Annals of Oncology Advance Access originally published online on April 6, 2006
Annals of Oncology 2006 17(7):1083-1089; doi:10.1093/annonc/mdl065
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© 2006 European Society for Medical Oncology
Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma
Departments of 1 Clinical Oncology and 2 Surgery, 3 Centre for Clinical Trials, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China; 4 Cancer Research UK, Institute for Cancer Studies, University of Birmingham, UK
* Correspondence to: Dr W. Yeo, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. Tel: +852-2632-2118; Fax: +852-2648-7097; E-mail: winnieyeo{at}cuhk.edu.hk
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Abstract |
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Background: Patients with unresectable hepatocellular carcinoma (HCC) have a dismal prognosis. The objective of this study was to evaluate whether patient-reported baseline quality of life (QoL) measured by the EORTC QLQ-C30 instrument is predictive of survival for these patients.
Materials and methods: Two hundred and thirty-three patients with unresectable HCC (mainly hepatitis B-associated) who were recruited into two separate randomized phase III clinical studies, based on palliative chemotherapy and palliative hormonal therapy, respectively, gave consent and received pretreatment QoL assessment. EORTC QLQ-C30 scores and clinical variables at the time of study entry were analyzed to identify factors that influenced survival by applying multivariate analysis. Independent prognostic factors for survival were studied by Cox regression analysis.
Results: Median survival of the 233 patients was 5.5 months (95% CI 4.2–6.5 months). Significant independent predictors of shorter survival were advanced Okuda staging (P = 0.0030; HR = 2.058), high baseline total bilirubin (P = 0.0008; HR = 1.013) and worse QoL score in the appetite score domain (P = 0.0028; HR for 10 point increase = 1.070). Patients who were entered into the chemotherapy trial (P = 0.0002; HR = 0.503), those who scored better in the physical functioning domain (P = 0.0034; HR for 10 point decrease = 0.911) and the role functioning domain (P = 0.0383; HR for 10 point decrease = 0.944) of the QoL questionnaire, were associated with longer survival.
Conclusions: In the studied HCC population, patient-reported baseline QoL provides additional prognostic information that supplements traditional clinical factors, and is a new prognostic marker for survival for patients with unresectable HCC.
Key words: liver cancer, QoL, prognostic markers
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introduction |
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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is one of the commonest causes of cancer morbidity and mortality in China and the Far East [1
, 2]. Eighty-five per cent of such patients carry the hepatitis B virus (HBV) [3, 4] and the presence of cirrhosis in the majority of cases further worsens the prognosis, resulting in an overall median survival of less than 3 months [5, 6]. Most cases are not suitable for surgical resection with curative intent [7, 8], and treatments with chemotherapy and hormonal therapy have been tested with palliative intent [9–12].
Quality of life (QoL) is an important aspect of palliative care treatment. QoL has been acknowledged as an important end point in cancer clinical trials and clinical practice, along with the traditional end points including tumor response rate, disease-free survival and overall survival [13, 14]. More recently, pretreatment QoL has been increasingly recognized as a potential prognostic factor of survival [15].
Several studies have investigated prognostic factors in patients with hepatocellular carcinoma and these have been reported to enable differentiation of patients with favorable and adverse prognosis [16–22]. While some studies have undertaken analysis on early operable HCC [22, 23], others have included patients with various stages of HCC [16–21]. Most prognostic systems including the Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), and French and Central European systems are based on patient population associated mostly with hepatitis C infection and alcoholic liver disease [17–20]. Prognostication based on those associated with chronic hepatitis B infection has mainly been addressed by the Chinese University Prognostic Index (CUPI) [21]. However, to date, there are no studies that assessed whether baseline QoL provides prognostic information in addition to conventional clinical factors for patients with unresectable disease. Prediction of clinical outcome may enable risk stratification and aid proper assignment of appropriate therapeutic strategies to individual patients.
The aim of the present study was to evaluate whether patient-reported baseline QoL is predictive of survival for patients with unresectable HCC who were mainly associated with chronic hepatitis B infection.
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materials and methods |
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The study population consisted of 233 patients from two phase III randomized studies for patients with unresectable HCC that were conducted during the same period in the Department of Clinical Oncology at Prince of Wales Hospital (Shatin, N.T., Hong Kong). One of the phase III randomized trials compared the efficacies and tolerability of two different palliative chemotherapeutic regimens: single-agent doxorubicin with combination cisplatin/interferon-
2b/doxorubicin/5-fluorouracil chemotherapy (hereby termed as the ‘chemotherapy study’) [24]. A total of 188 patients were recruited into this study; after the first 32 patients were entered, baseline QoL assessment was being incorporated into the protocol, which was being administered in the subsequent 156 patients. The other randomized phase III study compared high-dose tamoxifen versus placebo (termed as the ‘hormonal study’); this was a multicenter study conducted under the Asia Pacific Hepatocellular Carcinoma Trials Group [25]. A total of 324 patients were recruited from nine countries (10 centres); among these, 77 patients were recruited from our centre. The protocols of both studies were approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong.
entry and exclusion criteria
Patients were eligible if they had confirmed unresectable or metastatic disease HCC with no prior systemic therapy. The diagnosis of HCC was confirmed by either histology (biopsy), or radiology (a space occupying lesion on liver ultrasonography) and a raised -fetoprotein (AFP) 
500 µg/l. Other entry criteria included: age <80 years, ECOG performance score between 0 and 2, adequate renal function (creatinine clearance >50 ml/min), no prior history of malignancy except skin cancer and presence of encephalopathy, no cognitive impairment (as judged by attending clinician) and an ability to understand and read Chinese.
treatment received
For the chemotherapy study, patients were randomized to receive either single-agent doxorubicin (60 mg/m2 on day 1 every 3 weeks) or PIAF (cisplatin 20 mg/m2 days 1–4, interferon-2b 5 MU/m2 days 1–4, doxorubicin 40 mg/m2 day 1, 5-fluorouracil 400 mg/m2 days 1–4 every 3 weeks). The chemotherapy was administered for up to six cycles for responding disease and tolerable toxicities.
For the hormonal study, patients were randomized into one of the three groups, namely, placebo, tamoxifen 60 mg/day, or tamoxifen 120 mg/day in a ratio of 2:1:2. Treatment was continued for patients with tolerable toxicities.
qoL assessment
The Chinese version of the EORTC QLQ-C30 was used. After consent, all patients completed the questionnaire before the allocated treatment was commenced. The EORTC QLQ-C30 questionnaire is a widely used questionnaire. It incorporates a range of QoL issues relevant to a broad range of cancer patients. It has been translated into many languages and validated for many cancer types. It contains five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting), a global QoL scale and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) [26]. All scales and items of the EORTC QLQ-C30 range in score from 0 to 100. A high score for a functional or global QoL scale represents a relatively high/healthy level of functioning or global QoL, and a high score for a symptom scale or item represents a more severe symptoms or problems [27].
prognostic clinical variables
The following conventional clinical prognostic variables were included as potential clinical covariates: age, sex, ECOG performance score, AFP, total bilirubin, alanine transaminase and albumin levels, prothrombin time, HBsAg seropositivity, presence of ascites, Child–Pugh's grading of cirrhosis, vascular involvement, Okuda staging of HCC [16], TNM staging of HCC [28] and entries into the two respective studies (i.e. chemotherapy study versus hormonal study).
statistical analysis
Overall survival was measured from the day of randomization to the date of death or last contact. Both studies have their data updated for the final analysis and the frozen dataset were used for this analysis. Survival curves were estimated with the Kaplan–Meier method.
For the EORTC QLQ-C30 scores, all the five functioning domains, the global quality of life domain and the three symptom domains plus six single items related to symptoms were included in the prognostic factor analysis as continuous variables. They were transformed into a scale range from 0 to 100. EORTC QLQ-C30 scores and conventional clinical variables at the time of entry to the two respective studies were analyzed to identify factors that influenced survival by Cox proportional hazards model. Multivariate analysis was also carried out using a stepwise model building procedure based on a significance value of 0.05 for both inclusion and exclusion of prognostic factors. The statistical analysis was performed using SAS version 8 software package.
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study population
Two hundred and thirty-three patients with unresectable HCC were entered into the present study. These included 156 consecutive patients (67%) from the chemotherapy study and 77 consecutive patients (33%) from the hormonal study. Table 1 illustrates the baseline characteristics of the 233 patients in the present study. The median age of the patients was 57 years (range 16–80). Two hundred and twelve were males (91%). Eighty per cent of patients had an ECOG performance score of 0. Eighty-four per cent were HBsAg positive. The median AFP level was 3267 IU/l (range 1–1 892 600); that of the others were: albumin 33 g/l (range 4–46), total bilirubin 14 µmol/l (range 4–206), alanine transaminase 65 IU/l (range 13–346) and prothrombin time 11.6 s (range 9.2–24.9). Nineteen per cent had ascites. Sixty-nine per cent had Child–Pugh's grade A, 27% were of grade B and 4% were of grade C. Forty-nine per cent had vascular involvement. Most patients had extensive tumor involvement as classified by the Okuda staging: 7% were stage I, 80% stage II and 13% stage III. According to TNM staging, 12% were stage I and II, 17% were stage IIIA and IIIB, 54% were stage IVA and 17% were stage IVB.
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Table 2 illustrates the details of the two patient subgroups (from the chemotherapy study and the hormonal study) from the present study together with the baseline characteristics of the overall chemotherapy and hormonal trial populations. The two subgroups of patients who were recruited into the present study had similar baseline characteristics as that of the overall patient populations in the two respective trials.
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Two hundred and nine (90%) patients had died; these included 134 from the chemotherapy study and 75 from the hormonal study. The median survival of the 233 patients was 5.5 months (95% CI 4.2–6.5 months).
univariate analysis
Univariate analysis on the prognostic significance of the clinical predictors of survival are listed in Table 1. Variables that were statistically significant predictors of a shorter survival time included advanced Okuda staging (III versus I + II), presence of ascites, poor ECOG performance score (>0), and high AFP, total bilirubin and alanine transaminase levels. Variables that were statistically significant predictors of a longer survival time included early cirrhosis (Child–Pugh's grade), high albumin level and having been recruited to the treatment in the chemotherapy study. Age, gender, HBsAg seropositivity and prothrombin time were not significantly predictive.
Table 3 lists the univariate analysis of the predictive significance of QoL variables. A better score in physical functioning, role functioning, cognitive functioning, social functioning and global quality of life were significantly related to longer survival. While a worse score in fatigue, nausea, pain, appetite and constipation were significantly associated with shorter survival (P < 0.05). Emotional functioning, nausea/vomiting, dyspnoea, insomnia, diarrhea and financial difficulties were not significantly predictive.
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multivariate analysis
Multivariate analysis was performed to investigate the prognostic effect of QoL variables and the clinical variables simultaneously. The results are listed in Table 4. Significant independent predictors of shorter survival were advanced Okuda staging (P = 0.0030; HR = 2.058, 95% CI 1.278–3.315), high baseline total bilirubin (P = 0.0008; HR = 1.013, 95% CI 1.005–1.020) and worse score in the appetite scale of the QOL questionnaire. For a 10-point increase in score for appetite loss there was a 7% increase in the likelihood of death at any given time (P = 0.0028, HR = 1.070, 95% CI 1.023–1.118).
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Patients who were entered into the chemotherapy study (P = 0.0002; HR = 0.503, 95% CI, 0.352–0.721), those who scored better in the physical functioning domain and the role functioning domain of the QoL questionnaire were associated with longer survival. For a 10-point increase in physical functioning score there was an 8.9% reduction in the likelihood of death at any given time (P = 0.0034, HR = 0.911, 95% CI 0.856–0.969). For a 10-point increase in role functioning score there was a 5.6% reduction in the likelihood of death at any given time (P = 0.0383, HR = 0.944; 95% CI 0.894–0.996). Figure 1 shows the survival curves of patients according to different scores of physical functioning, role functioning and appetite loss. The cut-off points for physical functioning, role functioning and appetite loss were 70, 70 and 25, respectively. The determination of these cut-off points were based on the mean value score observed in the study patient population. For each figure, the difference between the two curves was significant (P = 0.0005, 0.0033 and <0.0001, respectively).
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70, lower curve) (n = 233, log-rank test: P value = 0.0005). (B) Survival (months) of patients with optimal role functioning (score >70, upper curve) versus survival of patients with less than optimal global QOL (score The study by QoL interaction was tested; results were similar between the two study groups (P = 0.7508).
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conclusions |
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To our knowledge, our study is the first retrospective analysis of two prospective studies in patients with unresectable hepatocellular carcinoma to confirm the prognostic significance of QoL in a fairly homogenous group of patients. The findings provide strong evidence to support a relationship between QoL scores and survival in this patient population, in which the majority suffered from chronic liver disease associated with hepatitis B infection. Several baseline predictors of survival were found upon multivariate Cox analysis, in particular, a major finding was that baseline EORTC QLQ-C30 scores in physical functioning, role functioning and appetite loss were significantly associated with survival and, therefore, have predictive value when used along with the current standard clinical prognostic variables.
Individuals who have worse baseline QoL scores were found to have shorter survival than those who have better QoL scores. While this relationship has not been universally observed in the literature, such positive correlation has been reported in a number of cancer types [29–32], specifically, in the breast [33–35], lung [36–39], esophagus [40–42], head and neck [43], colon [44], malignant melanoma [45], multiple myeloma [46], ovarian [47] and malignant glioma [48]. However, different QOL instruments have been used in these studies, and it may be difficult to generalize the findings. Using EORTC QLQ-C30 as a tool of assessment, global QoL [29, 30, 32, 36, 37, 42] and physical functioning [30, 31, 40, 41, 46] have been the most common domains that were shown to be predictors of survival. Other aspects that have been shown to be of prognostic significance include emotional functioning [29], social functioning [32], role functioning [42], cognitive functioning [43], pain [34] and appetite loss [35]. In HCC patients, appetite loss may be a reflection of the disease burden and severity of the often associated chronic liver disease; a large-sized tumor is likely to compress adjacent stomach, the presence of gross ascites may cause a feeling of abdominal fullness, hepatic dysfunction with hyperbilirubinemia may reduce mental state and impair appetite, and the reduction of body reserve as a consequence may lead to poor tolerance to intervention therapy and result in premature termination of the treatment.
The predictive value of baseline QoL for survival is probably due to the ability to provide information about patient well-being not captured by traditional measures. It is a patient-reported assessment of well-being. Historically, clinical observers have been reported to be poor judges of how a patient feels. Low correlations are found between patient-reported and clinician-reported overall QoL scores, symptoms, physical well-being and psychological well-being subscores [49, 50].
The present study was undertaken to explore further the relationship of baseline QoL with conventional clinical covariates and survival in patients with inoperable HCC. Advanced disease based on Okuda staging and high total bilirubin were two covariates strongly associated with shorter survival. These findings are incongruent with previous reports in which patients with various stages of HCC were studied by applying different prognostic systems [16, 18–21]. Tumor-related factors that have been predictive for survival include tumor size [16, 17, 21], lymph node involvement [19, 21], presence of vascular thrombosis or invasion [17–20] and high AFP levels [18, 19, 21]. Functional status of the non-tumorous liver, as reflected by adequacy of liver function, has also been widely accepted to have prognostic significance. Apart from high total bilirubin [16, 18–21], low albumin [16], high alkaline phosphatase [18, 21], presence of ascites [16, 21] or portal hypertension [20], prolonged prothrombin time [19] and advanced Child–Pugh stage for cirrhosis [17, 20] have been shown to be adverse prognostic factors for survival in HCC patients. Furthermore, in the absence of formal QoL assessment, patients who are asymptomatic at presentation of the disease [21] and those who have good performance status [18] have been associated with better outcome.
The other factor that predicted survival was the treatment an individual received, with patients receiving chemotherapy having a longer survival. The exact causal relationship was unclear. While it may be considered—chemotherapy represents a more aggressive approach in the management of HCC, which could theoretically result in a better outcome for the patients treated—it was likely that those who had more favorable baseline clinical features were more likely to be selected for chemotherapy. However, it is unlikely that treatment effect would impact on the analysis of prognostic factors since the two studies have negative results [24, 25]. This is supported by a subsequent exploratory analysis testing the study-by-QoL interactions, which did not show any significant difference between the two treatment groups.
It is possible that baseline QoL for HCC patients may be affected by other concurrent diseases or conditions. In the context of assessing treatment outcome of patients with cancer of the liver, pancreas, gall bladder and biliary ducts, addressing disease-specific issues has been acknowledged to be an important component of quality of life assessment. The Functional Assessment of Cancer Therapy hepatobiliary questionnaire (FACT-Hep) supplements the general quality of life questionnaire (FACT-G), and has been used as a tool for assessing treatment outcome for patients with hepatobiliary malignancies [51]. FACT-Hep has been put forth as a reliable and valid instrument that increases the accuracy of overall QoL assessment [51]. Specifically, for patients with hepatocellular carcinoma, with the majority of patients suffering from co-existing cirrhosis, the usefulness of a QoL instrument based on EORTC QLQ-C30 in assessing patients with HCC could be further enhanced by the addition of assessment related to disease-specific module in the recently reported EORTC QLQ-HCC18 questionnaire [52]. In the latter, symptoms from chronic liver disease have been taken into consideration and include that of abdominal distension from ascites, limb edema related to sodium and fluid retention, pruritus related to hyperbilirubinemia, bleeding related to clotting impairment and thrombocytopenia [52]. The inclusion of a HCC-specific questionnaire into the present study would potentially improve the sensitivity of baseline QoL as a prognosticator in these patients.
Our study suggests that baseline QoL as measured by EORTC QLQ-C30 could be applied as a new prognostic marker for survival in patients with unresectable hepatocellular carcinoma. When used together with conventional clinical factors, patient-reported baseline QoL assessment provides additional information and can be part of a more comprehensive prediction of patient prognosis. Furthermore, QoL assessment enables identification of symptoms whereby interventions to improve QoL may be useful in reducing the burden of the disease. QoL assessment may also assist clinicians to recalibrate clinical prediction of survival and optimize the use of palliative care. From a clinical research perspective, the identification of prognostic factors for survival could help to stratify patients into randomized clinical trials and aid the interpretation of results in a more transparent way.
The findings from this study support the use of QoL assessment in being informative in routine clinical practice in a HCC patient population with background chronic liver disease mainly associated with hepatitis B infection. Although the data was prospectively collected, the findings are limited by the retrospective nature of data analysis. Further studies incorporating QoL assessment together with clinical prognostic systems may provide additional information that may aid patient and clinician in decision-making in unresectable hepatocellular carcinoma.
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Acknowledgements |
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We thank Asia Pacific Hepatocellular Carcinoma Trials Group for providing QOL data for patients who consented to the randomized trial of high-dose tamoxifen versus placebo for the treatment of inoperable hepatocellular carcinoma.
Received for publication November 28, 2005. Revision received February 14, 2006. Accepted for publication February 28, 2006.
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