Liver International ISSN 1478-3223
LIVER CANCER
Trans-arterial chemo-embolization is safe and effective for elderly advanced hepatocellular carcinoma patients: results from an international database ndez-Ruiz4, Massimo Di Maio5, Francesco Matan J. Cohen1, Izhar Levy2, Orly Barak2, Allan I. Bloom3, Mario Ferna 5 6 2 7 Perrone , Ronnie T. Poon , Daniel Shouval , Thomas Yau and Oren Shibolet8 1 2 3 4 5 6 7 8
Division of Internal Medicine and Center for Clinical Quality and Safety, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Liver Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Interventional Radiology Unit, Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel n “Hospital 12 de Octubre” (i + 12), Madrid, Department of Internal Medicine, Hospital Universitario “12 de Octubre”, Instituto de Investigacio Spain Unit a Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Naples, Italy Department of Surgery, University of Hong Kong, Hong Kong, China Department of Medicine and Surgery, Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China Liver Unit, Department of Gastroenterology and Liver Disease, Tel-Aviv Sourasky Medical Center and Tel-Aviv University, Tel-Aviv, Israel
Keywords elderly patients – hepatocellular carcinoma – trans-arterial chemo-embolization
Correspondence Oren Shibolet, Liver Unit, Department of Gastroenterology, Tel Aviv Sourasky Medical Center & The Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel Tel: +972 3 6973 984 Fax: +972 3 6966 286 e-mail: [email protected] Received 7 August 2013 Accepted 1 February 2014 DOI:10.1111/liv.12486 Liver Int. 2014: 34: 1109–1117
Abstract Objective: Hepatocellular carcinoma (HCC) incidence among elderly patients is increasing. Trans-arterial chemo-embolization (TACE) prolongs survival in selected HCC patients. The safety and efficacy of TACE in elderly patients has not been extensively studied. The objective of this study was to assess the safety and efficacy of TACE in elderly patients (older than 75) with HCC. Design: Combined HCC registries (Spain, Italy, China and Israel) and cohort design analysis of patients who underwent TACE for HCC. Results: Five hundred and forty-eight patients diagnosed and treated between 1988 and 2010 were included in the analysis (China 197, Italy 155, Israel 102 and Spain 94,). There were 120 patients (22%) older than 75 years and 47 patients (8.6%) older than 80. Median (95% CI) survival estimates were 23 (17–28), 21 (17–26) and 19 (15–23) months (P = 0.14) among patients aged younger than 65, 65–75 and older than 75 respectively. An age above 75 years at diagnosis was not associated with worse prognosis, hazard ratio of 1.05 (95% CI 0.75–1.5), controlling for disease stage, sex, diagnosis year, HBV status and stratifying per database. No differences in complication rates were found between the age groups. Conclusions: TACE is safe for patients older than 75 years. Results were similar over different eras and geographical locations. Though selection bias is inherent, the results suggest overall adequate selection of patients, given the similar outcomes among the different age groups.
The proportion of elderly patients newly diagnosed with hepatocellular carcinoma (HCC) is increasing, and agespecific incidence rates are estimated to peak above the age of 70 years (1, 2). Few HCC patients are eligible for curative treatments such as liver resection, liver transplantation or radiofrequency ablation for small tumours. Most patients, therefore, receive palliative treatments including, transarterial chemo-embolization (TACE), selective internal radiation therapy, sorafenib or supportive care. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Liver Diseases (AASLD) guidelines for the treatment of HCC, as well as guidelines published by other professional societies, highlight the importance of patient risk assessment prior to treatment selection including both disease stage and comorbidities. Age per se is not considered to be a contraindication for HCC treatment in any of the guidelines except for eligibility for liver transplantation (3–7). However, elderly patients may still be expected to experience more adverse effects and enjoy less favourable prognosis compared to younger patients. Indeed, it has been shown that elderly HCC patients are poorer transplantation candidates (8). Similarly, elderly
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patients are reported to receive less aggressive treatment plans compared to younger patients with similar disease stages (9). Still, there is data to suggest that the outcome and prognosis of hepatic resection is similar among elderly and younger patients (10–13). To date, there have been only a few publications describing the results of TACE among elderly patients; these data come from diverse geographical regions, including East Asia, (14–17) the Middle East, Europe and the USA (18–22). The data from these publications suggested that TACE is safe and effective in selected elderly patients with HCC. Nevertheless, the studies were relatively small and heterogeneous. We sought to provide robust outcome estimates of elderly HCC patients treated with TACE and identify factors effecting prognosis. This information would be relevant for decision makers, physicians and patients. To that end, we collaborated together to form a large data set, combining our repositories. We hypothesized that, controlling for disease stage, the natural history of HCC would be similar and that there would be negligible heterogeneity between our data sets. The collaborative effort would provide the sample size and power enabling confident results and conclusions. Methods
We performed a literature search of the medical literature reporting prognosis following TACE among patients with HCC, which included data stratification according to age groups. We did not limit our search to the English language, nor did we search for a specified age cut-off for defining elderly patients. Relevant publications were reviewed to confirm that TACE was provided as sole treatment for HCC and that elderly patients were part of the data set. We contacted all corresponding authors and proposed collaboration and sharing of the databases to generate one structured database. These data were combined to create a metadatabase. Because the studies were designed in different countries at different times and with different parameters, there were only a few overlapping variables collected in all studies. The available data sets, together, allowed for the generation of a larger data set and provided insight into differences between the published series with regard to demographics, disease stage, outcome and side effects. We hypothesized that there would not be significant variability among study outcomes, confirming the role of TACE for elderly patients with advanced HCC. All data sets collected have no patient-unique identifying features (personal identification numbers, social security number etc.). Data included the following variables: age at diagnosis, patient sex, date of diagnosis, HBV status, HCV status, cirrhosis at diagnosis, ChildPugh score (CPT) at diagnosis, Okuda stage and Cancer of the Liver Italian Program (CLIP) score at diagnosis, survival time until censorship or death, mortality status.
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Each participating group had local institutional board approval for their cohort study. Two data sets also had available data regarding the number of TACE performed per patient and post-TACE complications: vascular damage, significant haemorrhage, acute kidney injury and deterioration in liver function. All data were collected into a single data set file and the geographical origin was also included as a variable. In all data sets, HCC diagnosis was determined in accordance with established guidelines published by both the EASL and the AASLD (3, 4). We note that IRB approval limited the Chinese cohort from providing data for patients younger than 65. TACE technique
The CLIP multicentre trials (CLIP-01 and CLIP-03) did not impose a specific TACE procedure and the technique was left at each centre’s discretion according to their best clinical practice. In the Spanish study, after arteriography and portography, a mixture of lipiodol and doxorubicin (40–60 mg) or cisplatin (50–100 mg) and iodized oil (5–30 ml) was injected into the hepatic artery until stasis within the tumour vessels occurred. The feeding arteries to the HCC were embolized with gelatin sponge particles. In the Israeli center, after vascular imaging, whenever possible, super selective TACE was attempted using a co-axial microcatheter and a mixture of 50 mg doxorubicin with lipiodol oil and gelfoam slurry or powder. If dictated by tumour burden and feasibility (hepatic reserve, Child Pugh status), segmental or lobar TACE was performed. Percutaneous vascular closure devices were routinely employed from 2007 onward. Finally, the procedure in Hong-Kong included arteriography and superior mesenteric arterial portovenography. The right or left hepatic artery feeding the tumour was superselectively catheterized. Using the pumping method an emulsion was prepared by mixing cisplatin (1 mg/ml) with Lipiodol in a volume ratio of 1 to 1. Various amounts of the emulsion, up to a maximum of 60 ml (containing 30 mg of cisplatin) were injected slowly under fluoroscopic monitoring according to the size of the tumour and the arterial blood flow. This was followed by embolization with small gelatin sponge (Spongostan; Ferrosan, Johnson & Johnson Medical Ltd., Skipton, England) pellets of 1 mm diameter mixed with 40 mg of gentamicin. Analysis
Descriptive statistics were employed to present age groups characteristics. Categorical variables are presented as percentages and distributions, and continuous variables are presented with mean and standard deviation (SD). Associations between categorical variables were assessed with the Fisher exact test, and comparison of continuous variables was performed with the Student’s t-test or with the Mann–Whitney U test. Survival Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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charts were generated employing the Kaplan–Meier method and survival curves were compared with the log-rank test. Follow-up times were estimated using the reverse Kaplan–Meier methods. (23) After confirming that the proportional hazard assumptions were met, we determined the association of age group and potential confounders with mortality using the Cox proportional hazard regression analysis. To this end, we assessed several models; firstly, we included age at diagnosis, sex, year of diagnosis, HBV and HCV status, cirrhosis on diagnosis and disease stage. Not all data sets had all these variables available, and therefore, we repeated the models without the missing variables. All analyses were stratified per study of origin. We performed several sensitivity analyses. We repeated analysis without stratifying per study of origin. In addition, we assessed age at diagnosis as a continuous variable and also as a categorical variable in two strategies: (i) either above 80 years of age or lower; (ii) In three categories – younger than 65, 65–75 and above 75. We repeated the analyses with various risk stratification/staging scores. Because of the absence of patients younger than 65 from the Chinese study, we additionally analysed all included data for patients 65 years of age at diagnosis and older and stratified age group to patients between 65 and 70, 70–75 and older than 75. In all analyses, two tailed P-values below 0.05 were considered statistically significant. Results
The initiative led to the cooperation of investigators from four countries and included data previously pub-
lished from five patient cohorts. These are the CLIP1 and CLIP 3 cohorts from Italy (21), a cohort from Spain (20), a cohort from Hong-Kong, China (14) and an Israeli cohort (22). These five original data sets were assembled into one metadatabase including 548 patients: CLIP1 with 80 patients (14.6%), CLIP3 with 75 patients (13.7%), the Spanish cohort with 94 patients (17.2%), a Chinese cohort with 197 patients (36%) and an Israeli cohort of 102 patients (18.6%). There were 159 patients below the age of 65 (29%) at diagnosis, 269 (49%) patients diagnosed between the ages of 65 and 75, and 120 (22%) patients diagnosed at age 75 and older. There were 47 (8.6% of the entire cohort) patients who were diagnosed at age 80 or more. The studies were conducted in different eras with the CLIP studies occurring in the 1990’s and the Spanish and Israeli studies conducted later. The Chinese study was the only one that spanned more than 20 years, although most of the recruitment was done during the same period as the Israeli and Spanish studies. Patient characteristics are presented in Table 1. In the combined data set, females account for 24% of the patients, and 325 subjects (93%) were cirrhotic at diagnosis. The Chinese cohort included older patients, none under the age of 65. Among the non-Chinese countries, HBV was found in 21%% of the patients (range 15– 27%), in contrast, in the Chinese cohort, 63% of the patients were HBV carriers. Tables S1–S3 present the distributions of HCC score/stages in the three age groups. Age at diagnosis was positively associated with the era when this study was conducted (r = 0.15,
Table 1. Patient characteristics in the included databases
Female Cirrhosis on diagnosis HCV positive HBV positive Child A Child B Child C OKUDA I OKUDA II OKUDA III CLIP 0 CLIP 1 CLIP 2 CLIP 3 CLIP 4 CLIP 5 CLIP 6 Alive at end of follow-up Age at diagnosis* Months of follow-up†
Italy CLIP 1
Italy CLIP 3
Spain
Hong-Kong
Israel
Total
15 (19%) 76 (95%) 58 (76%) 20 (27%) 40 (51%) 35 (44%) 4 (4%) 3 (5%) 55 (86%) 6 (9%) 10 (19%) 23 (43%) 13 (24%) 3 (6%) 3 (6%) 2 (4%) 0 14 (18%) 63 (8) 51 (43–59)
14 (19%) 73 (97%) 49 (73%) 17 (23%) 33 (45%) 33 (45%) 8 (11%) 5 (7%) 62 (87%) 4 (6%) 6 (12%) 24 (46%) 18 (35%) 4 (8%) 0 0 0 8 (11%) 64 (8) 85 (50–121)
21 (22%) 78 (83%) 52 (55%) 14 (15%) 56 (60%) 30 (32%) 8 (9%) 52 (55%) 34 (36%) 8 (9%) 29 (31%) 30 (32%) 19 (20%) 7 (7%) 5 (5%) 3 (3%) 1 (1%) 32 (34%) 64 (9) 48 (36–60)
54 (27%) NA NA 112 (63%) 165 (84%) 32 (16%) 0 79 (40%) 116 (59%) 2 (1%) 48 (24%) 80 (41%) 54 (27%) 14 (7%) 1 (1%) 0 0 14 (7%) 75 (4) 100 (68–131)
27 (27%) 98 (97%) 68 (67%) 21 (21%) 84 (82%) 15 (15%) 3 (3%) 80 (78%) 21 (21%) 1 (1%) 35 (34%) 29 (28%) 29 (28%) 8 (8%) 1 (1%) 0 0 16 (16%) 67 (9) 62 (34–89)
131 (24%) 325 (93%) 227 (67%) 184 (35%) 378 (69%) 145 (27%) 23 (4%) 219 (41%) 288 (55%) 21 (4%) 128 (26%) 186 (37%) 133 (27%) 36 (7%) 10 (2%) 5 (1%) 1 (0.2%) 84 (15%) 69 (9) 69 (60–79)
*Mean (SD) †Reverse Kaplan–Meier estimate – Median (95% CI).
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P = 0.001), patients diagnosed at late dates were on average older. There was a negative association between date of diagnosis and disease stage: patients with Okuda I comprised 17%, 23%, 46% and 62% of the included patient cohorts during 1988–1992, 1993–1997, 1998– 2002, 2003–2008 respectively. Okuda II patients comprised 79%, 70%, 51% and 36% of the included respectively (P < 0.001). Figure 1 depicts dates of diagnosis, age at diagnosis and overall survival histograms, showing the individual contribution of each data set. Survival probabilities are presented in Table S4. Crude survival rates were similar between patients aged younger than 65, 65–75 and 75 and older (Fig. 2A). Median (95% CI) survival estimates were 23 (17–28), 21 (17–26) and 19 (15–23) months (P = 0.14) in the different age groups respectively. Stratified survival analysis per study group did not demonstrate significant survival difference between the age groups (all P-values between 0.1 and 0.9). Limiting the analysis to patients diagnosed since 2000 had no effect on the results of the latter years. Because our Chinese cohort included only patients older than 65, we stratified this age group to three strata 65–70, 70–75 and >75. Using univariate analysis, we saw that younger age was associated with better survival (Fig. S1). However, age was no longer a significant factor in the multivariate analysis, and disease stage remained the only independent prognostic predictor. Figure 2B depicts study-specific survival curves per each study group. Multivariate analysis models generated non-significant hazard ratios associating age and mortality. Disease stage was the dominant predictor of mortality (Table 2). These results were consistent when analyses were not stratified for study and when the CLIP staging system or the Child score was used instead of the Okuda score. Figures S2–S11 depict crude survival curves in each separate HCC score/stage. Survival periods prior to and after 2000, as well as separate crude survival curves, comparing the three age groups, prior to and after 2000 are also presented in Table S5 and Figures S12 and S13. Two data sets had additional data regarding adverse events (the Chinese and Israeli cohorts). A total of 43/ 299 (14.4%) patients had documented acute renal failure and 122/299 (41%) patients had evidence of deterioration in liver function (DLF). It should be noted that patients younger than 65 were all from the Israeli cohort and all had evidence of DLF following TACE (>50% INR and hepatocellular enzyme increases above the upper limit of normal). Age group rates of these complications are presented in Table 3. Rare complications included vascular complications 4/299(1.3%) and
Fig. 1. Time of diagnosis, extent of survival and age at diagnosis of included patients. Composite histograms representing distribution of diagnosis date (top panel), survival time (middle panel) and age at diagnosis (lower panel). In all panels, the contribution of each data set is presented in a unique colour.
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(A)
(B)
Fig. 2. Survival curves per age groups. (A) cumulative survival per age group; (B) Study-specific survival curves per age group.
significant haemorrhage (blood loss, either into the gastrointentinal tract or through vessel puncture, requiring transfusion of at least two blood units) 15/299 (5%). Discussion
In the absence of trials dedicated to elderly patients, the results of our study demonstrate that TACE is safe and provides similar benefits to elderly eligible patients with HCC as it does to younger HCC patients. We merged several institutional databases to analyse the largest population of elderly patients treated with TACE to date. Elderly patients, included in this study, did not suffer more adverse events compared with younger patients. Furthermore, the results show that these outcomes are similar for patients diagnosed over a 20-year period and in different countries. Most notable are the similarities Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
between Chinese patients and patients from Mediterranean and European countries. Current literature of TACE for HCC includes inconsistent age cut-offs to define “elderly”. In a 2002 metaanalysis of randomized controlled trials, the mean patient age in the included trials ranged between 41 and 66 (24). These studies defined elderly patients as those above 60 or 65 years of age (19,25–28). As is the case of the available information for other diseases and treatments, there is notable misrepresentation of the elderly in the data published so far on HCC (29). Given the increasing longevity, there is a need for relevant novel and confirmatory data regarding septagenerians, octogenerians and even older patients. Only a few studies have estimated survival among HCC patients older than 70, treated by different treatment modalities. A study of a cohort of patients with a
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TACE in the elderly Table 2. Univariate and multivariate hazard ratios for mortality
Female sex Cirrhosis on diagnosis HCV positive HBV positive Okuda II* Okuda III* Year of diagnosis Age at diagnosis† Age at diagnosis >80 Age at diagnosis 65–75‡ Age at diagnosis >75‡
Univariate
Model 1
Model 2
Model 3
Model 4
Model 5
0.84 (0.67–1.03) 1.16 (0.7–1.9) 0.97 (0.75–1.2) 1.02 (0.84–1.2) 1.5 (1.2–1.8) 3.7 (2.3–5.8) 0.99 (0.97–1.01) 1.08 (0.97–1.2) – –
0.7 (0.5–0.99) 0.8 (0.4–1.3) 0.8 (0.6–1.1) 0.9 (0.6–1.3) 2.2 (1.5–3.3) 7.1 (3.9–12.8) 0.95 (0.88–1.03) 1.05 (0.9–1.23) – –
0.7 (0.5–0.97) 0.7 (0.4–1.2) – 1.02 (0.73–1.4) 2.3 (1.6–3.4) 7.2 (4.04–13) 0.95 (0.88–1.03) 1.05 (0.9–1.2) – –
0.8 (0.6–1.02) – – 0.8 (0.65–1.06) 1.6 (1.2–2.0) 5.2 (3.1–8.5) 0.98 (0.95–1.02) 0.99 (0.98–1.01) – –
0.81 (0.64–1.02) – – 0.8 (0.65–1.05) 1.5 (1.2–1.9) 5.1 (3.1–8.5) 0.98 (0.95–1.02) – 0.94 (0.7–1.3) –
0.8 (0.64–1.02) – – 0.84 (0.66–1.06) 1.5 (1.2–2.0) 5.1 (3.1–8.5) 0.99 (0.96–1.02) – – 1.07 (0.83–1.4)
–
–
–
–
–
1.05 (0.75–1.5)
All models were stratified per study *Compared to Okuda I †Ten-year increment ‡Compared to patients younger than 65. Models: (1) Including disease stage, sex, HCV and HBV status, cirrhosis. Year of diagnosis and age of diagnosis. (2) Similar to model 1 but without HCV status, allowing far more inclusion of patients. (3) Similar to model 2, excluding cirrhosis at diagnosis. It was felt that disease stag was predictive enough. (4) Similar to model 3, however, age is treated dichotomously. (5) Similar to model 3, but using age in categories (below 65, between 65–75 and older).
Table 3. Incidence of acute kidney injury and deterioration in liver function per age group*
Acute kidney injury Deterioration in liver function
Younger than 65
65–75
Older than 75
P-value
8 (21%) 38 (100%)
24 (16%) 57 (37%)
11 (10%) 27 (25%)
0.23
LIVER CANCER
Trans-arterial chemo-embolization is safe and effective for elderly advanced hepatocellular carcinoma patients: results from an international database ndez-Ruiz4, Massimo Di Maio5, Francesco Matan J. Cohen1, Izhar Levy2, Orly Barak2, Allan I. Bloom3, Mario Ferna 5 6 2 7 Perrone , Ronnie T. Poon , Daniel Shouval , Thomas Yau and Oren Shibolet8 1 2 3 4 5 6 7 8
Division of Internal Medicine and Center for Clinical Quality and Safety, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Liver Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Interventional Radiology Unit, Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel n “Hospital 12 de Octubre” (i + 12), Madrid, Department of Internal Medicine, Hospital Universitario “12 de Octubre”, Instituto de Investigacio Spain Unit a Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Naples, Italy Department of Surgery, University of Hong Kong, Hong Kong, China Department of Medicine and Surgery, Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China Liver Unit, Department of Gastroenterology and Liver Disease, Tel-Aviv Sourasky Medical Center and Tel-Aviv University, Tel-Aviv, Israel
Keywords elderly patients – hepatocellular carcinoma – trans-arterial chemo-embolization
Correspondence Oren Shibolet, Liver Unit, Department of Gastroenterology, Tel Aviv Sourasky Medical Center & The Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel Tel: +972 3 6973 984 Fax: +972 3 6966 286 e-mail: [email protected] Received 7 August 2013 Accepted 1 February 2014 DOI:10.1111/liv.12486 Liver Int. 2014: 34: 1109–1117
Abstract Objective: Hepatocellular carcinoma (HCC) incidence among elderly patients is increasing. Trans-arterial chemo-embolization (TACE) prolongs survival in selected HCC patients. The safety and efficacy of TACE in elderly patients has not been extensively studied. The objective of this study was to assess the safety and efficacy of TACE in elderly patients (older than 75) with HCC. Design: Combined HCC registries (Spain, Italy, China and Israel) and cohort design analysis of patients who underwent TACE for HCC. Results: Five hundred and forty-eight patients diagnosed and treated between 1988 and 2010 were included in the analysis (China 197, Italy 155, Israel 102 and Spain 94,). There were 120 patients (22%) older than 75 years and 47 patients (8.6%) older than 80. Median (95% CI) survival estimates were 23 (17–28), 21 (17–26) and 19 (15–23) months (P = 0.14) among patients aged younger than 65, 65–75 and older than 75 respectively. An age above 75 years at diagnosis was not associated with worse prognosis, hazard ratio of 1.05 (95% CI 0.75–1.5), controlling for disease stage, sex, diagnosis year, HBV status and stratifying per database. No differences in complication rates were found between the age groups. Conclusions: TACE is safe for patients older than 75 years. Results were similar over different eras and geographical locations. Though selection bias is inherent, the results suggest overall adequate selection of patients, given the similar outcomes among the different age groups.
The proportion of elderly patients newly diagnosed with hepatocellular carcinoma (HCC) is increasing, and agespecific incidence rates are estimated to peak above the age of 70 years (1, 2). Few HCC patients are eligible for curative treatments such as liver resection, liver transplantation or radiofrequency ablation for small tumours. Most patients, therefore, receive palliative treatments including, transarterial chemo-embolization (TACE), selective internal radiation therapy, sorafenib or supportive care. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Liver Diseases (AASLD) guidelines for the treatment of HCC, as well as guidelines published by other professional societies, highlight the importance of patient risk assessment prior to treatment selection including both disease stage and comorbidities. Age per se is not considered to be a contraindication for HCC treatment in any of the guidelines except for eligibility for liver transplantation (3–7). However, elderly patients may still be expected to experience more adverse effects and enjoy less favourable prognosis compared to younger patients. Indeed, it has been shown that elderly HCC patients are poorer transplantation candidates (8). Similarly, elderly
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patients are reported to receive less aggressive treatment plans compared to younger patients with similar disease stages (9). Still, there is data to suggest that the outcome and prognosis of hepatic resection is similar among elderly and younger patients (10–13). To date, there have been only a few publications describing the results of TACE among elderly patients; these data come from diverse geographical regions, including East Asia, (14–17) the Middle East, Europe and the USA (18–22). The data from these publications suggested that TACE is safe and effective in selected elderly patients with HCC. Nevertheless, the studies were relatively small and heterogeneous. We sought to provide robust outcome estimates of elderly HCC patients treated with TACE and identify factors effecting prognosis. This information would be relevant for decision makers, physicians and patients. To that end, we collaborated together to form a large data set, combining our repositories. We hypothesized that, controlling for disease stage, the natural history of HCC would be similar and that there would be negligible heterogeneity between our data sets. The collaborative effort would provide the sample size and power enabling confident results and conclusions. Methods
We performed a literature search of the medical literature reporting prognosis following TACE among patients with HCC, which included data stratification according to age groups. We did not limit our search to the English language, nor did we search for a specified age cut-off for defining elderly patients. Relevant publications were reviewed to confirm that TACE was provided as sole treatment for HCC and that elderly patients were part of the data set. We contacted all corresponding authors and proposed collaboration and sharing of the databases to generate one structured database. These data were combined to create a metadatabase. Because the studies were designed in different countries at different times and with different parameters, there were only a few overlapping variables collected in all studies. The available data sets, together, allowed for the generation of a larger data set and provided insight into differences between the published series with regard to demographics, disease stage, outcome and side effects. We hypothesized that there would not be significant variability among study outcomes, confirming the role of TACE for elderly patients with advanced HCC. All data sets collected have no patient-unique identifying features (personal identification numbers, social security number etc.). Data included the following variables: age at diagnosis, patient sex, date of diagnosis, HBV status, HCV status, cirrhosis at diagnosis, ChildPugh score (CPT) at diagnosis, Okuda stage and Cancer of the Liver Italian Program (CLIP) score at diagnosis, survival time until censorship or death, mortality status.
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Each participating group had local institutional board approval for their cohort study. Two data sets also had available data regarding the number of TACE performed per patient and post-TACE complications: vascular damage, significant haemorrhage, acute kidney injury and deterioration in liver function. All data were collected into a single data set file and the geographical origin was also included as a variable. In all data sets, HCC diagnosis was determined in accordance with established guidelines published by both the EASL and the AASLD (3, 4). We note that IRB approval limited the Chinese cohort from providing data for patients younger than 65. TACE technique
The CLIP multicentre trials (CLIP-01 and CLIP-03) did not impose a specific TACE procedure and the technique was left at each centre’s discretion according to their best clinical practice. In the Spanish study, after arteriography and portography, a mixture of lipiodol and doxorubicin (40–60 mg) or cisplatin (50–100 mg) and iodized oil (5–30 ml) was injected into the hepatic artery until stasis within the tumour vessels occurred. The feeding arteries to the HCC were embolized with gelatin sponge particles. In the Israeli center, after vascular imaging, whenever possible, super selective TACE was attempted using a co-axial microcatheter and a mixture of 50 mg doxorubicin with lipiodol oil and gelfoam slurry or powder. If dictated by tumour burden and feasibility (hepatic reserve, Child Pugh status), segmental or lobar TACE was performed. Percutaneous vascular closure devices were routinely employed from 2007 onward. Finally, the procedure in Hong-Kong included arteriography and superior mesenteric arterial portovenography. The right or left hepatic artery feeding the tumour was superselectively catheterized. Using the pumping method an emulsion was prepared by mixing cisplatin (1 mg/ml) with Lipiodol in a volume ratio of 1 to 1. Various amounts of the emulsion, up to a maximum of 60 ml (containing 30 mg of cisplatin) were injected slowly under fluoroscopic monitoring according to the size of the tumour and the arterial blood flow. This was followed by embolization with small gelatin sponge (Spongostan; Ferrosan, Johnson & Johnson Medical Ltd., Skipton, England) pellets of 1 mm diameter mixed with 40 mg of gentamicin. Analysis
Descriptive statistics were employed to present age groups characteristics. Categorical variables are presented as percentages and distributions, and continuous variables are presented with mean and standard deviation (SD). Associations between categorical variables were assessed with the Fisher exact test, and comparison of continuous variables was performed with the Student’s t-test or with the Mann–Whitney U test. Survival Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Cohen et al.
TACE in the elderly
charts were generated employing the Kaplan–Meier method and survival curves were compared with the log-rank test. Follow-up times were estimated using the reverse Kaplan–Meier methods. (23) After confirming that the proportional hazard assumptions were met, we determined the association of age group and potential confounders with mortality using the Cox proportional hazard regression analysis. To this end, we assessed several models; firstly, we included age at diagnosis, sex, year of diagnosis, HBV and HCV status, cirrhosis on diagnosis and disease stage. Not all data sets had all these variables available, and therefore, we repeated the models without the missing variables. All analyses were stratified per study of origin. We performed several sensitivity analyses. We repeated analysis without stratifying per study of origin. In addition, we assessed age at diagnosis as a continuous variable and also as a categorical variable in two strategies: (i) either above 80 years of age or lower; (ii) In three categories – younger than 65, 65–75 and above 75. We repeated the analyses with various risk stratification/staging scores. Because of the absence of patients younger than 65 from the Chinese study, we additionally analysed all included data for patients 65 years of age at diagnosis and older and stratified age group to patients between 65 and 70, 70–75 and older than 75. In all analyses, two tailed P-values below 0.05 were considered statistically significant. Results
The initiative led to the cooperation of investigators from four countries and included data previously pub-
lished from five patient cohorts. These are the CLIP1 and CLIP 3 cohorts from Italy (21), a cohort from Spain (20), a cohort from Hong-Kong, China (14) and an Israeli cohort (22). These five original data sets were assembled into one metadatabase including 548 patients: CLIP1 with 80 patients (14.6%), CLIP3 with 75 patients (13.7%), the Spanish cohort with 94 patients (17.2%), a Chinese cohort with 197 patients (36%) and an Israeli cohort of 102 patients (18.6%). There were 159 patients below the age of 65 (29%) at diagnosis, 269 (49%) patients diagnosed between the ages of 65 and 75, and 120 (22%) patients diagnosed at age 75 and older. There were 47 (8.6% of the entire cohort) patients who were diagnosed at age 80 or more. The studies were conducted in different eras with the CLIP studies occurring in the 1990’s and the Spanish and Israeli studies conducted later. The Chinese study was the only one that spanned more than 20 years, although most of the recruitment was done during the same period as the Israeli and Spanish studies. Patient characteristics are presented in Table 1. In the combined data set, females account for 24% of the patients, and 325 subjects (93%) were cirrhotic at diagnosis. The Chinese cohort included older patients, none under the age of 65. Among the non-Chinese countries, HBV was found in 21%% of the patients (range 15– 27%), in contrast, in the Chinese cohort, 63% of the patients were HBV carriers. Tables S1–S3 present the distributions of HCC score/stages in the three age groups. Age at diagnosis was positively associated with the era when this study was conducted (r = 0.15,
Table 1. Patient characteristics in the included databases
Female Cirrhosis on diagnosis HCV positive HBV positive Child A Child B Child C OKUDA I OKUDA II OKUDA III CLIP 0 CLIP 1 CLIP 2 CLIP 3 CLIP 4 CLIP 5 CLIP 6 Alive at end of follow-up Age at diagnosis* Months of follow-up†
Italy CLIP 1
Italy CLIP 3
Spain
Hong-Kong
Israel
Total
15 (19%) 76 (95%) 58 (76%) 20 (27%) 40 (51%) 35 (44%) 4 (4%) 3 (5%) 55 (86%) 6 (9%) 10 (19%) 23 (43%) 13 (24%) 3 (6%) 3 (6%) 2 (4%) 0 14 (18%) 63 (8) 51 (43–59)
14 (19%) 73 (97%) 49 (73%) 17 (23%) 33 (45%) 33 (45%) 8 (11%) 5 (7%) 62 (87%) 4 (6%) 6 (12%) 24 (46%) 18 (35%) 4 (8%) 0 0 0 8 (11%) 64 (8) 85 (50–121)
21 (22%) 78 (83%) 52 (55%) 14 (15%) 56 (60%) 30 (32%) 8 (9%) 52 (55%) 34 (36%) 8 (9%) 29 (31%) 30 (32%) 19 (20%) 7 (7%) 5 (5%) 3 (3%) 1 (1%) 32 (34%) 64 (9) 48 (36–60)
54 (27%) NA NA 112 (63%) 165 (84%) 32 (16%) 0 79 (40%) 116 (59%) 2 (1%) 48 (24%) 80 (41%) 54 (27%) 14 (7%) 1 (1%) 0 0 14 (7%) 75 (4) 100 (68–131)
27 (27%) 98 (97%) 68 (67%) 21 (21%) 84 (82%) 15 (15%) 3 (3%) 80 (78%) 21 (21%) 1 (1%) 35 (34%) 29 (28%) 29 (28%) 8 (8%) 1 (1%) 0 0 16 (16%) 67 (9) 62 (34–89)
131 (24%) 325 (93%) 227 (67%) 184 (35%) 378 (69%) 145 (27%) 23 (4%) 219 (41%) 288 (55%) 21 (4%) 128 (26%) 186 (37%) 133 (27%) 36 (7%) 10 (2%) 5 (1%) 1 (0.2%) 84 (15%) 69 (9) 69 (60–79)
*Mean (SD) †Reverse Kaplan–Meier estimate – Median (95% CI).
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P = 0.001), patients diagnosed at late dates were on average older. There was a negative association between date of diagnosis and disease stage: patients with Okuda I comprised 17%, 23%, 46% and 62% of the included patient cohorts during 1988–1992, 1993–1997, 1998– 2002, 2003–2008 respectively. Okuda II patients comprised 79%, 70%, 51% and 36% of the included respectively (P < 0.001). Figure 1 depicts dates of diagnosis, age at diagnosis and overall survival histograms, showing the individual contribution of each data set. Survival probabilities are presented in Table S4. Crude survival rates were similar between patients aged younger than 65, 65–75 and 75 and older (Fig. 2A). Median (95% CI) survival estimates were 23 (17–28), 21 (17–26) and 19 (15–23) months (P = 0.14) in the different age groups respectively. Stratified survival analysis per study group did not demonstrate significant survival difference between the age groups (all P-values between 0.1 and 0.9). Limiting the analysis to patients diagnosed since 2000 had no effect on the results of the latter years. Because our Chinese cohort included only patients older than 65, we stratified this age group to three strata 65–70, 70–75 and >75. Using univariate analysis, we saw that younger age was associated with better survival (Fig. S1). However, age was no longer a significant factor in the multivariate analysis, and disease stage remained the only independent prognostic predictor. Figure 2B depicts study-specific survival curves per each study group. Multivariate analysis models generated non-significant hazard ratios associating age and mortality. Disease stage was the dominant predictor of mortality (Table 2). These results were consistent when analyses were not stratified for study and when the CLIP staging system or the Child score was used instead of the Okuda score. Figures S2–S11 depict crude survival curves in each separate HCC score/stage. Survival periods prior to and after 2000, as well as separate crude survival curves, comparing the three age groups, prior to and after 2000 are also presented in Table S5 and Figures S12 and S13. Two data sets had additional data regarding adverse events (the Chinese and Israeli cohorts). A total of 43/ 299 (14.4%) patients had documented acute renal failure and 122/299 (41%) patients had evidence of deterioration in liver function (DLF). It should be noted that patients younger than 65 were all from the Israeli cohort and all had evidence of DLF following TACE (>50% INR and hepatocellular enzyme increases above the upper limit of normal). Age group rates of these complications are presented in Table 3. Rare complications included vascular complications 4/299(1.3%) and
Fig. 1. Time of diagnosis, extent of survival and age at diagnosis of included patients. Composite histograms representing distribution of diagnosis date (top panel), survival time (middle panel) and age at diagnosis (lower panel). In all panels, the contribution of each data set is presented in a unique colour.
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(A)
(B)
Fig. 2. Survival curves per age groups. (A) cumulative survival per age group; (B) Study-specific survival curves per age group.
significant haemorrhage (blood loss, either into the gastrointentinal tract or through vessel puncture, requiring transfusion of at least two blood units) 15/299 (5%). Discussion
In the absence of trials dedicated to elderly patients, the results of our study demonstrate that TACE is safe and provides similar benefits to elderly eligible patients with HCC as it does to younger HCC patients. We merged several institutional databases to analyse the largest population of elderly patients treated with TACE to date. Elderly patients, included in this study, did not suffer more adverse events compared with younger patients. Furthermore, the results show that these outcomes are similar for patients diagnosed over a 20-year period and in different countries. Most notable are the similarities Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
between Chinese patients and patients from Mediterranean and European countries. Current literature of TACE for HCC includes inconsistent age cut-offs to define “elderly”. In a 2002 metaanalysis of randomized controlled trials, the mean patient age in the included trials ranged between 41 and 66 (24). These studies defined elderly patients as those above 60 or 65 years of age (19,25–28). As is the case of the available information for other diseases and treatments, there is notable misrepresentation of the elderly in the data published so far on HCC (29). Given the increasing longevity, there is a need for relevant novel and confirmatory data regarding septagenerians, octogenerians and even older patients. Only a few studies have estimated survival among HCC patients older than 70, treated by different treatment modalities. A study of a cohort of patients with a
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TACE in the elderly Table 2. Univariate and multivariate hazard ratios for mortality
Female sex Cirrhosis on diagnosis HCV positive HBV positive Okuda II* Okuda III* Year of diagnosis Age at diagnosis† Age at diagnosis >80 Age at diagnosis 65–75‡ Age at diagnosis >75‡
Univariate
Model 1
Model 2
Model 3
Model 4
Model 5
0.84 (0.67–1.03) 1.16 (0.7–1.9) 0.97 (0.75–1.2) 1.02 (0.84–1.2) 1.5 (1.2–1.8) 3.7 (2.3–5.8) 0.99 (0.97–1.01) 1.08 (0.97–1.2) – –
0.7 (0.5–0.99) 0.8 (0.4–1.3) 0.8 (0.6–1.1) 0.9 (0.6–1.3) 2.2 (1.5–3.3) 7.1 (3.9–12.8) 0.95 (0.88–1.03) 1.05 (0.9–1.23) – –
0.7 (0.5–0.97) 0.7 (0.4–1.2) – 1.02 (0.73–1.4) 2.3 (1.6–3.4) 7.2 (4.04–13) 0.95 (0.88–1.03) 1.05 (0.9–1.2) – –
0.8 (0.6–1.02) – – 0.8 (0.65–1.06) 1.6 (1.2–2.0) 5.2 (3.1–8.5) 0.98 (0.95–1.02) 0.99 (0.98–1.01) – –
0.81 (0.64–1.02) – – 0.8 (0.65–1.05) 1.5 (1.2–1.9) 5.1 (3.1–8.5) 0.98 (0.95–1.02) – 0.94 (0.7–1.3) –
0.8 (0.64–1.02) – – 0.84 (0.66–1.06) 1.5 (1.2–2.0) 5.1 (3.1–8.5) 0.99 (0.96–1.02) – – 1.07 (0.83–1.4)
–
–
–
–
–
1.05 (0.75–1.5)
All models were stratified per study *Compared to Okuda I †Ten-year increment ‡Compared to patients younger than 65. Models: (1) Including disease stage, sex, HCV and HBV status, cirrhosis. Year of diagnosis and age of diagnosis. (2) Similar to model 1 but without HCV status, allowing far more inclusion of patients. (3) Similar to model 2, excluding cirrhosis at diagnosis. It was felt that disease stag was predictive enough. (4) Similar to model 3, however, age is treated dichotomously. (5) Similar to model 3, but using age in categories (below 65, between 65–75 and older).
Table 3. Incidence of acute kidney injury and deterioration in liver function per age group*
Acute kidney injury Deterioration in liver function
Younger than 65
65–75
Older than 75
P-value
8 (21%) 38 (100%)
24 (16%) 57 (37%)
11 (10%) 27 (25%)
0.23
