1. Introduction

With healthcare costs increasing globally, there is a marked transition towards value-based healthcare (VBHC) systems with the aim to improve health outcomes [1,2]. The main hurdle is to estab-lish uniform outcome metrics that allow effective monitoring and quality of care comparison, thus op-timizing medical practices and patient care pathways. A universally accepted definition of outcomes is necessary, encompassing both clinical results (CROMs – Clinical Reported Outcome Measurements) and patient-valued aspects such as symptoms and quality-of-life (PROMs – Patient Reported Outcome Measurements), which are crucial for serious conditions like liver cancers.

Hepatocellular carcinoma (HCC) is the most frequent type of liver tumors, primarily arising in cir-rhotic livers (75-80%), sometimes in non-cirrhotic chronic liver disease, and rarely in livers without any pre-existing condition. Globally, there are approximately 500,000 new liver cancer cases annually [3], making it the third leading cause of cancer-related death each year [4]. Among the various therapeutic decision-making frameworks, the Barcelona clinic liver cancer (BCLC) algorithm is the most widely used, considering tumor stage, liver function, and patient performance status to indicate a range of treatments from liver transplantation to supportive care, surgical resection, and other interventions [5]. Cholangiocarcinoma, another primary liver cancer, carries a poor prognosis [6].

Liver resection is a well-established treatment for colorectal liver metastases (CRLM), the leading cause of secondary liver cancers, with a 5-year survival rate of about 60% [7,8]. Over recent years, the management of CRLMs has evolved significantly due to the advances in perioperative medical care, the broadening of treatment indications, and the introduction of minimally invasive techniques [9], along-side the effective multimodal oncology treatments.

Despite the development of standardized questionnaires for assessing health outcomes via CROMs and PROMs in various cancers, such as breast [10], colon [11], lung [12], prostate [13,14], and pancreatic [15], there are no standardized outcome measurement sets for primary or secondary liver cancers.

Given our group's previous work in developing outcome sets for pancreatic carcinoma [15,16], we aimed to address this gap for liver cancer by creating the first standardized outcome measurement set, facilitating the monitoring of patient symptoms and quality-of-life, and aligning the best practices across care centers [17].

2. Methods

Our methodology followed the one used for pancreatic carcinoma outcomes set [15].

2.1. The role of the Working Group

A multidisciplinary Working Group (WG) was formed, comprising healthcare professionals, pa-tients, and other stakeholders. The WG started by analyzing existing care pathways for liver cancer pa-tients and gathering their inputs through interviews. They also conducted a systematic literature review to identify outcomes used in liver cancer clinical trials. After this review, duplicated outcomes were re-moved and the remaining ones were categorized into subjects of discussion. The WG then presented their selection to an international external validation committee (VC) for voting.

2.2. The role of the Validation Committee

The VC, comprising 102 members, including medical professionals (digestive surgeons, oncolo-gists, hepatologists, dieticians, nurses) and patients (Table 1), was tasked with a four-round Delphi pro-cess to refine and validate the final outcomes set (Figure 1). The patients involved were volunteers experiencing or having a liver cancer history. The tool used to conduct four rounds of surveys between De-cember 2018 and July 2019, focusing on CROMs and PROMs, was the Qualtrics platform. Participants were able to complete the surveys in either English or French, and phone assistance was available for those needing help. The final selection of the most appropriate patients related outcomes survey was choosen from eight questionnaires for the PROMs proposed earlier.

The WG determined the timeline to collect those outcomes confirming to various care episodes.

Table 1: Composition of the Validation Committee.

Figure 1: Systematic outcomes review flow chart.

2.3. The PROMs

PROMs data was used to create a radar chart for each patient, depicting symptoms and quali-ty-of-life from the patient's perspective (Figure 2). This was achieved using the EORTC QLQ-30 ques-tionnaire, with scores indicating better quality-of-life at lower values. The score of each question is represented: for the questions from 1 to 28, the answers are from 1 to 4 (the lower the score, the better the quality-of-life from the patient’s perspective); for the questions 29 and 30, the score from 1 to 7 represent respectively the degree of overall health and quality-of-life.

Figure 2: Radar chart representing the quality of life and symptoms of Patient 71 who had surgery for colon metastasis, assessed with EORTC QLQ-30 questionnaire at six-month, nine-month and one-year after surgery. The score of each question is represented: for the questions from 1 to 28, the answers are from 1 to 4 (the lower the score, the better the quality of life from the patient’s perspective); for the questions 29 and 30, the score from 1 to 7 represent respectively the degree of overall health and quality of life.

3. Results

The WG defined the objectives of the project as encompassing all patients with primary or second-ary liver cancers, irrespective of the type or intent of treatment received, including those who had not received curative treatment. Patients undergoing treatment with experimental agents were excluded because these studies have their own outcome evaluations.

After the systematic literature review, a total of 377 clinical studies were selected and reviewed. 1539 outcomes were listed, including CROMs (1493 items) and PROMs (46 items).

These outcomes were put into 7 categories: Adverse Events monitoring, Cost, Efficacy endpoint in oncology, Progression Disease, Pharmacokinetics, Quality-of-Life, Toxicity/Safety/Tolerability. Redun-dancies and no relevant outcomes due to specific analysis (e.g., drugs, gene research) were removed. At the end, the WG selected 141 outcomes (121 CROMs; 20 PROMs) to submit to the international Delphi vote committee. In total, 96 outcomes (86 CROMs; 10 PROMs) were retained. One additional variable (“Diagnosis date”) was suggested during the first round and retained during the second.

3.1. Outcomes classification

CROMs were divided into 2 parts: a baseline set (demographic factors, clinical characteristics, di-agnostic methodology, therapeutic strategy) (Table 2); a follow-up set: (treatment-related complications, survival and disease control indicators, evidence of relapse or disease progression (Table 3).

PROMs were grouped into health domains by the WG members using a method inspired by Mace-field et al. [18] and Van Rijssen et al. [19]. Quality-of-life (QOL) and functioning items were encom-passed in 3 categories: global health status, functional scales, symptom scales (Table 4).

3.2. CROMs: Clinical results

After the final validation process, 86 CROMs composed by demographic and baseline data, therapeutic strategy, treatment effects, rehabilitation and follow-up data were selected (Tables 2 & 3).

• Demographic factors: sex, age weight, height, units of weight and height, family history of liver-related cancer.
• Baseline clinical factors prioritized for inclusion: the Eastern Cooperative On-cology Group (ECOG) score performance status [20], presence of comorbidities, the level of alco-hol consumption. The Charlson comorbidity index was selected for the comorbidity reporting [21]. The different methodologies used to verify the diagnosis were included, as the date of the tests. In case of hepatocarcinoma on cirrhotic liver, specific variables of cirrhosis as etiology (al-coholic, viral, non-alcoholic steato-hepatitis...), clinical severity (Child-Pugh/Meld Classification, portal hypertension...) were recorded. Clinical signs, pathology stage (TNM stage) were also collected.
• Therapeutic strategy was divided into two groups: general and specific therapeutic strategy data.
• Follow-up items were included to monitor the trends of medical outcomes com-prising treatment-related adverse events, with a collection of surgical complications and their severity according to the Clavien-Dindo classification [22]; common terminology criteria for ad-verse events in radiotherapy and chemotherapy (version 4.0) [23] (Table 3).

Some postoperative complications related to liver surgery (biliary fistula, hepatocellular failure, bleeding) were assessed separately and classified according to their severity [24,25]. Similarly, the implementation of nutritional support and the need for new admissions were selected from a set of proposed variables.

The following measures were included for survival and disease control: overall survival, cause-specific survival, recurrence-free survival, progression-free survival, need for readmission.

For patients who received neoadjuvant therapy or surgery, complete pathological response and margin status were included.

Onset of tumor recurrence, date of relapse (curative treatment) or disease progression (pallia-tive treatment) were also included in follow-up and considered as a new reference point.

3.3. PROMs: Functioning, symptoms, quality-of-life variables

The final PROMs set (Quality-of-Life, functioning, symptom measures) is listed in table 4.

A total of 10 PROMs were selected, with validated questionnaires, the EORTC QLQ-C30 [26] and EORTC QLQ-HCC18 [27], for outcomes collection. Patients have to answer the questionnaires themselves, supervised by a pathway coordinator if needed. For patients with liver metastasis and other liver malignant pathologies, only the EORTC QLQ-C30 questionnaire is required. Although, both questionnaires are needed to assess the quality-of-life and symptoms of patients with HCC. The choice of questionnaires is then adjusted according to the types of liver malignant diseases. Patients with liver metastasis or non-HCC primary lesions only answered the EORTC QLQ-C30 questionnaire; that pre-senting HCC answered EORTC QLQ-C30 as EORTC QLQ-HCC18.

^µ baseline and follow-up.

Table 2: Clinical Reported Outcome Measurements (CROMs) Baseline set.

Table 3: Clinical Reported Outcome Measurements (CROMs) Follow-Up set.

QoL: Quality of Life.

Table 4: Patient Reported Outcome Measurements (PROMs) set.

The choice of using those questionnaires for outcomes collection was validated by the VC, after review of several common validated questionnaires and identification of those best covering the selected outcomes.

The use of PROMs improves the communication between clinicians and patients facilitating the discussion about some sensitive subjects.

The example chosen here concerns the Patient 71 who underwent hepatic resection for colon metastasis (Figure 2). He answered the EORTC-QLQ-C30 at six-month, nine-month, one-year after sur-gery reflecting his symptoms and the score evaluating his quality-of-life.

3.4. Planning of evaluation

The timing of the evaluation of the set of variables was determined by the WG to strike a balance between clinically relevant time periods ; pragmatic concerns faced by institutions and data collection practices.

The collection of CROMs and PROMs was recommended during the baseline, at 1 month (for sur-gical/loco-regional therapy), 3 months, 6 months, 9 months, one year after treatment, 18 months; annually up to 10 years, if possible.

3.5. First results of the French experience

Once the hepatic carcinoma standard set was validated, the Strasbourg’s team started collecting the patients’ outcomes after gathering their consents. From July 2019 to January 2021, 129 questionnaires were filled by 74 patients on the day of their surgical appointment with the 2 HBP surgeons implicated. The coordination nurse was present if needed to help patients understand the questionnaires. She noted that most of them felt well involved and found the PROMs collection as important as the clinical out-comes. The 74 patients answered at least one; 24 patients filled 2; 14 patients answered 3 questionnaires; 1 patient filled 4 of them. 65% were males; 51% presented with HCC, 40 % with colorectal metastasis, 5 patients with cholangiocarcinoma ; one patient had breast liver metastasis. 42% had liver surgery ; 10% still had a professional activity. The HBP surgeons found this approach complementary to the usual follow-up ; thanks to it, they could have each patient’s proper evolution chart (Figure 2).

This new evaluation combined to the usual medical check makes doctors tackle some points affecting the patient’s quality-of-life that are not generally discussed. Furthermore, the medical care is thus global and not from the surgeon’s but from the patient’s point of view.

4. Discussion

The objective of this study is to develop a set of outcome variables to facilitate the collaboration among the various stakeholders in the healthcare systems.

These outcome indicators need to be collectively agreed upon by each one involved in the care pathway.

This requires a collaborative approach where all participants in the chain of value contribute to the development of these outcomes. According to the strategy of this study, a multidisciplinary and multi-professional team was formed, including patients, who uniquely experience the entire care path-way, and healthcare providers (HCPs) who maintain ongoing contact with patients. This team compo-sition emphasized patient experiences and expectations alongside medical expertise. However, one limitation was the absence of palliative care specialists, who could enhance discussions on patients’ quality-of-life.

Comparing different centers can help improve care organization, and a set of outcome measures can help prioritize care under limited resources. For a specific disease, implementing a vali-dated set of outcomes requires digital data tracking of selected parameters. After data collection over time, stratified analyses should be conducted based on the disease stage and patient risk factors. Addi-tionally, HCPs can use the results from patient-reported outcome measures (PROMs) to refine treatment decisions [28]. In terms of rehabilitation, Enhanced Recovery after Surgery (ERAS) pathways, or other organizational innovations, systematic monitoring through Value-Based Healthcare (VBHC) question-naires provides real-life assessments of Clinical and Patient-Reported Outcome Measures (CROMs and PROMs).

These analyses enable comparisons, enhance care quality, and meet patient expectations. Once results are anonymously shared, each center can implement corrective actions if needed. This sets up a virtuous cycle for practices improvement through systematic results evaluation. Historically, quality assurance evaluations were not common practice. The aim is to prompt the conditions to create a virtuous circle to improve quality of care, notably to measure and compare means to better assess, understand and assert one’s results and learn from others. This constraint-free audit approach is ongoing and successfully led to better treatment of an increasing number of patients [29,30].

This approach parallels quality assurance practices in services and industries. It benefits practitioners by enhancing their methods, patients by receiving relevant care, and the healthcare system by reducing inefficiencies, which incur costs [31]. Modifying the financial system to focus on quality over quantity is a powerful motivator for adopting these systematic quality assessments. This work is not about evaluating care costs but about defining indicators representing "medical service rendered" on both the clinical level with CROMs and in terms of patient feelings and expectations through PROMs. Sometimes, discrepancies exist between clinical data and patient perceptions. This value appeals to subjective human emotions. No individual value exists in isolation; value judgments are collective. A theoretical survival gains through chemotherapy, despite risks like peripheral neuropathy, will be valued differently based on individual circumstances, such as whether the patient is a professional violinist. This introduces a hierarchy of values, assessing what is prioritized. The question is how much we are collectively willing to invest in results that matter to patients or, for a given cost, what minimum patient-valued results are expected.

To facilitate the implementation of outcome indicators important to patients, several factors must be addressed. For key patient data like quality of life, patients can complete questionnaires themselves, supervised by a pathway coordinator if necessary [32]. Clinical outcomes are already documented in patient records and can be gathered through standardized data collection. Authors report successful validation and easy adoption of value-based digital health by healthcare professionals in their daily practice [33]. To support the success of a VBHC approach, the European University Hospital Alliance provides a diagram with eight elements across six phases [34].

It is crucial to emphasize that this approach is about valuing quality, not penalizing poor results. Criticisms suggesting patient selection for management based on low risk should be countered. Stratified analyses according to disease stage and patient risks should be conducted to compare similar out-comes. A transition period is necessary for teams to anonymously review their results, allowing for corrective actions.

5. Conclusions

A standardized set of patient-centered outcome measures for liver cancers has been developed to facilitate international health outcomes comparisons and quality-of-care evaluations. Implementing tools that measure both clinical treatment response parameters and patient-reported outcomes in clinical research and routine practice is a step towards ensuring effective care to every patient, regardless of their circumstances. The key elements for the success of this approach are education, clarity, transpar-ency, and continuous improvement. This necessary approach is essential to maintain the sustainability of healthcare systems. The process of collecting the validated outcomes set for hepatic carcinoma is cur-rently underway in our digestive department, with plans to expand to other centers.

Author contributions

Conceptualization, Z.C., E.L., B.D., C.L. and P.P.; methodology, Z.C., E.L., B.D., C.L. and P.P.; software, Z.C., E.L., B.D. and C.L.; validation, Z.C., E.L., B.D., G.G., V.C., S.M., C.B., E.M., E.B., S.B., F.G.C., A.K., C.L. and P.P.; formal analysis, Z.C., E.L., B.D. and C.L.; investigation, Z.C., E.L., B.D. and C.L.; resources, Z.C., E.L., B.D. and C.L.; data curation, Z.C., E.L., B.D. and C.L.; writing—original draft preparation, Z.C., E.L., B.D., C.L. and P.P.; writing—review and editing, Z.C., E.L., B.D., G.G., V.C., S.M., C.B., E.M., E.B., S.B., F.G.C., F.A., A.K., C.L. and P.P.; visualization, Z.C., E.L., B.D., C.L. and P.P.; supervision, Z.C., C.L. and P.P.; project administration, Z.C., E.L., B.D., C.L. and P.P.; funding acquisition, E.L., B.D., and C.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by French state funds managed within the “Plan Investissements d’Avenir” and by the ANR (reference ANR-10-IAHU-02).

Research agreement between IHU & Medtronic : IHU pays a Medtronic translational team for data collection.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Conflicts of interest

The authors declare no conflict of interest.

Discloser

The abstract was presented at the 27^th Annual Conference of the International Society for Quality of Life.

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