Review
Copyright ©The Author(s) 2017.
World J Hepatol. Jul 18, 2017; 9(20): 867-883
Published online Jul 18, 2017. doi: 10.4254/wjh.v9.i20.867
Table 1 Health related quality of life instruments commonly used in hepatocellular carcinoma studies
General instruments
European Organization for Research and Treatment of Cancer QLQ-C30EORTC QLQ-C30 is a general cancer instrument containing multiple items, measured in multiple-point Likert scales, that reflect the multidimensionality of HRQOL construct[15]. It includes five functional domains (physical, role, cognitive, emotional and social), three symptom domains (fatigue, pain, nausea/vomiting), and a global health and QOL domain. Six single items assess common symptoms in cancer patients (dyspnea, appetite loss, sleep disturbance, constipation and diarrhea) and financial problem. All scales and domains are transformed to scores ranging from 0 to 100. A lower score for a functional or global QOL scale reflects a relatively poorer functioning level or global QOL, a higher score for a symptom/problem scale reflects a more disturbing symptom/problem
Functional Assessment of Cancer Therapy - GeneralThe FACT-G questionnaire is a commonly used tool for HRQOL assessment in general cancer patients[16]. It consists of 27 items for assessment of symptoms and four domains of HRQOL: (1) physical well being (PWB) containing seven items with a subscale score ranging from 0 to 28 points; (2) socio-family well being (SFWB) containing seven items with a subscale score of 0-28 points; (3) emotional well being (EWB) containing six items with a subscale score of 0-24 points; and (4) functional well being (FWB) containing seven items with a subscale score of 0-28 points. Patients were asked to score each item according to how true each statement was to them during the past week on a 5-point ordinal scale, from 0 indicating “not at all” to 4 indicating “very much”. The FACT-G total score is the summation of the four subscales (PWB, FWB, SFWB and EWB) scores and can range from 0 to 108. Higher scores reflect better HRQOL
Spitzer Quality of Life Index (Spitzer QoL index)Spitzer QoL index is a general cancer HRQOL measurement[17]. A score of 0 (worst QOL) to 10 (best QoL) was calculated after the patient answered five items of the questionnaire in the areas of activity, daily life, health perceptions, social support and behavior. Each item is rated on a 3-point Likert scale
Short form 36SF-36 is a general disease questionnaire to measure the following 8 domains of health: General health, bodily pain, social functioning, role-physical, physical functioning, vitality, role-emotional and mental health[18]. The raw scores of each subscale are converted to scores that range from 0 to 100, with higher scores indicating higher levels of functioning or well being. Scores representing overall physical functioning and mental functioning were calculated from the subscales and are grouped as the physical component summary scale and mental component summary scale
Short form 12SF-12 is a shortened version of SF-36. It contains a 12-item generic measure of health status developed from SF-36[19]. It also yields scores for eight domains: Physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. It likewise provides overall summaries of the physical and mental components
World Health Organization Quality of Life Assessment 100The WHOQOL-100 questionnaire comprises of 100 items grouped into 25 facets[20]. One of the facets measures overall quality of life/health. The remaining 24 facets are organized in 6 domains: (1) physical health; (2) psychological health; (3) level of independence; (4) social relationships; (5) environment; and (6) spirituality/religion/personal beliefs. Each facet includes four items, rated on a 5-point Likert scale, with higher scores indicating more positive evaluations. Domain and facet raw scores can also be transformed onto a 0 to 100 scale. Higher scores denote higher HRQOL
World Health Organization Quality of Life Assessment abbreviated versionThe original 6-domain structure of WHOQOL-100 was subsequently reduced into 4 comprehensive domains by the WHOQOL Group, comprising: (1) physical health (merging the level of independence domain); (2) psychological health (merging the spirituality/religion/personal beliefs domain); (3) social relationships; and (4) environment[21]. It contains a total of 26 questions. Attributes incorporated within the physical health domain of the WHOQOL-BREF include: activities of daily living, dependence on medicines or medical aids, energy and fatigue, mobility, pain and discomfort, sleep and rest and work capacity. Attributes incorporated within the psychological health domain are: body image and appearance, negative and positive feelings, self-esteem, spirituality, religion and personal beliefs, thinking, learning, memory and concentration. Measurements of social health domain include personal relationships, social support and sexual activity. Features incorporated in the environmental health domain are: Financial resources, freedom, physical safety and security, health and social care, home environment, opportunities for acquiring the new information and skills, participation in and opportunities for recreation, physical environment and transportation. Higher scores denote higher HRQOL
EuroQoL-5DEQ-5D is a general disease instrument for describing and valuing HRQOL developed by the EuroQoL Group[22,23]. The questionnaire consists of 2 sections: The EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system contains one question in each of the 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). In the 3-point Likert version (EQ-5D-3L), each question has three levels of response: No problems, some problems or extreme problems. A specific value (weight) is attached to each response of each question according to that country’s specific value sets. Studies have been conducted to elicit preferences from general population samples to derive these value sets. A summary score is calculated by deducting all values of the 5 responses from the full mark of 1. A summary score of 1 represents perfect health, 0 represents death, below 0 represents a state being worse than dead. This summary score could be used for quality adjusted life-year (QALY) calculations. Thus EQ-5D is an important tool for economic valuation. The EQ VAS lets the respondent place an “x” on a vertical VAS to reflect his/her self rated health. The endpoints are labeled "best imaginable health state" at 100 and "worst imaginable health state" at 0
Liver-cancer specific instruments
European Organization for Research and Treatment of Cancer QLQ-HCC18EORTC QLQ-HCC18 includes eighteen multiple item scales organized into six domains (fatigue, body image, jaundice, nutrition, pain and fever) and two items (abdominal swelling and sex life)[24]. All scales are grouped and transformed to score ranging from 0 to 100. A lower score represents a less severe symptom/problem. EORTC QLQ-HCC18 is used together with EORTC QLQ-C30
Functional Assessment of Cancer Therapy-HepatobiliaryThe FACT-Hep questionnaire is a 45-item instrument for measuring HRQOL in patients with hepatobiliary cancers (liver, bile duct and pancreas)[25]. FACT-Hep is used together with FACT-G. It consists of the 27 items (PWB, FWB, SFWB and EWB domains) in FACT-G together with an 18-item disease-specific hepatobiliary cancer subscale (HepCS) which address specific symptoms of hepatobiliary carcinoma, such as back/stomach pain, gastrointestinal symptoms, anorexia, weight loss, jaundice, as well as side-effects of treatment. An aggregate HepCS score could be obtained. The FACT-G and HepCS scores are summed to form the FACT-Hep total score. Higher scores on all scales of the FACT-Hep reflect better HRQOL or fewer symptoms
Functional Assessment of Cancer Therapy-Hepatobiliary Symptom IndexFHSI-8 is a subset of FACT-Hep. It includes eight items from the FACT-Hep that measure specific symptoms of patient priority concern and side effects of hepatobiliary carcinoma[26]. Higher scores on all items of the FHSI-8 reflect fewer symptoms
Trial Outcome IndexTOI is also a subset of FACT-Hep. It consists of the summation of the PWB, FWB and HepCS subscales[25]. Higher scores reflect better HRQOL and fewer symptoms
Table 2 Clinical studies in hepatocellular carcinoma that involved health related quality of life assessment
Ref.YearStudy typenHCC statusIntervention(s)HRQOL instruments usedHRQOL assessment time point(s)Remarks
Poon et al[34]2001Cohort76Resectable and unresectableResection (66) vs TACE (10)FACT-GBaseline, 3, 6, 7, 12, 18 and 24 moObservational study with QOL assessment during treatment
Brans et al[40]2002Cohort26UnresectableSIRT (14) vs TACE (14)EORTC QLQ-C30Baseline, 1 and 3 moObservational study with QOL assessment during treatment
Bianchi et al[32]2002Case-control101Any stageNASF-36BaselineTo describe symptomatology and/or HRQOL of HCC patients -HRQOL of HCC patients compared to 202 matched cirrhotic patients
Chow et al[59]2002Phase III trial329UnresectableTamoxifen 120 mg/d (121) vs tamoxifen 60 mg/d (76) vs placebo (132)Global QOL domain of EORTC QLQ-C30Baseline, then every 1 moPhase III trial with HRQOL endpoint
Steel et al[46]2004Cohort28Allocated to SIRT or TACESIRT (14) vs TACE (14)FACT-Hep, HepCS, TOI, FHSI8Baseline, 3, 6 and 12 moObservational study with QOL assessment during treatment. Included in[97]
Poon et al[47]2004Randomized phase II trial88Allocated to TACEBranched chained amino acid vs controlFACT-GBaseline, 3, 6, 9 and 12 moPhase II trial with HRQOL endpoint
Steel et al[84]2005Cohort82Any stageVarious treatmentsFACT-Hep, HepCS, TOI, FHSI8Baseline, 3 and 6 moTo describe symptomatology and/or HRQOL of HCC patients -Compared HRQOL between patients and proxy-raters. Included in[97]
Steel et al[96]2005Case-control21TNM stage III or IVNAFACT-Hep, Sexual History QuestionnaireBaselineTo describe symptomatology and/or HRQOL of HCC patients - Included 23 patients with chronic liver disease
Barbare et al[58]2005Phase III trial420Not eligible for resection or local treatmentTamoxifen (210) vs control (210)Spitzer QoL indexBaseline, then every 3 moPhase III trial with HRQOL endpoint
Kirchhoff et al[48]2005Randomized phase II trial70Eligible for TACETACE with microspheres (35) vs TACE (35)Global QOL of EORTC QLQ-C30Baseline, then every 6 moPhase II trial with HRQOL endpoint
Steel et al[97]2006Combined analysis of 3 studies157Mixed patient populations from 3 studiesVarious treatmentsFACT-Hep, HepCS, TOI, FHSI8Baseline, 3 and 6 moObservational study with QOL assessment during treatment - evaluates minimally important difference in HRQOL
Eid et al[36]2006Cohort7Allocated to hepatic ablation or resectionHepatic ablation (3) vs resection (4)EORTC QLQ-C30, FACT-Hep, FHSI8, Profile of Mood States (POMS)Baseline, postoperative visit, 1.5, 3 and 6 moObservational study with QOL assessment during treatment. Study included other liver tumor types (33 patients)
Yeo et al[65]2006Combined analysis of 2 phase III trials233Unresectable or metastaticChemotherapy, hormonal therapyEORTC QLQ-C30BaselineAs prognostic tools for overall survival - baseline HRQOL was prognostic of overall survival in advanced HCC
Wang et al[98]2006Cohort83Non-metastatic, 3 nodules or lessTACE + RFA (43) vs TACE (40)FACT-GBaseline, 3 moObservational study with QOL assessment during treatment
Cebon et al[49]2006Phase I/II trial63Not eligible for standard therapiesOctreotide long acting releaseFACT-Hep, patient disease and treatment assessment form (Pt DATA form), patient benefit formBaseline, then every 1 moPhase I/II trial with HRQOL endpoint
Llovet et al[12]2006Phase III trial602Not eligible for local treatment or had disease progression after surgery or local treatmentSorafenib (299) vs placebo (303)FHSI-8Baseline then every 3 wkPhase III trial with HRQOL endpoint
Lee et al[31]2007Case control161Any stageSurgical, TACE, percutaneous ethanol injection, supportive careEORTC QLQ-C30, WHOQOL-BREFCross sectional one-time assessmentTo describe symptomatology and/or HRQOL of HCC patients - compared with national matched healthy controls
Kondo et al[37]2007Case-control97Non-metastatic, 3 nodules or lessPercutaneous ablationSF-36BaselineTo describe symptomatology and/or HRQOL of HCC patients - HRQOL compared to 97 matched chronic liver disease controls, and normal population values
Steel et al[33]2007Case-control83Any stageNAFACT-HepBaselineTo describe symptomatology and/or HRQOL of HCC patients - HRQOL compared to 51 matched chronic liver disease controls, and 138 controls from general population
Martin et al[35]2007Cohort4ResectableResectionEORTC QLQ-C30, FACT-Hep, FHSI-8Baseline, discharge, postoperative visit, 1.5, 3, 6 and 12 moObservational study with QOL assessment during treatment. Included 28 patients with other liver tumors
Becker et al[50]2007Randomized phase II trial120Not eligible for resection or local treatmentOctreotide (61) vs placebo (59)EORTC QLQ-C30Baseline, 1, 3 mo, then every 3 moPhase II trial with HRQOL endpoint
Dimitroulopoulos et al[51]2007Randomized phase II trial127Advanced stage. Somatostatin receptor overexpression for randomisationOctreotide (31) vs placebo (30) observation (66)EORTC QLQ-C30Baseline then every 1 moPhase II trial with HRQOL endpoint
Sun et al[99]2008Cohort22Mainly advanced diseaseVarious treatmentsFACT-Hep, Functional assessment of chronic illness therapy spirituality subscale (FACIT-Sp-12 )Baseline, 1, 2 and 3 moObservational study with QOL assessment during treatment. Included 23 patients with pancreatic cancer
Méndez Romero et al[52]2008Phase I/II trial9Not eligible for other local treatmentsSBRTEORTC QLQ-C30 EQ-5D VASBaseline, 1, 3 and 6 moObservational study with QOL assessment during treatment. Included 19 patients with liver metastases. Phase I/II trial with HRQOL endpoint
Bonnetain et al[66]2008Combined analysis of 2 phase III trials[59,101]538Not eligible for resection, transplantation or percutaneous ablationTamoxifen vs supportive care; TACE + tamoxifen vs tamoxifenSpitzer QoL indexBaselineAs prognostic tools for overall survival - baseline HRQOL was prognostic of overall survival in advanced HCC
Doffoël et al[100]2008Phase III trial138Eligible for TACETACE + tamoxifen (70) vs tamoxifen (68)Spitzer QoL indexBaseline, then every 2 mo during treatment, every 3 mo after treatmentPhase III trial with HRQOL endpoint
Barbare et al[60]2009Phase III trial272Not eligible for curative treatmentOctreotide (135) vs placebo (137)EORTC QLQ-C30Baseline, then every 1 mo during treatment, every 3 mo after treatmentPhase III trial with HRQOL endpoint
Cheng et al[13]2009Phase III trial271Unresectable or metastatic, no prior systemic therapySorafenib (150) vs placebo (76)FHSI-8. Physical well being domain of FACT-HepBaseline then every 3 wkPhase III trial with HRQOL endpoint
Wible et al[44]2010Cohort73Allocated to TACETACESF-36Baseline, 4, 8 and 12 moObservational study with QOL assessment during treatment
Dollinger et al[101]2010Phase III trial135Locally advanced or metastaticThymostimulin (67) vs placebo (68)FACT = HepBaseline then every 3 moPhase III trial with HRQOL endpoint
Chow et al[61]2011Phase III trial204Advanced disease, not eligible for standard therapiesMegestrol acetate (195) vs placebo (69)EORTC QLQ-C30Baseline, then every 1 mo during treatment, then every 3 mo after treatment completedPhase III trial with HRQOL endpoint
Shun et al[102]2012Cohort89Allocated to TACETACESF-12, Symptom Distress Scale, Hospital Anxiety and Depression Scale3 d before discharge, 1 and 2 moObservational study with QOL assessment during treatment
Qiao et al[103]2012Observational140Any stageNANANAdadsdfsaNAFACT-epHHepBaselineTo describe symptomatology and/or HRQOL of HCC patients - HRQOL worsens with advancing stage
Eltawil et al[45]2012Cohort48Allocated to TACETACEWHOQOL-BREFBaseline then every 3-4 moObservational study with QOL assessment during treatment
Fan et al[104]2012Cross sectional286Any stageEORTC QLQ-C30, EORTC QLQ-HCC18BaselineTo describe symptomatology and/or HRQOL of HCC patients - HRQOL compared with population norms. Correlation between HRQOL and coping and illness perception
Diouf et al[67]2013Reanalysis of a phase III trial[61]215Not eligible for curative treatment, baseline HRQOL data availableOctreotide vs placeboEORTC QLQ-C30BaselineAs prognostic tools for overall survival - baseline HRQOL was prognostic of overall survival in advanced HCC. HRQOL data may improve existing staging systems
Soliman et al[53]2013Phase II trial21Not eligible for or refractory to standard therapies, symptomaticLiver radiotherapyEORTC QLQ-C30, FACT-Hep, HepCS, TOI, FACT-GBaseline, 1, 3 and 6 moPhase II trial with HRQOL endpoint. Included 20 patients with liver metastasis
Salem et al[41]2013Cohort56Allocated to SIRT or TACESIRT (29), TACE (27)FACT-HepBaseline, 2 and 4 wkObservational study with QOL assessment during treatment
Brunocilla et al[105]2013Cohort36Allocated to sorafenibSorafenibFACT-Hep, FHSI-8, FACT-GBaseline, 1 wk, 1 and 2 moObservational study with QOL assessment during treatment
Johnson et al[62]2013Phase III trial1150Not eligible for resection or local treatment, no prior systemic treatmentBrivanib (577) vs sorafenib (578)Physical function and role function of EORTC QLQ-C30Baseline then every 6 wkPhase III trial with HRQOL endpoint
Meyer et al[63]2013Phase II/III trial86Unresectable, non-metastaticTACE vs TAEEORTC QLQ-C30, EORTC QLQ-HCC18Baseline, 1.5, 3 and 6 moPhase II trial with HRQOL endpoint
Mise et al[106]2014Cohort69Allocated to resectionResectionSF-36Baseline then every 3 moObservational study with QOL assessment during treatment
Huang et al[38]2014Cohort388Solitary HCC ≤ 3 cmResection, radiofrequency ablationFACT-Hep, HepCS, TOI, FACT-GBaseline, 3, 6, 12, 24 and 36 moObservational study with QOL assessment during treatment
Zhu et al[64]2014Phase III trial564Progressive disease during or after sorafenibEverolimus (362) vs placebo (184)Global QOL and physical function of EORTC QLQ-C30Baseline, then multiple reassessmentsPhase III trial with HRQOL endpoint
Palmieri et al[107]2015Case control24Any stageNASF-36BaselineTo describe symptomatology and/or HRQOL of HCC patients - evaluates relationship between psychological profile and HRQOL in HCC. Included 22 cirrhotic patients without HCC, 20 control subjects
Chie et al[108]2015Cohort171Allocated to respective treatmentsSurgery (53), ablation (53), TACE (65)EORTC QLQ-C30, EORTC QLQ-HCC18Baseline, then 4-6 wk for post-ablation/post-TACE, 12-15 wk post-operationObservational study with QOL assessment during treatment
Heits et al[109]2015Cross sectional173Allocated to liver transplanationliver transplantationEORTC QLQ-C30At one variable time point post-transplantionTo describe symptomatology and/or HRQOL of HCC patients
Xie et al[110]2015Cohort102Allocated to resection or TACEresection (58), TACE (44)SF-36Baseline, 1, 3, 6, 12 and 24 moObservational study with QOL assessment during treatment
Xing et al[111]2015Cohort118Allocated to TACETACE with doxorubicin eluted beadsSF-36Baseline, 1-3, 6 and 12 moObservational study with QOL assessment during treatment
Kolligs et al[54]2015Randomized phase II trial28Allocated to SIRT or TACESIRT (13), TACE (15)FACT-HepBaseline, then every 6 wkPhase II trial with HRQOL endpoint
Klein et al[42]2015Combined analysis of prior phase I/II trials98Allocated to SBRTSBRTEORTC QL-C30, FACT-HepBaseline, 1, 3, 6 and 12 moPhase I/II trial with HRQOL endpoint
Kensinger et al[48]2016Case-control139Allocated to priority liver transplantationLiver transplantationSF-36Baseline, post transplantationObservational study with QOL assessment during treatment - included 362 subjects without HCC
Lei et al[39]2016Cohort205Allocated to resection or transplantationLiver transplantation (110), resection (95)SF-36Baseline, then every 1-2 mo for the first 6 mo, then every 2-3 mo for the next 6 mo, then every 6 moObservational study with QOL assessment during treatment
Yang et al[112]2016Cohort17Portal vein thrombosisTACE and transarterial ethanol ablationEORTC QLQ-C30Baseline then every 1 moObservational study with QOL assessment during treatment
Anota et al[55]2016Phase I trial21Not eligible for curative treatmentTACE with idaurubicin eluted beadsEORTC QLQ-C30Baseline, 15, 30 and 60 dPhase I trial with HRQOL endpoint
Chie et al[88]2016Case-control227Any stageVarious treatmentsEORTC QLQ-C30, EORTC QLQ-HCC18Baseline, post-treatmentObservational study with QOL assessment during treatment - Compared HRQOL between Asian and European HCC patients
Lv et al[56]2016Randomized phase II trial120Allocated to TACECOX2 inhibitor (60) vs placebo (60)Locally developed questionnaireBaseline, 24 and 48 hPhase II trial with HRQOL endpoint
Koeberle et al[57]2016Randomized phase II trial106Unresectable or metastaticSorafenib + everolimus (60) vs sorafenib (46)FACT-HepCS, EQ-VASBaseline, then every 2 wk until week 12Phase II trial with HRQOL endpoint
Shomura et al[113]2016Cohort54TNM stage IVSorafenibSF-36Baseline, then every 3 moObservational study with QOL assessment during treatment
Bruix et al[14]2016Phase III trial573Progressive disease during sorafenibRegorafenib (379) vs placebo (193)FACT-Hep, TOI, FACT-G, EQ-5D, EQ-VASBaseline, then multiple reassessmentsPhase III trial with HRQOL endpoint
Li et al[69]2017Cohort472Any stageVarious treatmentsEORTC QLQ-C30, EORTC QLQ-HCC18, C30 index score, HCC18 index scoreBaselineAs prognostic tools for overall survival - baseline HRQOL was prognostic of overall survival in advanced HCC. QOL derived scoring system resembles a staging system
Table 3 Algorithm of C30 and HCC18 index scores
QOL Index scores for survival prognostication
C30 index score∑ [(100-Physical functioning), (100-Role functioning), (100-Emotional functioning), (100-Cognitive functioning), (100-Social functioning), (100-global QOL), scores of Fatigue, Nausea/vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, Constipation, Diarrhea, Financial Difficulty]/15
HCC18 index score∑(scores of Fatigue, Body Image, Jaundice, Nutrition, Pain, Fever, Sex life, Abdominal distension)/8