discipline Reserve Leader of Beijing University of Chinese Medicine, the Traditional Chinese Medicine Innovation Team and Talent Support Program - National Traditional Chinese Medicine Multidisciplinary Cross-Innovation Team Project, Beijing Youth Talent Program for Colleges and Universities (YETP0797).

Footnotes

Edited by: Wen Yang , Eastern Hepatobiliary Surgery Hospital, China

Reviewed by: Fabrizio Di Costanzo , Newcastle University, United Kingdom

Archita Desai , Indiana University, United States

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Author contributions

LR: Formal Analysis, Visualization, Investigation, Writing – review & editing, Data curation, Writing – original draft. YL: Investigation, Writing – review & editing, Writing – original draft, Formal Analysis, Visualization, Data curation. SL: Formal Analysis, Writing – review & editing, Data curation. SY: Writing – review & editing, Supervision, Methodology. CS: Writing – review & editing, Methodology, Supervision, Investigation, Writing – original draft, Conceptualization. JW: Data curation, Writing – review & editing, Formal Analysis. YZ: Writing – review & editing, Data curation, Formal Analysis.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2026.1770579/full#supplementary-material

References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2024) 74:229–63. doi: 10.3322/caac.21834. PMID: . Epub 20240404.

2. Vogel A, Chan SL, Dawson LA, Kelley RK, Llovet JM, Meyer T, et al. Hepatocellular carcinoma: Esmo clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. (2025) 36:491–506. doi: 10.1016/j.annonc.2025.02.006. PMID: . Epub 20250220.

3. Zhang T, Merle P, Wang H, Zhao H, Kudo M. Combination therapy for advanced hepatocellular carcinoma: Do we see the light at the end of the tunnel? Hepatobiliary Surg Nutr. (2021) 10:180–92. doi: 10.21037/hbsn-2021-7. PMID:

4. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. (2008) 359:378–90. doi: 10.1056/NEJMoa0708857. PMID:

5. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (Resorce): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. (2017) 389:56–66. doi: 10.1016/s0140-6736(16)32453-9. PMID: . Epub 20161206.

6. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (Reach-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. (2019) 20:282–96. doi: 10.1016/s1470-2045(18)30937-9. PMID: . Epub 20190118.

7. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. (2020) 382:1894–905. doi: 10.1056/NEJMoa1915745. PMID:

8. Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. (2023) 20:203–22. doi: 10.1038/s41575-022-00704-9. PMID: . Epub 20221111.

9. Graupner C, Kimman ML, Mul S, Slok AHM, Claessens D, Kleijnen J, et al. Patient outcomes, patient experiences and process indicators associated with the routine use of patient-reported outcome measures (Proms) in cancer care: A systematic review. Support Care Cancer. (2021) 29:573–93. doi: 10.1007/s00520-020-05695-4. PMID: . Epub 20200902.

10. Basch E, Deal AM, Dueck AC, Scher HI, Kris MG, Hudis C, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. Jama. (2017) 318:197–8. doi: 10.1001/jama.2017.7156. PMID:

11. Research; U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health USDoHaHSFCfDEaRUSDoHaHSFCfBEa . Guidance for industry: Patient-reported outcome measures: Use in medical product development to support labeling claims: Draft guidance. Health Qual Life Outcomes. (2006) 4:79. doi: 10.1186/1477-7525-4-79. PMID: . Epub 20061011.

12. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol. (2003) 21:1404–11. doi: 10.1200/jco.2003.08.072. PMID:

13. Kyte D, Reeve BB, Efficace F, Haywood K, Mercieca-Bebber R, King MT, et al. International Society for Quality of Life Research commentary on the draft European Medicines Agency reflection paper on the use of patient-reported outcome (Pro) measures in oncology studies. Qual Life Res. (2016) 25:359–62. doi: 10.1007/s11136-015-1099-z. PMID: . Epub 20150815.

14. Mercieca-Bebber R, King MT, Calvert MJ, Stockler MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. (2018) 9:353–67. doi: 10.2147/prom.S156279. PMID: . Epub 20181101.

15. Gilbert A, Sebag-Montefiore D, Davidson S, Velikova G. Use of patient-reported outcomes to measure symptoms and health related quality of life in the clinic. Gynecol Oncol. (2015) 136:429–39. doi: 10.1016/j.ygyno.2014.11.071. PMID: . Epub 20141128.

16. Kotronoulas G, Kearney N, Maguire R, Harrow A, Di Domenico D, Croy S, et al. What is the value of the routine use of patient-reported outcome measures toward improvement of patient outcomes, processes of care, and health service outcomes in cancer care? A systematic review of controlled trials. J Clin Oncol. (2014) 32:1480–501. doi: 10.1200/jco.2013.53.5948. PMID: . Epub 20140407.

17. Weingärtner V, Dargatz N, Weber C, Mueller D, Stock S, Voltz R, et al. Patient reported outcomes in randomized controlled cancer trials in advanced disease: A structured literature review. Expert Rev Clin Pharmacol. (2016) 9:821–9. doi: 10.1586/17512433.2016.1164595. PMID: . Epub 20160407.

18. Brundage M, Bass B, Davidson J, Queenan J, Bezjak A, Ringash J, et al. Patterns of reporting health-related quality of life outcomes in randomized clinical trials: Implications for clinicians and quality of life researchers. Qual Life Res. (2011) 20:653–64. doi: 10.1007/s11136-010-9793-3. PMID: . Epub 20101126.

19. Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD. Reporting of patient-reported outcomes in randomized trials: The Consort Pro extension. Jama. (2013) 309:814–22. doi: 10.1001/jama.2013.879. PMID:

20. Roets E, van der Graaf W, van Riet BHG, Haas RL, Younger E, Sparano F, et al. Patient-reported outcomes in randomized clinical trials of systemic therapy for advanced soft tissue sarcomas in adults: A systematic review. Crit Rev Oncol Hematol. (2024) 197:104345. doi: 10.1016/j.critrevonc.2024.104345. PMID: . Epub 20240404.

21. Maring JG, Eijsink JFH, Tichelaar FD, Veluwenkamp-Worawutputtapong P, Postma MJ, Touw DJ, et al. Role of patient-reported outcomes in clinical trials in metastatic colorectal cancer: A scoping review. Cancers (Basel). (2023) 15(4):1135. doi: 10.3390/cancers15041135. PMID: . Epub 20230210.

22. Chakraborty R, Cannella L, Cottone F, Efficace F. Quality of patient-reported outcome reporting in randomised controlled trials of haematological Malignancies according to international quality standards: A systematic review. Lancet Haematol. (2020) 7:e892–901. doi: 10.1016/s2352-3026(20)30292-1. PMID:

23. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. Prisma extension for scoping reviews (Prisma-Scr): Checklist and explanation. Ann Intern Med. (2018) 169:467–73. doi: 10.7326/m18-0850. PMID: . Epub 20180904.

24. Mercieca-Bebber R, Rouette J, Calvert M, King MT, McLeod L, Holch P, et al. Preliminary evidence on the uptake, use and benefits of the Consort-Pro extension. Qual Life Res. (2017) 26:1427–37. doi: 10.1007/s11136-017-1508-6. PMID: . Epub 20170207.

25. Fabian A, Domschikowski J, Letsch A, Schmalz C, Freitag-Wolf S, Dunst J, et al. Use and reporting of patient-reported outcomes in trials of palliative radiotherapy: A systematic review. JAMA Netw Open. (2022) 5:e2231930. doi: 10.1001/jamanetworkopen.2022.31930. PMID: . Epub 20220901.

26. Group IEW . E8(R1) General considerations for clinical studies. In: ICH Harmonised Guideline E8(R1). Geneva, Switzerland: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (2022).

27. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, 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) 85:365–76. doi: 10.1093/jnci/85.5.365. PMID:

28. Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ, Usherwood T, et al. Validating the Sf-36 health survey questionnaire: New outcome measure for primary care. Bmj. (1992) 305:160–4. doi: 10.1136/bmj.305.6846.160. PMID:

29. Balestroni G, Bertolotti G. Euroqol-5d (Eq-5d): An instrument for measuring quality of life. Monaldi Arch Chest Dis. (2012) 78:155–9. doi: 10.4081/monaldi.2012.121. PMID:

30. Wan C, Fang J, Yang Z, Zhang C, Luo J, Meng Q, et al. Development and validation of a quality of life instrument for patients with liver cancer Qol-Lc. Am J Clin Oncol. (2010) 33:448–55. doi: 10.1097/COC.0b013e3181b4b04f. PMID:

31. Vyas J, Johns JR, Abdelrazik Y, Ali FM, Ingram JR, Salek S, et al. The Dermatology Life Quality Index (Dlqi) used as the benchmark in validation of 101 quality-of-life instruments: A systematic review. J Eur Acad Dermatol Venereol. (2025) 39:631–79. doi: 10.1111/jdv.20321. PMID: . Epub 20240913.

32. Anderson RT, Keating KN, Doll HA, Camacho F. The Hand-Foot Skin Reaction and Quality of Life Questionnaire: An assessment tool for oncology. Oncologist. (2015) 20:831–8. doi: 10.1634/theoncologist.2014-0219. PMID: . Epub 20150617.

33. Kearney BY, Fleischer BJ. Development of an instrument to measure exercise of self-care agency. Res Nurs Health. (1979) 2:25–34. doi: 10.1002/nur.4770020105. PMID:

34. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet. (2018) 391:1163–73. doi: 10.1016/s0140-6736(18)30207-1. PMID:

35. Mercieca-Bebber R, Aiyegbusi OL, King MT, Brundage M, Snyder C, Calvert M. Knowledge translation concerns for the Consort-Pro extension reporting guidance: A review of reviews. Qual Life Res. (2022) 31:2939–57. doi: 10.1007/s11136-022-03119-w. PMID: . Epub 20220326.

36. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a bevacizumab biosimilar (Ibi305) versus sorafenib in unresectable hepatocellular carcinoma (Orient-32): A randomised, open-label, phase 2–3 study. Lancet Oncol. (2021) 22:977–90. doi: 10.1016/s1470-2045(21)00252-7. PMID: . Epub 20210615.

37. Liver EAftSot . Easl clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol. (2018) 69:182–236. doi: 10.1016/j.jhep.2018.03.019. PMID: . Epub 20180405.

38. Kluetz PG, Slagle A, Papadopoulos EJ, Johnson LL, Donoghue M, Kwitkowski VE, et al. Focusing on core patient-reported outcomes in cancer clinical trials: Symptomatic adverse events, physical function, and disease-related symptoms. Clin Cancer Res. (2016) 22:1553–8. doi: 10.1158/1078-0432.Ccr-15-2035. PMID: . Epub 20160112.

39. Efficace F, Collins GS, Cottone F, Giesinger JM, Sommer K, Anota A, et al. Patient-reported outcomes as independent prognostic factors for survival in oncology: Systematic review and meta-analysis. Value Health. (2021) 24:250–67. doi: 10.1016/j.jval.2020.10.017. PMID: . Epub 20210106.

40. Gotay CC, Kawamoto CT, Bottomley A, Efficace F. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol. (2008) 26:1355–63. doi: 10.1200/jco.2007.13.3439. PMID: . Epub 20080128.

41. Huang RS, Chen D, Benour A, Cortez R, Mihalache A, Johnny C, et al. Patient-reported outcomes as prognostic indicators for overall survival in cancer: A systematic review and meta-analysis. JAMA Oncol. (2025) 11 (11):1303–12. doi: 10.1001/jamaoncol.2025.3153. PMID: . Epub 20250911.

42. Blazeby JM, Currie E, Zee BC, Chie WC, Poon RT, Garden OJ. Development of a questionnaire module to supplement the Eortc Qlq-C30 to assess quality of life in patients with hepatocellular carcinoma, the Eortc Qlq-Hcc18. Eur J Cancer. (2004) 40:2439–44. doi: 10.1016/j.ejca.2004.06.033. PMID:

43. Rimassa L, Danesi R, Pressiani T, Merle P. Management of adverse events associated with tyrosine kinase inhibitors: Improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev. (2019) 77:20–8. doi: 10.1016/j.ctrv.2019.05.004. PMID: . Epub 20190515.

44. Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (Rescue): A nonrandomized, open-label, phase II trial. Clin Cancer Res. (2021) 27:1003–11. doi: 10.1158/1078-0432.Ccr-20-2571. PMID: . Epub 20201021.

45. Aiyegbusi OL, Cruz Rivera S, Roydhouse J, Kamudoni P, Alder Y, Anderson N, et al. Recommendations to address respondent burden associated with patient-reported outcome assessment. Nat Med. (2024) 30:650–9. doi: 10.1038/s41591-024-02827-9. PMID: . Epub 20240229.

46. Luijten MAJ, Schalet BD, Roorda LD, Haverman L, Terwee CB. Reducing patient burden of Proms in healthcare through advanced computerized adaptive testing stopping rules. Qual Life Res. (2025) 34(11):3205–214. doi: 10.1007/s11136-025-04079-7. PMID: . Epub 20251016.

47. Belzer A, Pach JJ, Valido K, Leventhal JS. The impact of dermatologic adverse events on the quality of life of oncology patients: A review of the literature. Am J Clin Dermatol. (2024) 25:435–45. doi: 10.1007/s40257-024-00847-2. PMID: . Epub 20240216.

48. Haanen J, Obeid M, Spain L, Carbonnel F, Wang Y, Robert C, et al. Management of toxicities from immunotherapy: Esmo clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. (2022) 33:1217–38. doi: 10.1016/j.annonc.2022.10.001. PMID: . Epub 20221018.

49. Basch E, Schrag D, Henson S, Jansen J, Ginos B, Stover AM, et al. Effect of electronic symptom monitoring on patient-reported outcomes among patients with metastatic cancer: A randomized clinical trial. Jama. (2022) 327:2413–22. doi: 10.1001/jama.2022.9265. PMID:

50. Yip R, Arnolda G, Lamprell K, Nic Giolla Easpaig B, Chittajallu R, Delaney G, et al. Experience of patients considering or using checkpoint inhibitors in cancer treatment: A systematic review of qualitative research. J Immunother Cancer. (2024) 12(1):e007555. doi: 10.1136/jitc-2023-007555. PMID: . Epub 20240111.

51. Basch E, Deal AM, Kris MG, Scher HI, Hudis CA, Sabbatini P, et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: A randomized controlled trial. J Clin Oncol. (2016) 34:557–65. doi: 10.1200/jco.2015.63.0830. PMID:

52. Al-Naesan I, Krepper D, Sparano F, Sztankay M, Efficace F, Giesinger JM. Patient-reported outcomes in randomized controlled trials evaluating Braf inhibitors in patients with cutaneous melanoma: A systematic scoping review of quality of reporting and trial results. Melanoma Res. (2025) 35:77–86. doi: 10.1097/cmr.0000000000001014. PMID:

53. Baragar B, Schick-Makaroff K, Manns B, Love S, Donald M, Santana M, et al. You need a team": Perspectives on interdisciplinary symptom management using patient-reported outcome measures in hemodialysis care-a qualitative study. J Patient Rep Outcomes. (2023) 7:3. doi: 10.1186/s41687-022-00538-8. PMID:

54. McKigney N, Houston F, Ross E, Velikova G, Brown J, Harji DP. Systematic review of patient-reported outcome measures in locally recurrent rectal cancer. Ann Surg Oncol. (2023) 30:3969–86. doi: 10.1245/s10434-023-13388-5. PMID:

55. Ojo AS, Araoye MO, Ali A, Sarma R. The impact of current therapeutic options on the health-related quality of life of patients with relapse/refractory multiple myeloma: A systematic review of clinical studies. J Cancer Surviv. (2024) 18:673–97. doi: 10.1007/s11764-023-01332-1. PMID:

56. Kyte D, Retzer A, Ahmed K, Keeley T, Armes J, Brown JM, et al. Systematic evaluation of patient-reported outcome protocol content and reporting in cancer trials. J Natl Cancer Inst. (2019) 111:1170–8. doi: 10.1093/jnci/djz038. PMID:

57. Coens C, Pe M, Dueck AC, Sloan J, Basch E, Calvert M, et al. International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: Recommendations of the Sisaqol Consortium. Lancet Oncol. (2020) 21:e83–96. doi: 10.1016/s1470-2045(19)30790-9. PMID:

58. US Food and Drug Administration (FDA) . Fda patient-focused drug development guidance series for enhancing the incorporation of the patient’s voice in medical product development and regulatory decision making. Silver Spring, MD, USA: U.S. Food and Drug Administration (FDA) (2025).

59. Bylicki O, Gan HK, Joly F, Maillet D, You B, Péron J. Poor patient-reported outcomes reporting according to Consort guidelines in randomized clinical trials evaluating systemic cancer therapy. Ann Oncol. (2015) 26:231–7. doi: 10.1093/annonc/mdu489. PMID:

60. Khan A, Nguyen T, Dunford B, Khan T, Khalid M, Hillman C, et al. Adherence to Consort-Pro extension guidelines for patient-reported outcomes in randomized controlled trials focused on peripheral nerve blocks: A meta-epidemiological study. Pain Ther. (2025) 14:1531–46. doi: 10.1007/s40122-025-00766-y. PMID:

61. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase iii randomised, double-blind, placebo-controlled trial. Lancet Oncol. (2009) 10:25–34. doi: 10.1016/s1470-2045(08)70285-7. PMID:

62. Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (Tace 2): A randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. (2017) 2:565–75. doi: 10.1016/S2468-1253(17)30156-5. PMID:

63. Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (Sarah): An open-label randomised controlled phase 3 trial. Lancet Oncol. (2017) 18:1624–36. doi: 10.1016/S1470-2045(17)30683-6. PMID:

64. Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, et al. Tivantinib for second-line treatment of Met-High, advanced hepatocellular carcinoma (Metiv-Hcc): A final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. (2018) 19:682–93. doi: 10.1016/S1470-2045(18)30146-3. PMID:

65. Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. Sirvenib: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. (2018) 36:1913–21. doi: 10.1200/JCO.2017.76.0892. PMID:

66. Jouve JL, Lecomte T, Bouché O, Barbier E, Khemissa Akouz F, Riachi G, et al. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol. (2019) 71:516–22. doi: 10.1016/j.jhep.2019.04.021. PMID:

67. Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, et al. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: Patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. (2021) 6:649–58. doi: 10.1016/S2468-1253(21)00110-2. PMID:

68. Ryoo BY, Merle P, Kulkarni AS, Cheng AL, Bouattour M, Lim HY, et al. Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: Keynote-240. Cancer. (2021) 127:865–74. doi: 10.1002/cncr.33317. PMID:

69. Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, et al. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (Imbrave150): An open-label, randomised, phase 3 trial. Lancet Oncol. (2021) 22:991–1001. doi: 10.1016/S1470-2045(21)00151-0. PMID:

70. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. (2022) 1:EVIDoa2100070. doi: 10.1056/EVIDoa2100070. PMID:

71. Sangro B, Galle PR, Kelley RK, Charoentum C, De Toni EN, Ostapenko Y, et al. Patient-reported outcomes from the phase iii Himalaya study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. J Clin Oncol. (2024) 42:2790–9. doi: 10.1200/JCO.23.01462. PMID:

72. Sangro B, Kudo M, Erinjeri JP, Qin S, Ren Z, Chan SL, et al. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (Emerald-1): A multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. (2025) 405:216–32. doi: 10.1016/S0140-6736(24)02551-0. PMID:

73. Koeberle D, Dufour JF, Demeter G, Samaras P, Saletti P, Li Q, et al. Sorafenib with or without everolimus in patients with unresectable hepatocellular carcinoma (Hcc): A randomized multicenter phase ii trial (Sakk 77/08 and Sasl 29). J Clin Oncol. (2014) 32:4099–4099. doi: 10.1200/jco.2014.32.15_suppl.4099. PMID:

74. Qiao C, Zhang X, Cheng X, Cai X, Liu Q. Fuzheng Guben therapy improves quality of life in patients with hepatocellular carcinoma on targeted therapy. World Chin J Digestology. (2015) 33:5383–7. doi: 10.11569/wcjd.v23.i33.5383

75. Xulan C, Jingnan F, Ying L, Zhiqun Z, Bo Q. The effect of radiofrequency ablation combined with targeted therapy guided by ultrasound on quality of life of patients with advanced hepatocellular carcinoma. Clin Misdiagnosis Mistherapy. (2015) 6:81–4. doi: 10.3969/j.issn.1002-3429.2015.06.032

76. Hongmei L, Lili S, Jinrui L, Xinping Z. Clinical efficacy of radiofrequency ablation combined with Dc-Cik and its effect on quality of life in patients with advanced hepatocellular carcinoma. Hainan Med J. (2015) 26(21):3136–40. doi: 10.3969/j.issn.1003-6350.2015.21.1141

77. Hongxia Z, Hong S, Lin L, Hongwei F. Effects of gefitinib on pain degree and life quality in patients with middle and advanced liver cancer. J Logistics Univ PAPF (Medical Scienees). (2015) 24:352–5.

78. Cuixia Q, Xinfeng Z, Xufeng C, Qi L, Xiaoping C. The influence of autologous cytokine-induced killer cells combined with targeted therapy for liver cancer on the quality of life of elderly patients with liver cancer. Chin J Gerontology. (2017) 37:111–2. doi: 10.3969/j.issn.1005-9202.2017.01.048

79. Shuiping J. The influence of autologous cytokine-induced killer cells combined with targeted therapy for liver cancer on the quality of life of elderly patients with advanced liver cancer. Chin J Clin Rational Drug Use. (2018) 11:116–7. doi: 10.15887/j.cnki.13-1389/r.2018.02.074

80. Huang J, Luo X, Gong A. Effects of camrelizumab combined with transcatheter arterial chemoembolization arterial chemoembolization on serum Egfl7, Vegf, and Opn levels and recurrence rate in patients with hepatocellular carcinoma with microvascular invasion after radical operation: A prospective study. World Chin J Digestology. (2021) 29:182–9. doi: 10.11569/wcjd.v29.i4.182

81. Pengtao Z, Hongtao P. Analysis of the application value of interventional therapy combined with targeted drug apatinib in the treatment of primary liver cancer. Guizhou Med J. (2021) 45:887–8. doi: 10.3969/j.issn.1000-744X.2021.06.019

82. Wang X, Zhang X. The influence of transcatheter arterial chemoembolization combined with sorafenib and targeted intervention on the liver function levels of tumor markers in patients with liver cancer. J Med Forum. (2021) 42:124–7.

83. Zefeng D, Lijuan P. Clinical study of camrelizumab combined with lenvatinib in the treatment of advanced hepatocarcinoma. Med Innovation China. (2022) 19:153–7. doi: 10.3969/j.issn.1674-4985.2022.09.038

84. Wenqian L, Guiyan Y. The clinical efficacy and safety of sintilimab combined with lenvatinib as second-line treatment for unresectable hepatocellular carcinoma. Chin Sci Technol J Database (Citation Edition): Med Health. (2022) 9:097–099.

85. Ping M, Yuanmin Z, Gaiyunzhu, Gengxin Y. Clinical efficacy of Tace combined with lenvatinib in the treatment of intermediate to advanced hepatocellular carcinoma. Syst Med. (2022) 7:173–7. doi: 10.19368/j.cnki.2096-1782.2022.24.173

86. Fengqi Z, Lingling W. Effect of lenvatinib combined with transcatheter arterial chemoembolization on patients with advanced liver cancer. Chin Foreign Med Res. (2022) 20:33–7. doi: 10.14033/j.cnki.cfmr.2022.31.009

87. Feng C, Yongming X, Jie F. Targeted drugs combined with immunotherapy in patients with primary liver cancer complicated with microvascular invasion discussion on the value of development. Smart Healthcare. (2023) 9:9–12. doi: 10.19335/j.cnki.2096-1219.2023.31.003

88. Liang D, Qingliang G, Binwei D, Xiaofei Z, Jing D. Effect of immunocheckpoint inhibitor combined with ranvartinib on Tace resistance to advanced primary liver cancer and its influence on serum Pdgf and Vegf. Chin J Difficult Complicated cases. (2023) 22:54–9. doi: 10.3969/j.issn.1671-6450.2023.01.010

89. Fu Y, Chen X, Fu Y. Clinical study of sintilimab combined with radiofrequency ablation in the treatment of stage IIa liver cancer. China Pharm. (2023) 32:106–9. doi: 10.3969/j.issn.1006-4931.2023.06.027

90. Zhichao H, Hang L, Jinchun Z, Hua F. Efficacy of natural killer cell assisted radio frequency ablation on patients with liver cancer and its influence on T cell subsets and survival rate. J Guangxi Med Univ. (2023) 40 (11):1871–77. doi: 10.16190/j.cnki.45-1211/r.2023.11.015

91. Quanhui L, Geng L, Yuheng W. Observation on the therapeutic effect of transcatheter arterial chemoembolization combined with transcatheter arterial infusion chemotherapy on advanced liver cancer. Shenzhen J Integrated Traditional Chin Western Med. (2023) 33:116–9. doi: 10.16458/j.cnki.1007-0893.2023.23.035

92. Haihui Y, Hua J. The clinical efficacy of tirelizol on the treatment of advanced liver cancer and its influence on peripheral Prmt5 and Pivka-II levels. Chin Hepatol. (2023) 28 (12):1435–9. doi: 10.3969/j.issn.1008-1704.2023.12.012

93. Zhaohui L, Xiaoxiao Z, Duo Z, Lala L. Effect of sorafenib tosylate tablets combined with oxaliplatin in treatment of chemotherapeutic patients with hepatocellular carcinoma and its influence on liver function. Lab Med Clinic. (2024) 21:976–9. doi: 10.3969/j.issn.1672-9455.2024.07.024

94. Yan Q. The influence of Dc+Cik cell immunotherapy on the effect of postoperative patients with primary liver cancer. Chin Sci Technol J Database (Abstract Edition) - Med Health. (2024) 10:0076–0079.

95. Xiaolong W, Jing D, Tao L. Efficacy of toripalimab combined with lenvatinib and Tace in the treatment of advanced hepatocellular carcinoma and its impact on tumor markers and prognosis. Hebei Med. (2024) 30:1745–51. doi: 10.3969/j.issn.1006-6233.2024.10.030

96. Fan Y, Jun Y, Fei G. Clinical study on Tace combined with Pd⁃1 inhibitor and Dc⁃Cik in the treatment of advanced liver cancer. J Navy Med. (2024) 45:1046–50. doi: 10.3969/j.issn.1009-0754.2024.10.012

97. Lifen Y, Shaowei Y, Guoxi X. The efficacy of camrelizumab combined with lenvatinib mesylate in the treatment of liver cancer and its impact on tumor markers and quality of life. Chin J Clin Rational Drug Use. (2024) 17:104–106,10. doi: 10.15887/j.cnki.13-1389/r.2024.21.029

98. Xing Y, Jian X, Tao Y, Li D, Lili G. An evaluation of immune function, clinical efficacy and safety of ramucirumab combined with sorafenib treatment in patients with hepatocellular carcinoma. Chin Hepatol. (2024) 29:1189–93. doi: 10.3969/j.issn.1008-1704.2024.10.008

99. Zhong G, Xu Z, Zeng G, Pan W, Wei H, Huang J, et al. The influence of transradial Tace+Haic combined immunotargeted therapy on patients with postoperative liver cancer complicated with portal vein tumor thrombus. J Med Theory Pract. (2024) 37:4019–21. doi: 10.19381/j.issn.1001-7585.2024.23.019

100. Yan C, Dingsheng W, Sina L, Qiaozhen L, Jing Y. To explore the clinical effects of apatinib mesylate and sorafenib on patients with advanced liver cancer. Chin Sci Technol J Database (Abstract Edition) - Med Health. (2025) 2:075–078.

101. Hao F, Zhengzhong, Jinfu S, Ling Z. Analysis of the impact of transarterial chemoembolization combined with targeted therapy on the therapeutic effect of liver cancer patients. Contemp Med Forum. (2025) 23:80–3. doi: 10.3969/j.issn.2095-7629.2025.03.023

102. Junyao Y, Guowen Y, Qingyu X, Ran Y, Jinxia Q. Efficacy and safety of radiofrequency ablation plus atezolizumab in the treatment of patients with unresectable hepatocellular carcinoma. J Pract Hepatol. (2025) 28:262–5. doi: 10.3969/j.issn.1672-5069.2025.02.026

103. Dayan Z, Yanhao L, Guili Z. The effect of Pd-1 antibody combined with mfolfox6 hepatic arterial infusion chemotherapy on tumor marker levels and quality of life in patients with advanced primary liver cancer. Pract J Cancer. (2025) 40:492–5. doi: 10.3969/j.issn.1001-5930.2025.03.037

104. Ren Z, Zhu K, Kang H, Lu M, Qu Z, Lu L, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol. (2015) 33:894–900. doi: 10.1200/jco.2013.52.9651. PMID:

105. Jie G. The influence of optimized nursing intervention on anxiety and depression in patients undergoing cell immunotherapy for primary liver cancer. Nurs Pract Res. (2016) 13 (21):70–70,71. doi: 10.3969/j.issn.1672-9676.2016.21.028

106. Hongmei L, Yu S, Yueli Y, Lan M, Xinping Z. Effect of cognitive intervention on quality of life, pain degree and clinical efficacy of patients with middle-ad-vanced hepatocellular carcinoma by dc-cik therapy. Med Pharm J Chin People’s Liberation Army. (2016) 28:48–53. doi: 10.3969/j.issn.2095-140X.2016.05.012

107. Jiao K, Ruiying Z. The value of early rapid rehabilitation nursing in the treatment of liver cancer patients with surgery combined with sorafenib. Strait Pharm J. (2020) 32:120–2. doi: 10.3969/j.issn.1006-3765.2020.04.042

108. Jianzhu C. Influence of high-quality nursing on quality of life and sleep of patients with primary liver cancer complicated with side effects caused by molecular targeted drugs. World J Sleep Med. (2021) 8:506–7. doi: 10.3969/j.issn.2095-7130.2021.03.055

109. Youjin D. Clinical observation on treating liver cancer by the fuzheng guben method plus targeted therapy. Clin J Chin Med. (2021) 13:95–7. doi: 10.3969/j.issn.1674-7860.2021.16.030

110. Shuang W. Application effect of humanized nursing mode combined with narrative nursing in the treatment of liver cancer with sorafenib and tacrolimus and its influence on subjective well-being and negative emotions. J Math Med. (2021) 34 (1):155–6. doi: 10.3969/j.issn.1004-4337.2021.01.067

111. Yali Y. Application effects of clinical nursing pathway in patients with primary liver cancer treated by sorafenib. Med J Chin People’s Health. (2022) 34 (1):177–9. doi: 10.3969/j.issn.1672-0369.2022.01.056

112. Yanfang Z, Lei Y. To evaluate the effects of tigio combined with sorafenib on adverse mood and sleep quality in patients with primary liver cancer. World Joumnal Sleep Med. (2022) 9(5):801–3. doi: 10.3969/j.issn.2095-7130.2022.05.006

113. Yao L. Application research of orim self-care model in patients with liver cancer treated with tace combined with sorafenib. Med Forum. (2023) 27:75–7. doi: 10.19435/j.1672-1721.2023.15.025

114. Liuqing Y, Yan W, Feifeng Z, Xiuyun W. Analysis of the impact of exercise psychological sleep nursing intervention combined with aromatherapy on targeted immunotherapy combined with sleep disorders in patients with liver cancer. World J Sleep Med. (2023) 10:2663–6. doi: 10.3969/j.issn.2095-7130.2023.11.049

115. Dan Y, Shengli H, Jie S, Nanhua H, Yunyun C, Tieliu C. Clinical observation of ruyi jinhuang powder combined with icis in the treatment of advanced liver cancer complicated with dampness and heat syndrome of liver and gallbladder. China Pharm. (2023) 34:1488–92. doi: 10.6039/j.issn.1001-0408.2023.12.15

116. Yahui Z. Observation on the therapeutic effect of qigui zicao oil on capillary hyperplasia after immunotherapy for liver cancer. Henan University of Chinese Medicine. (2023).

117. Lijuan D, Yu C, Xiaojia H. Effects of cloud hospital nursing management model on compliance and adverse reactions of patients with hepatocellular carcinoma treated with targeted drugs. Clin Res Pract. (2024) 9:146–9. doi: 10.19347/j.cnki.2096-1413.202416034

118. Dongyan J. The influence of high-quality nursing on the cognition and sleep quality of patients with liver cancer undergoing immunotherapy. Chin Sci Technol J Database: Med. (2024) 4:0171–0174.

119. Pei L, Lu Z, Lina C, Shuling H. Application of psychological intervention based on dignity therapy in patients receiving targeted therapy for advanced liver cancer. China J Health Psychol. (2024) 32:1679–83. doi: 10.13342/j.cnki.cjhp.2024.11.015

120. Peiying Y, Jiaying H, Honggen L, Yingjie J. Efficacy observation of peiyuan chuzhuo decoction on moderate or advanced liver cancer. Shanxi J Traditional Chin Med. (2024) 40:21–4. doi: 10.20002/j.issn.1000-7156.2024.02.009

121. Yang Y, Di L, Yitong W, Xuejing W, Minyue Z, Chun Z, et al. Clinical study of huqi zhengxiao decoction with lenvatinib in treating 93 patients with stage III hepatitis B related liver cancer. Chin J Integrated Traditional Chin Western Med Digestion. (2024) 32:208–13.

122. Kun Z, Wei Y, Jing W, Zhang X, Fan Z. The clinical efficacy of shugan jianpi jiedu formula combined with tislelizumab and bevacizumab in patients with advanced liver cancer. Chin Traditional Patent Med. (2024) 46:4221–4. doi: 10.3969/j.issn.1001-1528.2024.12.052

Associated Data

Supplementary Materials

Data Availability Statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.