Hepatocellular carcinoma (HCC) is one of the

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1 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 Wei-Chu Chie, 1 Jane M. Blazeby, 2 Chin-Fu Hsiao, 3 Herng-Chia Chiu, 4 Ronnie T. Poon, 5 Naoko Mikoshiba, 6 Gillian Al-Kadhimi, 7 Nigel Heaton, 7 Jozer Calara, 7 Peter Collins, 8 Katharine Caddick, 8 Anna Costantini, 9 Valerie Vilgrain, 10 Ludovic Trinquart, 11 and Chieh Chiang 3 ; On behalf of the EORTC Quality of Life Group This international field validation study examined the psychometric properties and clinical validity of the European Organization for Research and Treatment of Cancer (EORTC) questionnaire module for hepatocellular carcinoma (HCC), the EORTC quality-of-life questionnaire (QLQ)-HCC18. The EORTC QLQ-HCC18 was administered with the core questionnaire, the EORTC QLQ-C30, to 272 patients from seven centers in 6 countries. Patient acceptability of the module was examined with a debriefing questionnaire, and psychometric and clinical properties were assessed. Multitrait scaling analyses confirmed the hypothesized scale structure without any scaling error, and the fatigue scale demonstrated satisfactory internal consistency. The test-retest reliability scores were high for all scales, except abdominal swelling and sexual interest. The correlations between all scales of the QLQ-HCC18 and the QLQ-C30 were low or moderate, and many scales could distinguish patients with different clinical conditions. The module demonstrated responsiveness to clinical change in pain before and after surgery and some borderline change in patients undergoing systemic treatment. Conclusion: The EORTC QLQ-HCC18 can be used as a supplementary module for the EORTC QLQ-C30 in clinical trials for patients with HCC. (HEPATOLOGY 2012;55: ) Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, with a large geographic and ethnic difference in incidence. 1 Treatments for HCC have developed in the past few decades, and selected patients may undergo hepatectomy, thermal or chemical ablation (e.g., the Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; EORTC, European Organization for Research and Treatment of Cancer; FACT, Functional Assessment of Cancer Therapy; FACT-G, Functional Assessment of Cancer Therapy Generic; FACT-Hep, Functional Assessment of Cancer Therapy Hepatobiliary; HCC, hepatocellular carcinoma; HRQL, health-related quality of life; KPS, Karnofsky performance status; QLQ, quality-of-life questionnaire. From the 1 Graduate Institute of Epidemiology and Preventive Medicine, Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan; 2 School of Social and Community Medicine, University of Bristol, Bristol, UK; 3 Division of Clinical Trial Statistics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; 4 Graduate Institute of Healthcare Administration, Kaoshiung Medical University, Kaoshiung, Taiwan; 5 Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong City, Hong Kong; 6 Department of Adult Nursing/Palliative Care Nursing, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; 7 Institute of Liver Studies, King s College Hospital, London, UK; 8 Department of Hepatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; 9 Psychoncology Unit, Sant Andrea Hospital Faculty of Medicine and Psychology Sapienza University of Rome, Rome, Italy; 10 Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy, France; Universite Paris Diderot, Sorbonne Paris Cite, INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon, CRB3, Paris, France; and 11 Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Centre d Epidemiologie Clinique, Paris, France. Received August 17, 2011; accepted October 30, This study was funded, in part, by the EORTC Quality of Life Group. J.M.B. is funded, in part, by the MRC ConDuCT Hub. W.C.C. is funded by the National Science Council, Taiwan (no. NSC B MY3). H.C.C. is funded by the National Science Council, Taiwan (no. NSC B MY3). 1122

2 HEPATOLOGY, Vol. 55, No. 4, 2012 CHIE ET AL most common procedure being radiofrequency ablation), embolization, systemic chemotherapy, l-3 and/or liver transplantation. 4 New approaches, such as gene therapy and targeted therapy, have been developed for advanced disease. 5-7 Many studies describe survival and other clinical outcomes after treatment for HCC, 8 but there is limited information available about the effect of different treatments on patients health-related quality of life (HRQL). The most widely used generic instruments to assess HRQL for patients with cancer are the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ) the EORTC QLQ-C30 9 and the Functional Assessment of Cancer Therapy Generic (FACT-G). 10 Both questionnaires may be supplemented with disease-specific modules, and the FACT tool has developed an instrument for patients with hepatic, biliary, and pancreatic malignancies: the Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep). 11 A module specific for patients with HCC has been developed by the EORTC Quality of Life Group based on an international patient group, the EORTC QLQ-HCC The aim of this current study was to test the reliability as well as clinical and psychometric validity of the EORTC QLQ-HCC18 in an international sample of patients with HCC. Patients and Methods Patient Selection Criteria. This multicenter study opened in September 2008 and closed in May Patients over 18 years of age, with histologically confirmed HCC or specialist multidisciplinary diagnosis of HCC based on alpha-fetoprotein (AFP; >400 ng/ml) and radiological images, were included. 13 Patients were also able to understand the language of the questionnaire and were without any psychological, familial, sociological, or geographical conditions that would potentially hamper compliance with the study protocol. Patients with concurrent malignancies, except basal cell carcinoma of the skin, participation in other quality-oflife studies that might interfere with this study, or previous participation in this study (in a different subgroup), were excluded. Ethics committee approval and written informed consent were obtained, and the protocol was approved by the EORTC Quality of Life Group and each research center. Questionnaire. The participants completed the EORTC QLQ-C30 (version 3.0) and QLQ-HCC18 at two assessment points as well as a debriefing questionnaire with the initial assessment. The debriefing tool recorded the time taken to complete the questionnaires and patients views of whether questions were upsetting, confusing, or inappropriate. The QLQ- HCC18 contains 18 items hypothesized to include five multi-item symptom scales: fatigue (Q45-Q47), jaundice (Q36, Q37), nutrition (Q31, Q32, and Q42- Q44), pain (Q37, Q38), and fever (Q40, Q41), two single-item symptom scales abdominal swelling (Q34) and sexual interest (Q48) and one multi-item functional scale body image (Q33, Q35). 12 Standard translation guidelines were used to produce Chinese, Japanese, Italian, and French modules, 14 and all item responses scores were converted into scores according to the EORTC guidelines for scoring. 15 For all scales, a higher score means a worse symptom or a poorer HRQL (Fig. 1). Groups of Patients and Timing of Assessment. Five groups of patients were created for clinical validity assessment according to the following treatments: (group A) surgical treatment (i.e., hepatectomy); (group B) ablation; (group C) embolization; (group D) systemic treatment; and (group E) off-treatment (with stable condition) for at least 1 year. Patients in groups A, B, and C completed the questionnaires before and after treatment as follows: group A at weeks and groups B and C at 4-6 weeks after treatment. Patients in group D completed the questionnaires at any time during treatment and 7-10 days after the first assessment. Patients in group E completed the questionnaires once at any time point and then a retest reliability study 1 week later. Patients demographic and clinical characteristics, including initial medical condition at the first assessment and changes between two assessments, were recorded. During this study, targeted therapies, such as sorafenib, 5-7 became more widely available. The protocol was therefore updated to test whether the module was applicable in this patient group by extending group D to include patients receiving targeted treatments. Address reprint requests to: Wei-Chu Chie, M.D., M.S., Ph.D., Graduate Institute of Epidemiology and Preventive Medicine, Department of Public Health, College of Public Health, National Taiwan University, Room 520, 17 Xuzhou Road, Taipei 10055, Taiwan. fax: weichu@ntu.edu.tw. Copyright VC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Nothing to report.

3 1124 CHIE ET AL. HEPATOLOGY, April 2012 Fig. 1. European Organization for Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire-HCC18. Statistical Analyses. Initial multitrait scaling restructured the questionnaire into final scales and single items. The final scale structure was tested in the whole patient group, in patients with and without cirrhosis, and in patients whose HCCs were detected by surveillance and clinically detected. Further testing of the module included reliability (i.e., internal consistency and test-retest reliability), correlation analyses with the QLQ-C30, clinical validity, such as known-group comparisons (i.e., sensitivity), and responsiveness to change over time in statistical analyses. P < 0.05 was considered as statistically significant. Alpha level for P value was adjusted for multiple comparisons using the Benjamini and Hochberg method. Multitrait scaling and other construct examination. Multitrait scaling analysis was employed to examine whether the individual items in the QLQ-HCC18 could be aggregated into hypothesized multi-item scales. Evidence of item convergent validity was defined as a correlation of 0.40 or greater between an item and its own scale (corrected for overlap). Evidence of item discriminant validity was based on a comparison of the correlation of an item with its own scale and with other scales. Scaling success for any item was defined as an item correlated significantly higher with its own scale than with another scale. Reliability. Internal consistency of the multi-item questionnaire scales was assessed by Cronbach s alpha coefficient. 16 A magnitude of >0.70 was considered acceptable for group comparisons. Test-retest reliability of scales was assessed using weighted kappa and intraclass correlations. 17 Validity. We examined the validity of the questionnaire by using the correlation with the core questionnaire and clinical validity. Correlation analyses. Correlations among the scales of QLQ-HCC18 and QLQ-C30 were examined using Pearson s product moment correlation. We expected that those scales that are conceptually related would show moderate or high correlations with one another (Pearson s r >0.40). Conversely, those scales that were conceptually unrelated were expected to exhibit lower correlations (Pearson s r <0.40). Clinical validity. In this category, we tested the known-groups comparison (i.e., sensitivity) and responsiveness overtime of the scales in the questionnaire. Known-groups comparison (sensitivity). Known-groups comparison was used to assess whether the questionnaire scores were able to discriminate between subgroups of patients of clinical status, such as treatment groups, Karnofsky performance status (KPS), and related clinical conditions, by using Wilcoxon s ranksum test or the Kruskal-Wallis test, depending on the number of groups. Groups with different degrees of liver disease were also created with the Barcelona Clinic Liver Cancer (BCLC) stage and the Child-Pugh score. Responsiveness over time. Wilcoxon s signed-rank test was used to test for the significance of changes in HRQL scores before and after treatment in groups A-D. Sample-size requirements and recruitment. Sample size was calculated based on the recommendation of Tabachnik and Fidell that, for multivariate analysis techniques to obtain reliable estimates, the number of observations should be 10 times the number of variables in the model. 18 Thus, a minimum sample size of 180 patients were needed. Taking loss to follow-up into consideration, this was increased to the total size to 250 patients. Results Patient Characteristics, Completion Rate, and Feasibility. Two hundred and thirty-two patients were enrolled from seven centers in six countries. Among

4 HEPATOLOGY, Vol. 55, No. 4, 2012 CHIE ET AL Table 1. Demographic and Clinical Details for Overall Sample and for Each Study Group* Demographics Group A (n ¼ 53) Group B (n ¼ 53) Group C (n ¼ 65) Group D (n ¼ 24) Group E (n ¼ 32) Total (N ¼ 227) Age (SD) (12.11) (11.16) (11.50) (13.57) (14.00) (12.74) Gender, male (%) 43 (81.13) 35 (66.04) 53 (81.54) 20 (83.33) 23 (71.88) 174 (76.65) Race (%) European 2 (3.77) 6 (11.32) 22 (33.85) 8 (33.33) 0 (0.00) 38 (16.74) Asian 51 (96.23) 47 (88.68) 40 (61.54) 13 (54.17) 30 (93.75) 181 (79.74) Others 0 (0.00) 0 (0.00) 3 (4.62) 3 (12.50) 2 (6.25) 8 (3.52) Postcompulsory education or above (%) 28 (52.83) 29 (54.72) 31 (47.69) 10 (41.67) 17 (53.13) 115 (50.66) Employed full-time (%) 27 (50.94) 6 (11.32) 15 (23.08) 5 (20.83) 13 (40.63) 66 (29.07) Married or living with partner (%) 49 (92.45) 45 (84.91) 45 (69.23) 17 (70.83) 24 (75.00) 180 (79.30) Living with family (%) 50 (94.34) 50 (94.34) 50 (76.92) 20 (83.33) 27 (84.38) 197 (86.78) Diagnosis by surveillance (%) 47 (88.68) 44 (83.02) 53 (81.54) 15 (62.50) 25 (78.13) 184 (81.06) Histologically diagnosed (%) 51 (96.23) 31 (58.49) 37 (56.92) 18 (75.00) 28 (87.50) 165 (72.69) BCLC stage (%) A 48 (90.57) 31 (58.49) 24 (36.92) 4 (16.67) 23 (71.88) 130 (57.27) BþCþD 3 (5.66) 22 (41.51) 40 (61.54) 16 (66.67) 9 (28.13) 90 (39.65) Missing 2 (3.77) 0 (0.00) 1 (1.54) 4 (16.67) 0 (0.00) 7 (3.08) Cirrhosis (%) 34 (64.15) 43 (81.13) 44 (67.69) 13 (54.17) 25 (78.13) 159 (70.04) Comorbid disease Hypertension 15 (28.30) 21 (39.62) 12 (18.46) 9 (37.50) 7 (21.88) 64 (28.19) Diabetes 13 (24.53) 21 (39.62) 10 (15.38) 3 (12.50) 3 (9.38) 50 (22.03) Renal 3 (5.66) 5 (9.43) 6 (9.23) 0 (0.00) 2 (6.25) 16 (7.05) Rheumatic 0 (0.00) 0 (0.00) 2 (3.08) 0 (0.00) 1 (3.13) 3 (1.32) Cardiovascular 3 (5.66) 8 (15.09) 12 (18.46) 4 (16.67) 0 (0.00) 27 (11.89) Respiratory 1 (1.89) 3 (5.66) 1 (1.54) 0 (0.00) 0 (0.00) 5 (2.20) Other 5 (9.43) 25 (47.17) 15 (23.08) 1 (4.17) 9 (28.13) 55 (24.23) KPS (%) (62.26) 23 (43.40) 20 (30.77) 8 (33.33) 19 (59.38) 103 (45.37) 80 or (35.85) 28 (52.83) 39 (60.00) 14 (58.33) 11 (34.38) 111 (48.90) (1.89) 2 (3.77) 6 (9.23) 2 (8.33) 2 (6.25) 13 (5.73) Significant portal hypertension (%) 1 (1.89) 15 (28.30) 4 (6.15) 2 (8.33) 3 (9.38) 25 (11.01) Child-Pugh grade for HCC (%) A 49 (92.45) 37 (69.81) 49 (75.38) 16 (66.67) 29 (90.63) 180 (79.30) B 2 (3.77) 15 (28.30) 15 (23.08) 4 (16.67) 2 (6.25) 38 (16.74) C 0 (0.00) 1 (1.89) 0 (0.00) 0 (0.00) 1 (3.13) 2 (0.88) Missing 2 (3.77) 0 (0.00) 1 (1.54) 4 (16.67) 0 (0.00) 7 (3.08) Bilirubin 2 mg/dl (%) 10 (18.87) 21 (39.62) 28 (43.08) 10 (41.67) 12 (37.50) 81 (35.68) AFP 20 ng/ml (%) 23 (43.40) 21 (39.62) 37 (56.92) 16 (66.67) 3 (9.38) 100 (44.05) Past medical history Surgery 4 (7.55) 8 (15.09) 13 (20.00) 9 (37.50) 21 (65.63) 55 (24.23) Ablation 2 (3.77) 31 (58.49) 6 (9.23) 3 (12.50) 10 (31.25) 52 (22.91) Embolization 11 (20.75) 18 (33.96) 42 (64.62) 9 (37.50) 7 (21.88) 87 (38.33) Systemic therapy 0 (0.00) 0 (0.00) 1 (1.54) 11 (45.83) 2 (6.25) 14 (6.17) No medical history 38 (71.70) 16 (30.19) 20 (30.77) 6 (25.00) 1 (3.13) 81 (35.68) Abbreviation: SD, standard deviation. *Group A: surgical treatment; group B: ablation; group C: embolization; group D: systemic treatment; group E: off-treatment. Bleeding varices, significant ascites. them, 227 successfully completed the first assessment (Table 1). Demographically, most patients were male, from Asia, having had more than compulsory education, not working full-time, married, and living with family. Clinically, most HCCs were detected by surveillance, histologically diagnosed, classified as BCLC stage A, with low-grade cirrhosis (Child-Pugh A), and normal bilirubin level. In most patients, the etiology of liver cirrhosis was hepatitis B (data not shown). The most prevalent comorbidity was hypertension. Past treatments included all modalities available. One hundred and seventy-eight patients in groups A-D (for responsiveness) and 32 patients in group E (for testretest reliability) completed the second assessment. Two thirds of patients completed the two questionnaires within minutes. Half had some help to read the questions from interviewers or family. Seven, one, and two items were reported to be difficult to understand or confusing by 1, 2, and 3 patients, respectively. Five and three items were reported to be difficult to answer by 1 and 2 patients, respectively. One item was reported to be upsetting by 1 patient and one item by 2 patients. Two and one items were reported to be irrelevant by 1 and 2 patients, respectively. Very few

5 1126 CHIE ET AL. HEPATOLOGY, April 2012 Table 2. Internal Consistency and Item Convergent and Discriminant Validity for the HCC18 Items Cronbach s Alpha Item to Own Scale Correlation Item to Other Scale Correlation Scaling Error Overall (n ¼ 227) Fatigue /21 Nutrition /35 Jaundice /14 Pain /14 Fever /14 Body image /14 Abdominal swelling Sexual interest Cirrhosis (n ¼ 159) Fatigue /21 Nutrition /35 Jaundice /14 Pain /14 Fever /14 Body image /14 Abdominal swelling Sexual interest No cirrhosis or unknown (n ¼ 68) Fatigue /21 Nutrition /35 Jaundice /14 Pain /14 Fever /14 Body image /14 Abdominal swelling Sexual interest Surveillance (n ¼ 185) Fatigue /21 Nutrition /35 Jaundice /14 Pain /14 Fever /14 Body image /14 Abdominal swelling Sexual interest Clinical diagnosis (n ¼ 42) Fatigue /21 Nutrition /35 Jaundice /14 Pain /14 Fever /14 Body image /14 Abdominal swelling Sexual interest items were reported to be problematic by more than 2 patients. Whole questionnaires were missing in 2 patients (1 with the QLQ-C30 and 1 with the QLQ- HCC18). Patients undergoing targeted therapy made written suggestions that the questionnaire should be modified to assess skin complications, but no additional HRQL issues were raised by the other patients. Scale Structure. The scale structure was examined by internal consistency as well as item convergent and discriminant analyses (i.e., multitrait scaling) (Table 2). Some of the item-to-scale correlation coefficients were not high. However, there were no scaling errors in all scales for all patients, for patients with and without cirrhosis, and for patients whose HCCs were detected by surveillance and clinically detected. Examining other combinations of scales did not improve scaling results. Reliability. We examined the internal consistency and test-retest reliability of the questionnaire. Internal consistency. For the whole patient group, only the Cronbach s alpha coefficient of fatigue was satisfactory (>0.70), but examining results within subgroups of patients with cirrhosis and those whose tumors were clinically detected showed better alpha coefficients. Similarly, these groups showed better coefficients in the fever scale.

6 HEPATOLOGY, Vol. 55, No. 4, 2012 CHIE ET AL Table 3. Test-Retest Reliability for Group E (Off-Treatment Group) Between-Subject SD Within-Subject SD ICCs Scales Fatigue Jaundice Nutrition Pain Fever Body image Single items Absolute Score Difference Missing Simple Kappa Weighted Kappa Abdominal swelling Sexual interest SD, standard deviation; ICCs, intraclass correlation coefficients. Test-retest reliability. Test-retest reliability scores were >0.75 for patients in group E (off-treatment and in stable condition) for fatigue, jaundice, nutrition, and body image. The intraclass correlation coefficients for the pain and fever scales, and the weighted kappa for abdominal swelling and body image, however, were less satisfactory (Table 3). Validity. We examined the correlation with the core questionnaire, known-groups comparison, and responsiveness over time. Correlation analyses with the core questionnaire. Absolute values of correlation coefficients between scales of the EORTC QLQ-C30 and that of EORTC QLQ- HCC18 were moderate ( ) to low (below 0.40) (Table 4). Known-groups comparison. The scores of three (one after adjusting the P values for multiple comparisons) of the eight scales in the QLQ-HCC18 module were different among the five groups of patients: Patients in group A had the best quality of life (Table 5). Half of the scales of the core questionnaire also showed similar differences (data not shown). We further compared the scores of different scales for patients of different BCLC stages, KPS, the presence of cirrhosis, bilirubin, and AFP levels. The KPS and bilirubin level were more differentiating than other clinical conditions. Patients with lower KPS had poorer HRQOL scores than those with higher KPS in fatigue, fever, and body image after adjusting the P values using the Benjamini and Hochberg method. Patients with a higher bilirubin level than those with normal bilirubin had poorer HRQOL scores in fatigue, jaundice, nutrition, and more sexual problems both before and after adjusting the P values (Table 6). The comparison among patients with different Child-Pugh classes had similar results (data not shown). Comparison of the core questionnaire showed similar results (data not shown). Responsiveness over time. Significant change in pain scores over time were observed in group A after surgical treatment, in group B for body image after ablative therapy, in group C for body image after embolization, and in patients in group D in the nutrition and bodyimage scales in the second assessment 1 week later. But, after adjusting P values using the Benjamini and Hochberg method, only the pain scale in group A remained significant. Patients suffered from a higher pain score after surgical treatment (Table 7). Some scales of the core questionnaire also showed change over time of different groups, as expected (data not shown). Table 4. Correlation Between Scales of QLQ-C30 and QLQ-HCC18 Subscales of HCC18 Subscales of C30 Fatigue Jaundice Nutrition Pain Fever Abdominal Swelling Sexual Interest Body Image Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning Global health status/qol Fatigue Nausea and vomiting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhea Financial difficulties

7 1128 CHIE ET AL. HEPATOLOGY, April 2012 Table 5. Mean Baseline Scores and Standard Deviation for Scales and Items in the QLQ-HCC18 for Different Clinical Groups* Group A (n ¼ 53) Group B (n ¼ 53) Group C (n ¼ 65) Group D (n ¼ 24) Group E (n ¼ 32) P Value of Kruskal-Wallis Test Adjusted p Value Fatigue 16 (17) 24 (21) 25 (25) 26 (18) 24 (20) Jaundice 11 (16) 20 (22) 14 (18) 12 (15) 20 (21) Nutrition 12 (14) 13 (12) 12 (12) 19 (17) 13 (13) Pain 8 (10) 15 (15) 16 (22) 18 (14) 18 (19) Fever 3 ( 8) 5 (10) 3 ( 9) 8 (15) 4 (10) Abdominal swelling 7 (18) 19 (22) 18 (28) 23 (21) 18 (22) Sexual interest 16 (30) 16 (32) 16 (30) 21 (32) 13 (25) Body image 10 (13) 21 (21) 17 (22) 15 (16) 19 (19) *Group A, surgical treatment; group B, ablation; group C, embolization; group D, systemic treatment; group E, off-treatment. Adjusted by the Benjamini and Hochberg method. Discussion This study examined the feasibility, psychometric properties, reliability, and validity of the module, EORTC QLQ-HCC18, in an international cross-cultural sample of patients with HCC. The core instrument and supplementary module were completed easily, mostly within 15 minutes. The results confirm the scale structure of the new module and demonstrate that it is psychometrically and clinically valid, being able to detect differences between known subgroups, measuring different constructs to the QLQ-C30, and that it is sensitive to changes over time in hypothetically relevant domains. This study had the following strengths. The study was conducted cross-culturally. Patients from European and Asian countries both participated. In addition to testing psychometric properties, it assessed HRQL of patients of different clinical conditions and at different times; thus, it covered both known-groups comparison and the assessment of responsiveness to change. The module examined is a multidimensional instrument covering all aspects of HRQL of patients with primary liver cancer. Before our instrument was developed, there were only the FACT-G 10 and the FACT-Hep, combining the original 27-item questions of the FACT-G and an 18-item questionnaire specific to hepatobiliary symptoms for patients with hepatic, biliary, and pancreatic malignancies. 11 The FACT-Hep may cover too broad a spectrum of different diseases to be specific and relevant to each individual disease. The EORTC QLQ-HCC18, however, is entirely focused on detailed HRQL issues relevant to this population of patients. This may help health care professionals understand different problems in detail and to provide specific care. A recent systematic review compared this module with other HCC-specific instruments, including the FACT-Hep, the FACT Hepatobiliary Symptom Index, and the Quality of Life Liver Cancer for Chinese patients. The review commented that the Table 6. Known-Group Comparisons: Mean Baseline Scores and Standard Deviation for Scales and Items in the QLQ-HCC18 for Patients With Different Clinical Characteristics* BCLC stage A (n ¼ 130) B or above (n ¼ 90) p Value of Wilcoxon s Rank-Sum Test Adjusted p Value Abdominal swelling 13 (22) 21 (25) Cirrhosis Yes (n ¼ 159) No or unknown (n ¼ 68) Jaundice 18 (20) 9 (15) Abdominal swelling 18 (24) 12 (21) Body image 19 (20) 11 (14) KPS 100 (n ¼ 103) (n ¼ 111) <80 (n ¼ 13) Fatigue 19 (19) 23 (20) 50 (30) < Pain 12 (14) 14 (17) 31 (28) Fever 3 ( 8) 5 (11) 10 (13) Abdominal swelling 12 (19) 18 (25) 33 (33) Body image 12 (16) 19 (19) 33 (28) Bilirubin <2 mg\dl (n ¼ 143) 2 mg\dl (n ¼ 80) Fatigue 20 (20) 28 (23) Jaundice 12 (17) 22 (21) < Nutrition 12 (13) 16 (14) Sexual interest 10 (25) 26 (34) <0.001 <0.001 *Only results of significant differences, mean (standard deviation). Adjusted by the Benjamini and Hochberg method.

8 HEPATOLOGY, Vol. 55, No. 4, 2012 CHIE ET AL Table 7. Responsiveness of Scales Before and After Different Treatments* 1st 2nd P Value of Wilcoxon s Signed-Rank Test Adjusted P Value Surgery (n ¼ 53) Pain 7.86 ( 10.13) ( 12.97) < Ablation (n ¼ 53) Body image ( 20.77) ( 24.26) Embolization (n ¼ 65) Body image ( 21.64) ( 17.96) Systemic treatment Nutrition ( 16.53) ( 25.27) (n ¼ 24) Pain ( 14.14) ( 21.55) Body image ( 15.82) ( 22.37) *Only results of significant change, mean (standard deviation). Adjusted by the Benjamini and Hochberg method. EORTC QLQ-HCC18 is focused specifically on HCC patients with clear subdimensions of disease concerns. 19 We agree with the findings of the review and consider therefore that the QLQ-HCC18 is ideal to assess HRQL in patients with HCC. This study had the following weakness. Many participants were recruited from Asian centers of highincidence countries that provide surveillance or screening programs, and therefore many patients had early disease and few HRQL problems, which may have weakened the psychometric results. This may also be a source of selection bias. Although a protocol amendment was made to include patients undergoing targeted therapies, we did not undertake in-depth interviews with these patients. Some informal feedback showed that patients receiving targeted treatment suffered problems with skin toxicity. It is therefore necessary to consider that, in the future, some further developmental work and testing is necessary to supplement this module with individual items/scales of relevance to patients receiving targeted therapies. This study also did not include patients undergoing transplantation, and future work should assess the measurement properties of this module in that group of patients. 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