Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Prognostic values of EORTC QLQ-C30 and QLQ-HCC18 index-scores in patients with hepatocellular carcinoma – clinical application of health-related quality-of-life data

  • Leung Li1,
  • Frankie KF Mo1,
  • Stephen L Chan1,
  • Edwin P Hui1,
  • Nelson SL Tang4,
  • Jane Koh1,
  • Linda KS Leung1,
  • Annette NY Poon1,
  • Joyce Hui2,
  • Cheuk M Chu2,
  • Kit F Lee3,
  • Brigette BY Ma1,
  • Paul BS Lai3,
  • Anthony TC Chan1,
  • Simon CH Yu2 and
  • Winnie Yeo1Email author
BMC Cancer201717:8

https://doi.org/10.1186/s12885-016-2995-5

Received: 8 January 2016

Accepted: 13 December 2016

Published: 4 January 2017

Abstract

Background

Health-related quality-of-life (HRQOL) assessment with EORTC QLQ-C30 was prognostic for overall survival (OS) in patients with advance-stage hepatocellular carcinoma (HCC), but no data existed for early-stage patients. The HCC-specific QLQ-HCC18 has not been evaluated for prognostic value in HCC patients. Utilization of raw HRQOL data in clinical setting has been impractical and non-meaningful. Therefore we developed index scores of QLQ-C30 and QLQ-HCC18 in an attempt to enable clinical utilization of these HRQOL measurements. This study investigates the prognostic significance of QLQ-C30, QLQ-HCC18 and C30/HCC18 index-scores in patients with newly diagnosed HCC which encompasses all stages.

Methods

From 2007–2011, 517 patients were prospectively recruited. HRQOL was assessed at diagnosis using QLQ-C30 and QLQ-HCC18; C30 and HCC18 index-scores were calculated from raw HRQOL data. Cox regression was performed using continuous, dichotomized QLQ-C30 and QLQ-HCC18 variables, or index-scores, together with clinical factors to identify independent factors for OS. Various multivariate models were validated with c-index and bootstrapping for 1000 replications.

Results

Four hundred and seventy two patients had complete HRQOL data. Their median OS was 8.6 months. In multivariate analysis, independent prognostic HRQOL variables for OS were QLQ-C30 pain (HR 1.346 [1.092–1.661], p = 0.0055), QLQ-C30 physical functioning (HR 0.652 [0.495–0.860], p = 0.0024); QLQ-HCC18 pain (HR 1.382 [1.089–1.754], p = 0.0077) and QLQ-HCC18 fatigue (HR 1.441 [1.132–1.833], p = 0.0030). C30 index-score (HR 2.143 [1.616–2.841], p < 0.0001) and HCC18 index-score (HR 1.957 [1.411–2.715], p < 0.0001) were highly significant factors for OS. The median OS of patients with C30 index-score of 0–20, 21–40, 41–60, 61–100 were 16.4, 7.3, 3.1, 1.8 months respectively (p < 0.0001); while for HCC18 index-score: 16.4, 6.0, 2.8, 1.8 months respectively (p < 0.0001). All the multivariate models were validated, with mean optimism <0.01. The bootstrap validated c-index was 0.78.

Conclusions

QLQ-C30 and QLQ-HCC18 were prognostic for OS in patients with newly diagnosed HCC irrespective of stage. Both C30 and HCC18 index-scores were highly significant prognostic factors for OS in newly diagnosed HCC patients. Index-scoring provides an effective way to summarize, analyze and interpret raw HRQOL data, and renders QLQ-C30 and QLQ-HCC18 meaningful and communicable in clinical practice. Index-scores could potentially serve as a standardized tool for future HRQOL research.

Keywords

Health-related quality-of-life QLQ-HCC18 QLQ-C30 Index-score Prognosis Overall survival Hepatocellular carcinoma Liver cancer

Background

Three studies have shown health-related quality-of-life (HRQOL) being prognostic for overall survival (OS) in patients with advance-stage hepatocellular carcinoma (HCC) [13]. These used general cancer HRQOL measurement tools, namely the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [4] and Spitzer QOL index [5]. On the other hand, one negative study recruited both early- and advance-stage HCC patients and used another general cancer HRQOL measurement, Functional Assessment of Cancer Therapy – General (FACT-G) [6, 7]. To date, there has been no study evaluating the prognostic value of QLQ-C30 for patients with newly diagnosed HCC which encompasses all stages.

Patients with HCC often suffer from chronic liver disease. In Asia, this is mainly due to chronic hepatitis B virus (HBV) infection [810]. Therefore liver-specific HRQOL measurement could be more relevant for these patients. EORTC QLQ-HCC18 [11] is a specific HRQOL module which addresses QOL issues specific for patients with primary liver cancer. It has been validated in Asian HCC patients [12, 13] and many scales of QLQ-HCC18 have been reported to enable the identification of patients with different clinical conditions. However, the prognostic value of EORTC QLQ-HCC18 in HCC patients has not been evaluated.

So far it has been a common practice to analyze raw HRQOL data as a collection of continuous variables, and various HRQOL factors have been proven to be prognostic for survival in various malignancies. Despite the wide utilization of EORTC QLQ-C30, there has been no domain/item identified to be consistently prognostic [14]. Difficulties in HRQOL research were well recognized: multi-collinearity among numerous raw HRQOL data causing multivariate analysis model instability, overfitting of variables leading to excessive multiple comparisons and type I error [14, 15], and lack of means to meaningfully translate raw HRQOL data into clinical use. Diouf et al. dichotomized all HRQOL data at a universal cut-off at 50 for analysis. This addressed the issues of multi-collinearity and overfitting and provided a way to interpret HRQOL data by clinicians [3]. A separate analysis was performed to determine the true cut-off for various domains/items, and these cut-offs have been considered to be potentially population-specific [16].

In an attempt to determine a generalizable way to analyze and interpret HRQOL data while minimizing multi-collinearity and over-fitting, we derived two index-scores, namely the C30 and HCC18 index-scores, to represent all domains and items within the EORTC QLQ-C30 and QLQ-HCC18 respectively.

The objectives of this study are: (1) to evaluate the prognostic value of QLQ-C30 in a prospective cohort of newly diagnosed patient with HCC which encompasses all stages; (2) to investigate the prognostic significance of the liver-specific QLQ-HCC18 in this cohort; and (3) to evaluate the prognostic significance of C30 and HCC18 index-scores.

Methods

From January 2007 to December 2011, all patients with newly diagnosed HCC presented to the multidisciplinary hepatoma clinic of Prince of Wales Hospital were considered for recruitment. The study was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee.

Eligibility criteria included: adult patients with newly diagnosed and treatment-naïve HCC; the diagnosis of HCC as confirmed by either histology, the combination of radiological and biochemical findings (space-occupying lesion in the liver with raised α-fetoprotein (AFP ≥ 400ug/L), or 2 typical radiological findings with ultrasonography, triphasic computed tomography, angiography or magnetic resonance imaging; ability to read and comprehend Chinese was a pre-requisite. Patients were excluded if they had history of malignancy, encephalopathy or cognitive impairment.

Treatment

After confirmation of diagnosis and stage, patients were offered appropriate treatment as clinically indicated. Treatment options included surgical resection, local ablative therapies – radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), transarterial therapies - transarterial chemo-embolisation (TACE) or transarterial injection of lipiodol-ethanol mixture (LEM), systemic therapies – sorafenib, chemotherapy, clinical trials and best supportive care (BSC) alone.

HRQOL assessment

Consented patients would complete two HRQOL questionnaires: the EORTC QLQ-C30 and QLQ-HCC18, at their baseline visit before treatment commencement.

EORTC QLQ-C30

The Chinese version of QLQ-C30 was used [4]. It is a cancer-specific 30-item questionnaire composed of multiple items that reflect the multidimensionality of HRQOL construct, presented in multiple-point Likert scales. These items are grouped into 9 domains and 6 single items. It incorporates 5 functional domains (physical, role, cognitive, emotional and social), 3 symptom domains (fatigue, pain, nausea and vomiting) and a global health and QOL domain. The remaining 6 single items assess additional 5 symptoms commonly reported by cancer patients (dyspnea, appetite loss, sleep disturbance, constipation and diarrhea) as well as perceived financial problem. All domains and scales were converted to scores ranging from 0 to 100 according to the scoring manual [17]. A higher score for a functional or global QOL scale represents a relatively higher/healthier level of functioning or global QOL, whereas a higher score for a symptom/problem scale represents a more severe symptom/problem.

EORTC QLQ-HCC18

The Chinese version of EORTC QLQ-HCC18 [11] includes 18 multi-item scales. These items are grouped into 6 domains namely fatigue, body image, jaundice, nutrition, pain and fever. Two remaining single items address abdominal swelling and sex life. All scales were grouped and converted to score 0 to 100 according to the scoring manual; a higher score represents a more severe symptom or problem.

C30 and HCC18 index-scores

C30 and HCC18 index-scores were derived in order to have an overall representation of all domains/items in QLQ-C30 and QLQ-HCC18 respectively.

To calculate C30 index-score, individual functioning scale was subtracted by 100 to convert them into having the same meaning as symptom/problem scales. These 6 subtracted scores were subsequently summed with the 9 symptom/problem scales, and then divided by 15 (the total number of QLQ-C30 scales). A higher C30 index-score reflects a worse overall HRQOL. This is the mathematical formula:
$$ \begin{array}{l}\mathsf{C}\mathsf{30}\ \mathsf{index}\hbox{-} \mathsf{score}=\varSigma \left[\left(\mathsf{100}\hbox{-} \mathsf{Physical}\ \mathsf{functioning}\right),\Big(\mathsf{100}\hbox{-} \mathsf{Role}\ \mathsf{functioning}\right),\left(\mathsf{100}\hbox{-} \mathsf{Emotional}\ \mathsf{functioning}\right),\ \\ {}\left(\mathsf{100}\hbox{-} \mathsf{Cognitive}\ \mathsf{functioning}\right),\ \left(\mathsf{100}\hbox{-} \mathsf{Social}\ \mathsf{functioning}\right),\ \left(\mathsf{100}\hbox{-} \mathsf{global}\ \mathsf{Q}\mathsf{O}\mathsf{L}\right),\ \mathsf{scores}\ \mathsf{of}\ \mathsf{Fatigue},\ \\ {}\mathsf{Nausea}/\mathsf{vomiting},\ \mathsf{Pain},\ \mathsf{Dyspnoea},\ \mathsf{Insomnia},\ \mathsf{Appetite}\ \mathsf{loss},\ \mathsf{C}\mathsf{onstipation},\ \mathsf{Diarrhea},\ \mathsf{Financial}\ \mathsf{Diffculty}\Big] \div \mathsf{15}\end{array} $$
HCC18 index-score was defined as the sum of all 8 QLQ-HCC18 symptom/problem scales divided by 8 (the total number of QLQ-HCC18 scales). A higher HCC18 index-score reflects a worse overall HRQOL. This is the mathematical formula:
$$ \mathsf{H}\mathsf{C}\mathsf{C}\mathsf{18}\mathsf{index}{\textstyle \hbox{-}}\mathsf{score}=\varSigma \left(\mathsf{scoresofFatigue},\mathsf{BodyImage},\mathsf{Jaundice},\mathsf{Nutrition},\mathsf{Pain},\mathsf{Fever},\mathsf{Sexlife},\mathsf{Abdominaldistension}\right)\div \mathsf{8} $$

Clinical factors and follow-up

Demographic, clinical and laboratory parameters were collected. All patients were followed up for treatment and monitoring until death or last contact.

Statistical analysis

Standard descriptive analyses were performed to assess sample characteristics. OS was defined as the time from the date-of-consent to date-of-death. In the absence of death confirmation, survival time was censored at the date-of-last-seen. Survival estimation was performed by the Kaplan-Meier method, and compared using the log-rank test.

Only patients with complete HRQOL data were included in statistical analysis. EORTC QLQ-C30 and QLQ-HCC18 scales were included in the prognostic factor analysis as (i) continuous variables, (ii) dichotomized (≥50 or <50) variables, and (iii) index-scores. Univariate analysis was performed with baseline HRQOL scores and non-overlapping clinical variables to identify factors that influenced survival using Cox proportional-hazards regression model. A stepwise model building procedure was used for multivariate analysis, based on a significance value of 0.05 for both inclusion and exclusion of prognostic factors. For analyses involving continuous variables, higher scores (better function and worse symptoms/problems respectively) were compared to lower scores (worse function or better symptoms/problems); whereas for dichotomized data, symptom/problem domain/item scores of ≥50 (worse scores) were compared to <50 (better scores), while functional domain scores of <50 (worse scores) were compared to ≥50 (better scores).

Treatment options were grouped into curative-intent treatment (surgical/locoablative therapies), palliative-intent treatment (transarterial/systemic therapies) or BSC.

Performance of the final multivariate models were assessed and compared by Harrell’s concordance-index (c-index) [18]. The c-index estimates the probability of concordance between predicted and observed responses. A value of 1.0 indicates perfect separation of patients with different outcomes, and a value of 0.5 indicates no predictive discrimination. Internal validation was carried out by comparing the c-index of each model with the c-indexes of 1000 bootstrap replications to obtain optimisms, which were averaged and bootstrap-corrected performance was estimated.

The statistical analyses were performed using SAS version 9.3 software package. A p-value of less than 0.05 was considered significant. The c-index and 95% confidence intervals (CI) of the different models were calculated by using the SAS macro program.

Results

Patient characteristics

Among the 517 patients who consented, 472 (91%) had complete HRQOL data and were included for analysis. Table 1 listed the clinical characteristics of these patients. The median age at diagnosis was 60, the majority were male (89%). Most patients had Eastern Cooperative Oncology Group (ECOG) performance status 0–1 (94%). HBV infection was present in 82%, while hepatitis C in 6%. Fifty nine percent had cirrhosis and 68% was of Child-Pugh class A. Eighteen percent of patients received first-line curative intent treatment, the rest received palliative treatment (44%) or BSC (38%).
Table 1

Baseline characteristics and univariate Cox regression analyses of overall survival for patients with complete HRQOL data (n = 472)

 

n

%

HR

95% C.I.

p-value

Demographics/clinical

 Age < = 65

328

69

0.909

0.730–1.131

0.3898

 Male gender

419

89

1.299

0.919–1.835

0.1381

 ECOG ≥ 2

29

6

2.885

1.927–4.317

<0.0001

Laboratory

 Hemoglobin <10g/dL

27

6

1.294

0.840–1.995

0.2424

 White cell count >10×109/L

64

14

2.507

1.885–3.333

<0.0001

 Platelet count < 100×109/L

33

7

1.696

1.158–2.485

0.0067

 International normalized ratio >1.4

36

8

1.410

0.945–2.104

0.0922

 Creatinine ≥ ULN

67

14

1.115

0.833–1.491

0.4644

 Bilirubin ≥ 20umol/l

239

51

1.974

1.594–2.445

<0.0001

 Albumin ≤35g/l

182

39

2.186

1.765–2.708

<0.0001

 Alanine aminotransferase >2xULN

81

17

1.567

1.201–2.044

0.0009

 Alkaline phosphatase >2xULN

145

31

2.417

1.938–3.014

<0.0001

Underlying liver condition

 Hepatitis B surface antigen +

386

82

1.196

0.908–1.575

0.2029

 Hepatitis C antibody +

30

6

0.641

0.403–1.019

0.0600

 Ascites

278

59

0.894

0.721–1.107

0.3036

 Cirrhosis (radiological)

122

26

2.237

1.775–2.820

<0.0001

 Child-Pugh class

  A

319

68

1.000

-

-

  B

130

28

2.187

1.740–2.750

<0.0001

  C

23

4

4.360

2.774–6.854

<0.0001

Tumor characteristics

 α-fetoprotein ≥200 mg/ml

250

53

2.318

1.865–2.882

<0.0001

 Tumor morphology

  Uninodular

122

26

1.000

-

-

  Multinodular

143

30

2.097

1.509–2.914

<0.0001

 Diffuse

207

44

4.360

3.027–3.822

<0.0001

 Extrahepatic metastasis (nodal or distant)

108

23

3.003

2.360–3.822

<0.0001

 Portal vein thrombosis

152

32

3.647

2.899–4.587

<0.0001

1st line Treatment

 Curative

83

18

1.000

-

 

 Palliative or best supportive care alone

389

82

5.802

3.820–8.810

<0.0001

 Surgical treatment

54

12

1.000

-

 

 Local ablative therapies

29

6

2.526

1.131–5.643

0.0238

 Trans-arterial therapies

116

25

4.597

2.446–8.637

<0.0001

 Systemic therapies

91

19

10.209

5.380–19.372

<0.0001

 Best supportive care alone

182

38

15.624

8.442–28.914

<0.0001

ECOG Eastern Cooperative Oncology Group performance status, ULN upper limit of normal, CI confidence interval, HR hazard ratio

The median follow-up duration was 29.8 months (95% CI [26.8–32.8]), 377 patients had died. The median OS was 8.6 months (95% CI [7.3–10.2]).

Mean scores of QLQ-HCC18 and QLQ-C30 scales and mean HCC18 and C30 index-scores were listed in Table 2.
Table 2

Baseline HRQOL and univariate analyses using continuous, dichotomized variables, C30 and HCC18 index scores for patients with complete HRQOL data (n = 472)a

 

Mean

±SD

Continuous variables

Dichotomized variablesa

 

HR [95% CI]

p-value

HR [95% CI]

p-value

EORTC QLQ-C30

 Physical Functioning

72.27

23.74

0.432 [0.351–0.533]

<0.0001

2.026 [1.571–2.612]

<0.0001

 Role Functioning

74.61

32.60

0.517 [0.443–0.603]

<0.0001

2.108 [1.645–2.702]

<0.0001

 Emotional Functioning

70.67

25.48

0.777 [0.632–0.954]

0.0164

1.448 [1.100–1.908]

0.0084

 Social Functioning

76.80

24.68

0.698 [0.571–0.853]

0.0004

1.611 [1.162–2.234]

0.0042

 Cognitive Function

68.46

30.33

0.634 [0.531–0.756]

<0.0001

1.573 [1.233–2.007]

0.0003

 Global Quality of Life

52.22

26.34

0.515 [0.417–0.635]

<0.0001

1.611 [1.299–1.998]

<0.0001

 Fatigue

42.93

30.23

1.973 [1.657–2.349]

<0.0001

2.072 [1.672–2.568]

<0.0001

 Nausea/Vomiting

11.26

21.41

2.050 [1.643–2.559]

<0.0001

2.308 [1.679–3.173]

<0.0001

 Pain

32.87

31.97

1.865 [1.584–2.197]

<0.0001

2.108 [1.698–2.617]

<0.0001

 Dyspnoea

29.73

31.46

1.396 [1.189–1.639]

<0.0001

1.666 [1.314–2.113]

<0.0001

 Insomnia

41.88

36.41

1.344 [1.162–1.556]

<0.0001

1.415 [1.144–1.750]

0.0014

 Appetite loss

32.34

35.88

1.923 [1.668–2.217]

<0.0001

2.360 [1.889–2.949]

<0.0001

 Constipation

16.67

27.13

1.201 [0.999–1.444]

0.0512

1.368 [1.021–1.834]

0.0359

 Diarrhea

16.45

26.87

1.520 [1.252–1.845]

<0.0001

1.666 [1.248–2.224]

0.0005

 Financial difficulties

51.20

37.22

1.353 [1.169–1.566]

<0.0001

1.579 [1.276–1.954]

<0.0001

 C30 index score

30.69

19.61

3.658 [2.726–4.909]

<0.0001

-

-

EORTC QLQ-HCC18

 Fatigue

35.23

25.86

2.381 [1.942–2.919]

<0.0001

2.484 [1.968–3.136]

<0.0001

 Body Image

25.35

22.98

2.261 [1.819–2.811]

<0.0001

2.167 [1.718–2.733]

<0.0001

 Jaundice

23.41

22.15

1.289 [1.024–1.623]

0.0307

1.271 [0.977–1.652]

0.0739

 Nutrition

26.96

21.35

2.934 [2.317–3.716]

<0.0001

2.663 [2.026–3.502]

<0.0001

 Pain

23.34

24.57

2.107 [1.717–2.587]

<0.0001

1.871 [1.465–2.391]

<0.0001

 Fever

6.60

14.39

1.568 [1.123–2.187]

0.0081

1.697 [0.929–3.099]

0.0851

 Sex life

28.74

34.76

1.213 [1.040–1.415]

0.0139

1.436 [1.128–1.828]

0.0033

 Abdominal swelling

33.33

35.43

1.721 [1.486–1.994]

<0.0001

2.192 [1.752–2.743]

<0.0001

 HCC18 index score

25.37

17.21

3.028 [2.340–3.919]

<0.0001

-

-

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 Diffculty] ÷ 15

HCC18 index-score = ∑ (scores of Fatigue, Body Image, Jaundice, Nutrition, Pain, Fever, Sex life, Abdominal distension) ÷ 8

aIn dichotomization, worse (≥50 in symptoms/problem or <50 in functioning/global QOL) scores in QLQ-C30 were analyzed with respect to better scores; worse (≥50) scores in QLQ-HCC18 were analyzed with respect to better scores

SD standard deviation, CI confidence interval, HR hazard ratio, HRQOL health-related quality of life

Univariate analysis of HRQOL and clinical factors

Tables 1 and 2 summarized the univariate Cox regression analyses for clinical variables, QLQ-C30 and QLQ-HCC18 scores, as well as C30 and HCC18 index-scores.

Univariate HRQOL analysis based on continuous variables

For QLQ-C30, higher (better) scores in all functioning (e.g. physical functioning, HR 0.432 [0.351–0.533]) or global domains were significantly associated with longer OS (p < 0.03); whereas higher (worse) scores in fatigue, nausea/vomiting, pain (HR 1.865 [1.584–2.197]), dyspnea, insomnia, appetite loss, diarrhea and financial difficulties were significantly associated with shorter OS (p < 0.01).

For QLQ-HCC18, higher (worse) scores in all 8 symptom/problem domains (e.g. fatigue HR 2.381 [1.942–2.919]) were significantly associated with shorter OS (p < 0.05).

Univariate QOL analysis based on dichotomization of scores

For QLQ-C30, scores ≥50 (better) in global QOL, physical, role, cognitive and social functioning and scores <50 (better) in all symptom/problem domains (e.g. financial difficulties HR 1.579 [1.276–1.954]) were significantly associated with longer OS (p < 0.05).

For QLQ-HCC18, scores ≥50 (worse) in fatigue (HR 2.484 [1.968–3.136]), body image, nutrition, pain, sex life, abdominal swelling domains were significantly associated with shorter OS (p < 0.01).

Univariate QOL analysis based on the newly derived index-scores

Higher C30 index-score (reflecting worse overall functions/symptoms/problems) was significantly associated with shorter OS (HR 3.658 [2.726–4.909] p < 0.0001).

Higher HCC18 index-score (reflecting worse overall symptoms/problems) was significantly associated with shorter OS (HR 3.028 [2.340–3.919] p < 0.0001).

Multivariate analysis of HRQOL data with clinical factors

Table 3 shows the results of the multivariate Cox regression analyses involving HRQOL variables or index-scores identified in univariate regression with non-overlapping clinical factors.
Table 3

Multivariate analysis of HRQOL variables or index scores with significant clinical factors (n = 472)

 

Continuous QOL variables

Dichotomized QOL variables

Index score

 

HR

95% CI

p-value

HR

95% CI

p-value

HR

95% CI

p-value

EORTC QLQ-C30

 Physical Functioning

0.652

0.495–0.860

0.0024

1.475

1.095–1.986

0.0106

-

-

-

 Pain

1.346

1.092–1.661

0.0055

1.523

1.192–1.947

0.0008

-

-

-

 Financial difficulties

-

-

-

1.331

1.059–1.673

0.0141

-

-

-

 C30 Index score

-

-

-

-

-

-

2.143

1.616–2.841

<0.0001

 Portal vein thrombosis

1.723

1.342–2.212

<0.0001

1.702

1.325–2.187

<0.0001

1.661

1.291–2.136

<0.0001

 Tumor Morphology – Multinodular

1.604

1.147–2.243

0.0058

1.614

1.152–2.260

0.0054

1.719

1.229–2.403

0.0015

 Tumor Morphology – Diffuse

2.449

1.763–3.401

<0.0001

2.556

1.841–3.550

<0.0001

2.636

1.902–3.651

<0.0001

 Albumin ≤35g/l

1.442

1.125–1.848

0.0039

1.541

1.199–1.981

0.0007

1.641

1.311–2.055

<0.0001

 Bilirubin ≥20umol/l

1.785

1.400–2.275

<0.0001

1.784

1.398–2.277

<0.0001

1.752

1.390–2.208

<0.0001

 α-fetoprotein ≥200 ng/ml

1.830

1.439–2.328

<0.0001

1.878

1.476–2.389

<0.0001

1.749

1.380–2.218

<0.0001

 Extrahepatic metastasis

1.696

1.303–2.209

<0.0001

1.753

1.342–2.288

<0.0001

1.805

1.386–2.351

<0.0001

 Alkaline phosphatase >2xULN

1.456

1.145–1.852

0.0022

1.420

1.116–1.806

0.0043

1.472

1.159–1.870

0.0015

 Creatinine ≥ ULN

1.538

1.129–2.094

0.0063

1.637

1.204–2.227

0.0017

1.712

1.263–2.322

0.0005

 Ascites

1.327

1.015–1.736

0.0385

1.325

1.012–1.734

0.0408

-

-

-

EORTC QLQ-HCC18

 Fatigue

1.441

1.132–1.833

0.0030

1.805

1.411–2.310

<0.0001

-

-

-

 Pain

1.382

1.089–1.754

0.0077

-

-

-

-

-

-

 HCC18 index score

-

-

-

-

-

-

1.957

1.411–2.715

<0.0001

 Portal vein thrombosis

1.701

1.320–2.191

<0.0001

1.672

1.295–2.160

<0.0001

1.688

1.312–2.172

<0.0001

 Tumor Morphology – Multinodular

1.638

1.172–2.289

0.0038

1.709

1.223–2.388

0.0017

1.681

1.203–2.348

0.0024

 Tumor Morphology – Diffuse

2.510

1.805–3.490

<0.0001

2.813

2.034–3.891

<0.0001

2.624

1.893–3.637

<0.0001

 Albumin ≤35g/l

1.684

1.344–2.111

<0.0001

1.704

1.360–2.135

<0.0001

1.666

1.329–2.088

<0.0001

 Bilirubin ≥20umol/l

1.687

1.333–2.134

<0.0001

1.662

1.316–2.100

<0.0001

1.659

1.312–2.098

<0.0001

 α-fetoprotein ≥200 ng/ml

1.744

1.371–2.218

<0.0001

1.805

1.423–2.289

<0.0001

1.735

1.367–2.201

<0.0001

 Extrahepatic metastasis

1.788

1.370–2.334

<0.0001

1.830

1.402–2.389

<0.0001

1.773

1.361–2.309

<0.0001

 Alkaline phosphatase >2xULN

1.426

1.124–1.810

0.0035

1.341

1.054–1.705

0.0169

1.445

1.139–1.832

0.0024

 Creatinine ≥ ULN

1.695

1.249–2.301

0.0007

1.600

1.181–2.167

0.0024

1.701

1.253–2.348

0.0007

ULN upper limit of normal, CI confidence interval, HR hazard ratio, HRQOL health-related quality of life

Multivariate Analysis of clinical factors

Multifocal or diffuse HCC, presence of extra-hepatic metastasis, portal vein thrombosis, hypoalbuminemia, hyperbilirubinemia, high AFP, alkaline phosphatase and creatinine were consistently significant clinical factors associated with shorter OS in all multivariate analyses.

Multivariate HRQOL analysis based on continuous variables

For QLQ-C30, higher (better) score in physical functioning (HR 0.652 [0.495–0.860], p = 0.0024) was significantly associated with longer OS and higher (worse) score in pain (HR 1.346 [1.092–1.661], p = 0.0055) was significantly associated with shorter OS.

For QLQ-HCC18, higher (worse) scores in fatigue (HR 1.441 [1.132–1.833], p = 0.0030) and pain (HR 1.382 [1.089–1.754], p = 0.0077) were significantly associated with shorter OS.

Multivariate QOL analysis based on dichotomization of scores

For QLQ-C30, scores ≥50 (worse) in pain (HR 1.523 [1.192–1.947], p = 0.0008), and financial difficulties (HR 1.331 [1.059–1.673], p = 0.0141) and score <50 (worse) in physical functioning (HR 1.475 [1.095–1.986], p = 0.0106) were significant independent factors for shorter OS.

For QLQ-HCC18, worse fatigue score (≥50) (HR 1.805 [1.411–2.310], p < 0.0001) was significantly associated with shorter OS.

Figure 1 shows the survival of patients with different scores in significant dichotomized HRQOL domains/items. The median OS for patients with better (≥50) and worse (<50) scores in QLQ-C30 physical functioning were 10.1 (95%CI 8.6–12.8) and 2.3 months (95% CI 1.9–4.9) respectively (p < 0.0001). The median OS for patients with better (<50) and worse (≥50) scores in QLQ-C30 pain were 13.4 (95% CI 9.6–16.4) and 3.3 months (95%CI 2.7–4.7) respectively (p < 0.0001), that of QLQ-C30 financial difficulties were 12.8 (95% CI 9.8–15.9) and 5.2 months (95% CI 4.0–7.8) (p < 0.0001) and QLQ-HCC18 fatigue were 12.1 (95% CI 9.8–14.8) and 2.6 months (95% CI 1.9–3.1) (p < 0.0001) respectively.
Fig. 1

Overall survival curves for significant dichotomized HRQOL factors found in multivariate analysis. a QLQ-C30 Physical Functioning <50 vs ≥50. b QLQ-C30 Pain <50 vs ≥50. c QLQ-C30 Financial difficulties <50 vs ≥50. d QLQ-HCC18 Fatigue <50 vs ≥50. Phys: QLQ-C30 Physical functioning; HCC fatigue: QLQ-HCC18 Fatigue; OS: overall survival

Multivariate QOL analysis based on the newly derived index-scores

In the multivariate analysis using C30 index-score with clinical factors, higher (worse) C30 index-score was a significant independent risk factor for shorter OS (HR 2.143 [1.616–2.841], p < 0.0001).

In the multivariate analysis using HCC18 index-score with clinical factors, higher (worse) HCC18 index-score was a significant independent risk factor for shorter OS (HR 1.957 [1.411–2.715], p < 0.0001).

Figure 2 shows the OS plots for patients with stratified C30 and HCC18 index-scores respectively. Lower (better) C30 index-score ranges were associated with longer OS in a step-wise fashion (p < 0.0001); similarly, the lower (better) HCC18 index-score ranges, the longer the OS (p < 0.0001).
Fig. 2

Overall survival curves according to stratified C30 and HCC18 index-scores. a Overall survival curves according to stratified C30 index-score. b Overall survival curves according to stratified HCC18 index-score

The median OS in patients with C30 index-score of 0–20 was 16.4 (95% CI 13.4–22.3) months, that for score 21–40 was 7.3 (95% CI 4.5–10.4) months, score 41–60 was 3.1 (95%CI 2.3–5.1) months, score 61–80 was 1.8 (95% CI 0.8–4.3) months, and score 81–100 was 1.8 (95% CI 0.5–6) months (p < 0.0001). The median OS of patients with HCC18 index-score of 0–20 was 16.4 (95% CI 31-not reached) months, that for score 21–40 was 5.9 (95%CI 4.4–8.9) months, score 41–60 was 2.9 (95% CI 1.6–4.3) months, score 61–80 was 1.8 (95% CI 0.5–3.0) months, and score 81–100 was 1.8 (95% CI 0.7–2.9) months (p < 0.0001) (Table 4).
Table 4

Overall survival data for patients stratified according to C30 and HCC18 index score range (n = 472)

 

N

Median OS (M)

95% CI

Survival% at 6M

Survival% at 12M

Survival% at 24M

Survival% at 36M

C30 Index Score

 0–20

179

16.4

13.4–22.3

79.7

60.4

41.3

25.6

 21–40

153

7.3

4.5–10.4

52.0

39.2

26.0

21.4

 41–60

98

3.1

2.3–5.1

36.5

27.0

18.3

8.1

 61–80

34

1.8

0.8–4.3

27.5

10.7

7.1

7.1

 81–100

8

1.8

0.5–6.0

25.0

-

-

-

HCC18 Index Score

 0–20

213

16.4

31.0-NR

74.6

59.9

43.1

27.8

 21–40

169

6.0

4.4–8.9

49.6

33.1

19.3

14.5

 41–60

72

2.8

1.6–4.3

31.1

16.7

11.8

5.3

 61–80

16

1.8

0.5–3.0

25.0

18.8

9.4

-

 81–100

2

1.8

0.7–2.9

-

-

-

-

M month (s), CI, confidence interval, NR not reached

Internal validation of the multivariate cox proportional hazard models

C-index of original dataset and mean c-index of 1000 bootstrap samples for multivariate model are described below. Using QLQ-C30 as continuous variables, the corresponding values were 0.7872 (95% CI 0.7648–0.8905) and 0.7891 (95% CI 0.7678–0.8111) respectively. Using QLQ-C30 as dichotomized variables, the values were 0.7842 (95% CI 0.7617–0.8066) and 0.7878 (95% CI 0.7660–0.8103) respectively. When assessed using C30 index score, the values were 0.7817 (95%CI 0.7591–0.8043) and 0.7840 (95% CI 0.7626–0.8066) respectively. Using QLQ-HCC18 as continuous variables, the values were 0.7810 (95% CI 0.7588–0.8032) and 0.7841 (95% CI 0.7638–0.8056) respectively. For QLQ-HCC18 as dichotomized variables, the values were 0.7821 (95%CI 0.7598–0.8043) and 0.7839 (95% CI 0.7621–0.8072) respectively. For HCC18 index score, the values were 0.7791 (95% CI 0.7564–0.8018) and 0.7715 (95% CI 0.7604–0.8034) respectively. All optimisms were within ±0.01 (Table 5). The internally validated optimism-corrected c-index was estimated to be 0.78.
Table 5

Performance and internal validation of all the multivariate cox proportional hazard models

MV model

c-index

95% CI

Mean c-index from 1000 bootstraps

95% CI based on 1000 bootstrap samples

Optimism

Optimism in %

M1

0.7872

0.7648–0.8095

0.7891

0.7678–0.8111

0.0019

0.24%

M2

0.7842

0.7617–0.8066

0.7878

0.7660–0.8103

0.0036

0.46%

M3

0.7817

0.7591–0.8043

0.7840

0.7626–0.8066

0.0023

0.29%

M4

0.7810

0.7588–0.8032

0.7841

0.7638–0.8056

0.0031

0.40%

M5

0.7821

0.7598–0.8043

0.7839

0.7621–0.8072

0.0018

0.23%

M6

0.7791

0.7564–0.8018

0.7715

0.7604–0.8034

−0.0076

−0.96%

MV multivariate, CI confidence interval

M1: the multivariate cox model using QLQ-C30 as continuous variables

M2: the multivariate cox model using QLQ-C30 as dichotomized variables

M3: the multivariate cox model using C30 index score

M4: the multivariate cox model using QLQ-HCC18 as continuous variables

M5: the multivariate cox model using QLQ-HCC18 as dichotomized variables

M6: the multivariate cox model using HCC18 index score

Multiple comparisons showed no statistically significant difference in c-index among related multivariate cox proportional hazard models (Table 6).
Table 6

Multiple comparison of c index among various multivariate cox proportional hazard models

MV model

MV model

p-value

M1

M2

0.93067

M1

M3

0.74456

M2

M3

0.81230

M4

M5

0.99435

M4

M6

0.86892

M5

M6

0.87639

M1

M4

0.74687

M2

M5

0.81263

M3

M6

0.87526

MV multivariate

M1: the multivariate cox model using QLQ-C30 as continuous variables

M2: the multivariate cox model using QLQ-C30 as dichotomized variables

M3: the multivariate cox model using C30 index score

M4: the multivariate cox model using QLQ-HCC18 as continuous variables

M5: the multivariate cox model using QLQ-HCC18 as dichotomized variables

M6: the multivariate cox model using HCC18 index score

Discussion

This is the first prospective study to demonstrate that the prognostic significance of QLQ-C30 was not limited to advance-stage HCC patients but valid for newly diagnosed patients with various stages of disease. Worse scores in physical functioning, pain and financial difficulties were associated with shorter OS in dichotomized variable analyses, while worse scores in physical functioning and pain were significant in continuous variable analyses.

This is also the first prospective study to demonstrate that baseline QLQ-HCC18 is a significant prognostication tool for OS in newly diagnosed HCC patients. Worse dichotomized score in fatigue was an independent prognostic factor for shorter OS, while worse continuous scores in fatigue and pain were also significant poor prognostic factors.

Physical functioning domain in the present study concurred with previous findings by Yeo et al. [1] (where physical and role functioning, appetite loss were significant prognostic factors for OS), and Diouf et al. [3] (where physical [dichotomized] or role functioning [continuous] were significant factors).

The HRQOL factors identified in this study varied from previous studies and could be due to a number of reasons. Firstly, patient populations were different, our study involved early as well as advanced stage HCC patients while prior studies involved only advanced stage disease. Secondly, patients of different cultural backgrounds could have different HRQOL perceptions. Thirdly, studies conducted more recently carried more available treatment options than earlier era, which may have led to differences in perception of disease and thus HRQOL. Fourthly, although different studies might utilize the same HRQOL tool, the methodologies of data analysis varied across trials.

The failure to identify consistent HRQOL factors for OS across studies makes clinically meaningful utilization of HRQOL for prognostication difficult. On the other hand, using simple algorithm and calculation, C30 and HCC18 index-scores could be derived from the raw data of all domains and items within QLQ-C30 and QLQ-HCC18 respectively. It is a meaningful representation of the overall HRQOL of an individual patient.

The C30 and HCC18 index-scores were proven to be highly significant prognostic factors for survival, and were more significant than any individual HRQOL factor, whether continuous or dichotomized. When the index-scores were stratified into subgroups, distinct OS outcomes could be identified. Clinical use of either C30 or HCC18 index-score at baseline provides another means of survival estimation in patients with newly diagnosed HCC apart from conventional staging systems. Index-score could be calculated in the clinical setting in a user-friendly manner. With the aid of modern computer technology, patients may be able to self-administer the QLQ-C30 or QLQ-HCC18 questionnaire and have the respective index-score generated by handheld devices.

One limitation of this study was the lack of a separate patient population, for instance, that of a different geographical or cultural background, to allow external validation of the multivariate cox proportional hazard models. However, bootstrapping has enabled internal validation of the multivariate models.

HRQOL assessment is important to aid clinical management in HCC patients. Being an aggressive disease, patients commonly present at advanced stage when treatment option is limited, of modest benefit and associated with disabling toxicities. HRQOL assessment enables the identification of symptoms/problems, whereby symptom control and psychosocial support measures could be offered as part of palliative care in parallel with anti-neoplastic therapy.

HRQOL tools could further be utilized to provide prognostic information. HRQOL analyses may potentially supplement available clinical staging systems in prognostication. External validation of the role of QLQ-C30 and HCC18 index-scores in prognostication in HCC patients is warranted. Index-scoring may prove useful in HRQOL research for other cancer types and further studies are encouraged.

Conclusions

Both EORTC QLQ-HCC18 and QLQ-C30 measurements at presentation are prognostic for OS in newly diagnosed patients with HCC of various stages. Index-scores of QLQ-HCC18 and QLQ-C30 are highly significant prognostic factors for OS in newly diagnosed HCC patients. Index-scoring provides an effective way to summarize, analyze and interpret raw HRQOL data, and renders QLQ-HCC18 and QLQ-C30 meaningful and communicable in clinical practice. Index-scores of both EORTC QLQ-C30 and QLQ-HCC18 could potentially serve as a standardized tool for future HRQOL research.

Abbreviations

AFP: 

α-fetoprotein

BSC: 

Best supportive care

ECOG: 

Eastern Cooperative Oncology Group

EORTC: 

European Organization for Research and Treatment of Cancer

FACT-G: 

Functional Assessment of Cancer Therapy – General

HBV: 

Hepatitis B virus

HCC: 

Hepatocellular carcinoma

HRQOL: 

Health-related quality-of-life

LEM: 

Transarterial injection of lipiodol-ethanol mixture

OS: 

Overall survival

PEI: 

Percutaneous ethanol injection

RFA: 

Radiofrequency ablation

TACE: 

Transarterial chemo-embolisation

Declarations

Acknowledgement

Not applicable.

Funding

Not applicable.

Availability of data and materials

Dataset of the study contains individual privacy and is therefore not publicly available. The dataset upon request could be provided at the discretion of the investigators.

Authors’ contributions

WY1, LL1 designed research directions. WY, LL, JK1, SLC1, EPH1, BBYM1, LKSL1, ANYP1, CMC2, JH2, KFL3, PBSL3, NSLT4, ATCC1 and SCHY2 acquired clinical, radiology and laboratory data. WY, LL, FKFM1 analyzed and interpreted data. WY, LL wrote the manuscript. All authors read, revised and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

There is no individual person’s data included in the publication.

Ethics approval and consent to participate

The study was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee. All participants consented to participate in the study and signed a written informed consent.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong
(2)
Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital
(3)
Department of Surgery, Prince of Wales Hospital
(4)
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong

References

  1. Yeo W, Mo FK, Koh J, Chan AT, Leung T, Hui P, Chan L, Tang A, Lee JJ, Mok TS, et al. Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma. Ann Oncol. 2006;17(7):1083–9.View ArticlePubMedGoogle Scholar
  2. Bonnetain F, Paoletti X, Collette S, Doffoel M, Bouche O, Raoul JL, Rougier P, Masskouri F, Barbare JC, Bedenne L. Quality of life as a prognostic factor of overall survival in patients with advanced hepatocellular carcinoma: results from two French clinical trials. Qual Life Res. 2008;17(6):831–43.View ArticlePubMedGoogle Scholar
  3. Diouf M, Filleron T, Barbare JC, Fin L, Picard C, Bouche O, Dahan L, Paoletti X, Bonnetain F. The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma. J Hepatol. 2013;58(3):509–21.View ArticlePubMedGoogle Scholar
  4. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, 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(5):365–76.View ArticlePubMedGoogle Scholar
  5. Spitzer WO, Dobson AJ, Hall J, Chesterman E, Levi J, Shepherd R, Battista RN, Catchlove BR. Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chronic Dis. 1981;34(12):585–97.View ArticlePubMedGoogle Scholar
  6. Fielding R, Wong WS. Quality of life as a predictor of cancer survival among Chinese liver and lung cancer patients. Eur J Cancer. 2007;43(11):1723–30.View ArticlePubMedGoogle Scholar
  7. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11(3):570–9.PubMedGoogle Scholar
  8. Chin PL, Chu DZ, Clarke KG, Odom-Maryon T, Yen Y, Wagman LD. Ethnic differences in the behavior of hepatocellular carcinoma. Cancer. 1999;85(9):1931–6.View ArticlePubMedGoogle Scholar
  9. Lok AS, Lai CL, Wu PC, Wong VC, Yeoh EK, Lin HJ. Hepatitis B virus infection in Chinese families in Hong Kong. Am J Epidemiol. 1987;126(3):492–9.View ArticlePubMedGoogle Scholar
  10. Ho J, Wu PC, Kung TM. An autopsy study of hepatocellular carcinoma in Hong Kong. Pathology. 1981;13(3):409–16.View ArticlePubMedGoogle Scholar
  11. 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(16):2439–44.View ArticlePubMedGoogle Scholar
  12. Chie WC, Blazeby JM, Hsiao CF, Chiu HC, Poon RT, Mikoshiba N, Al-Kadhimi G, Heaton N, Calara J, Collins P, et al. International cross-cultural field validation of an European Organization for Research and Treatment of Cancer questionnaire module for patients with primary liver cancer, the European Organization for Research and Treatment of Cancer quality-of-life questionnaire HCC18. Hepatology. 2012;55(4):1122–9.View ArticlePubMedGoogle Scholar
  13. Mikoshiba N, Tateishi R, Tanaka M, Sakai T, Blazeby JM, Kokudo N, Koike K, Kazuma K. Validation of the Japanese version of the EORTC hepatocellular carcinoma-specific quality of life questionnaire module (QLQ-HCC18). Health Qual Life Outcomes. 2012;10:58.View ArticlePubMedPubMed CentralGoogle Scholar
  14. 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.View ArticlePubMedGoogle Scholar
  15. Van Steen K, Curran D, Kramer J, Molenberghs G, Van Vreckem A, Bottomley A, Sylvester R. Multicollinearity in prognostic factor analyses using the EORTC QLQ-C30: identification and impact on model selection. Stat Med. 2002;21(24):3865–84.View ArticlePubMedGoogle Scholar
  16. Diouf M, Bonnetain F, Barbare JC, Bouche O, Dahan L, Paoletti X, Filleron T. Optimal cut points for quality of life questionnaire-core 30 (QLQ-C30) scales: utility for clinical trials and updates of prognostic systems in advanced hepatocellular carcinoma. Oncologist. 2015;20(1):62–71.View ArticlePubMedGoogle Scholar
  17. Fayers P. EORTC QLQ-C30 scoring manual. 2nd ed. EORTC: EORTC Data Center; 1999.Google Scholar
  18. Harrell Jr FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361–87.View ArticlePubMedGoogle Scholar

Copyright

© The Author(s). 2017

Advertisement