Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma

Research Article

Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma Rita Golfieri1,⇑, Josè Ignacio Bilbao2, Livio Carpanese3, Roberto Cianni4, Daniele Gasparini5, Samer Ezziddin6, Philipp Marius Paprottka7, Francesco Fiore8, Alberta Cappelli1, Macarena Rodriguez2, Giuseppe Maria Ettorre9, Adelchi Saltarelli4, Onelio Geatti5, Hojjat Ahmadzadehfar6, Alexander R. Haug7, Francesco Izzo8, Emanuela Giampalma1, Bruno Sangro2,10, Giuseppe Pizzi3, Ermanno Notarianni4, Alessandro Vit5, Kai Wilhelm6, Tobias F. Jakobs7, Secondo Lastoria8, on behalf of the European Network on Radioembolization with Yttrium-90 Microspheres (ENRY) study collaborators  1 Azienda Ospedaliero-Universitaria, Policlinico S. Orsola-Malpighi, Bologna, Italy; 2Clinica Universidad de Navarra, Pamplona, Spain; 3IFO Regina Elena National Cancer Institute, Rome, Italy; 4Ospedale Santa Maria Goretti, Latina, Italy; 5Azienda Ospedaliera Santa Maria della Misericordia, Udine, Italy; 6Uniklinik Bonn, Bonn, Germany; 7Ludwig-Maximilians Klinikum der Universität München, Munich, Germany; 8Istituto Nazionale Dei Tumori G. Pascale, Naples, Italy; 9San Camillo Hospital, Rome, Italy; 10Centro de Investigacion Biomedica en Red de Enfermedades Hepaticasy Digestivas (CIBEREHD), Spain

See Focus, pages 643–645

Background & Aims: The European Network on Radioembolization with Yttrium-90 resin microspheres study group (ENRY) conducted a retrospective study to evaluate the outcomes among elderly (P70 years) and younger patients (<70 years) with unresectable hepatocellular carcinoma (HCC) who received radioembolization at 8 European centers.

Keywords: Elderly patients; Hepatocellular carcinoma; HCC; Radioembolization; SIRT; Safety; Tolerability; Survival. Received 20 December 2012; received in revised form 19 April 2013; accepted 10 May 2013; available online 23 May 2013 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2013.07.007. ⇑ Corresponding author. Address: Department of Digestive Diseases and Internal Medicine, Radiology Unit, Sant’Orsola-Malpighi Hospital, Azienda OspedalieroUniversitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy. Tel.: +39 051 6362 311; fax: +39 051 6362 699. E-mail address: rita.golfi[email protected] (R. Golfieri).   See Addendum for collaborators. Abbreviations: HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; TACE, transarterial chemoembolization; BCLC, Barcelona Clinic Liver Cancer; AEs, adverse events; INR, International Normalized Ratio; MELD, Model for End-Stage Liver Disease; SIRT, selective internal radiation therapy; 90Y, Yttrium-90; ENRY, European Network on Radioembolization with Yttrium-90; EASL, European Association for the Study of the Liver; CT, computed tomography; AFP, alpha fetoprotein; ECOG, European Cooperative Oncology Group; 99mTc-MAA, Technetium-99m macroaggregated albumin; CTCAE, common toxicity criteria adverse events; GI, gastrointestinal; ANOVA, analysis of variance; SD, standard deviation; ALT, alanine transaminase; GBq, gigabecquerel; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, non-alcoholic steatohepatitis; REILD, radioembolization-induced liver disease; GGTP, gammaglutamyl transpeptidase.

Methods: Patients with confirmed diagnosis of unresectable HCC who either progressed following resection or locoregional treatment and/or who were considered poor candidates for chemoembolization were evaluated by a multidisciplinary team for radioembolization with 90Y-resin microspheres (SIR-Spheres; Sirtex Medical). The survival outcome and all adverse events were compared between the two age groups. Results: Between 2003 and 2009, 128 elderly and 197 younger patients received radioembolization. Patients in both groups had similar demographic characteristics. Many elderly and younger patients alike had multinodular, BCLC stage C disease, invading both lobes (p = 0.648). Elderly patients had a lower tumor burden, a smaller median target liver volume (p = 0.016) and appeared more likely to receive segmental treatment (p = 0.054). Radioembolization was equally well tolerated in both cohorts and common procedure-related adverse events were predominantly grade 1–2 and of short duration. No significant differences in survival between the groups were found (p = 0.942) with similar median survival in patients with early, intermediate or advanced BCLC stage disease. Conclusions: Radioembolization appears to be as well-tolerated and effective for the elderly as it is for younger patients with unresectable HCC. Age alone should not be a discriminating factor for the management of HCC patients. Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Research Article Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and its incidence is increasing [1,2] particularly in the elderly population, defined in this paper as those over the age of 70 years [3–5]. As the life expectancy improves within the general population, discussions on the best way to manage ageing HCC patients have become increasingly relevant. The elderly tend to be considered clinically ‘fragile’ due to comorbidities and a poorer performance status, which make them less amenable and/or tolerant to resection, transarterial or systemic treatment [6–8]. In the past, the elderly have been considered poor candidates for major surgery and non-surgical treatments such as radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), and transarterial chemoembolization (TACE). This assumption has been challenged by recent evidence, which suggests that the outcome of radical and/or other effective HCC treatments is not influenced by age, when the correct selection of patients is adopted [5,6]. However, since the majority of these data come from undifferentiated groups, not distinguished by prognostic factors [1,6], these results remain controversial and the impact of old age per se, as an independent factor affecting outcome, has yet to be clarified. After major hepatectomy for HCC, there is a trend towards higher morbidity and mortality rates in the elderly compared with the young [9], but these differences tend not to be statistically significant [9–11]. TACE is widely used as a non-surgical treatment and is considered to be effective in prolonging survival in patients with HCC and may be an acceptable alternative to surgery for high-risk elderly patients. The literature, however, reflects the divergent experience with TACE with equivalent outcomes in the young and old subjects in some studies [6,9,12,13], and poorer outcomes in the elderly in other studies [14,15]. RFA and PEI are radical therapies, which are recommended for very early stage HCC by the most recent amendment to the Barcelona Clinic Liver Cancer (BCLC) staging system [16]. Although the published data in the elderly are limited, a large series from Japan [17,18] has recently suggested that RFA might be as safe and as effective in elderly and non-elderly patients alike, and that both should be treated in the same manner. There is, however, some evidence from the US National Organ Procurement and Transplantation Network which suggests that age may be a key factor determining prognosis amongst the few elderly transplant recipients [19]. Overall, survival for septuagenarians with liver transplants (compared with younger patients) declined more rapidly with time when they have undergone transplantation (even though elderly transplant recipients tended to be healthier than younger transplant recipients with a lower incidence of diabetes, lower Body Mass Indices, lower International Normalized Ratios [INR], higher serum albumin levels, and a lower Model for End-Stage Liver Disease [MELD] score) [19]. Due to the greater incidence of confounding factors with increasing age, elderly patients are less likely to be eligible for treatment with resection and/or loco-regional therapies, regardless of disease stage, and instead tend to be managed with systemic therapies such as sorafenib [8]. The limited published data on sorafenib in the elderly indicated that increasing age does not appear to impact on the tolerability of sorafenib with a similar frequency of sorafenib-associated adverse events (AEs) and median

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treatment duration across the age groups [20,21]. However, Morimoto and colleagues observed that those patients older than 75 years tend to experience more frequent side effects with standard doses of sorafenib [20] and for those at increased risk for thromboembolic and/or bleeding events, therapy interruptions may increase the risk of a rapid disease progression [7]. Radioembolization (also known as selective internal radiation therapy [SIRT]) has been recently confirmed as an effective and well-tolerated therapy in intermediate- and advanced-stage HCC patients [22–26], but the effects of advancing age on the tolerance and clinical outcomes following radioembolization in elderly patients are largely unknown with only one previous published report in a cohort with either primary or metastatic liver tumors [27]. Therefore, a retrospective analysis was conducted by the European Network on Radioembolization with Yttrium-90 (90Y) resin microspheres (ENRY) study group to evaluate the clinical outcomes among elderly compared with younger patients based on the database generated by the radioembolization treatment of 325 patients with unresectable HCC performed at eight European centers. This analysis supplements the data, published in Hepatology [25], from the primary analyses of this cohort.

Materials and methods Patient enrollment Local Review Board authorization was received to conduct a retrospective analysis of consecutive elderly and younger patients with unresectable HCC who received radioembolization between 25 September, 2003 and 17 December, 2009. Prior to treatment, patients were evaluated by multidisciplinary teams for their suitability for radioembolization with 90Y resin microspheres (SIR-SpheresÒ; Sirtex Medical Limited, Sydney, Australia). All patients in these analyses had a confirmed diagnosis of HCC with liver-only or liver-dominant tumors, which had either progressed following surgical resection or loco-regional treatment and/or who were considered poor candidates for TACE because of presence of portal vein invasion or thrombosis or extensive tumor burden. Diagnosis of HCC was either histologically proven or based on the European Association for the Study of the Liver (EASL) criteria [16,28]. Baseline computed tomography (CT) scans of the abdomen and chest were performed in order to evaluate tumor burden, location, the volume of both the target tumor and liver. Laboratory blood tests, including a complete blood count, prothrombin time, liver function tests, creatinine, and alpha-fetoprotein level (AFP) measurements were obtained. Baseline functional performance status of each patient was determined according to the European Cooperative Oncology Group (ECOG) criteria. The appropriateness of radioembolization was considered by multidisciplinary teams consisting of hepatologists, oncologists, radiotherapists, physicians, and radiologists. Only patients who met the following inclusion criteria were considered for radioembolization [25]: ECOG performance status of 0–2; an untreated life expectancy of >12 weeks; not amenable to curative therapy (surgical resection, ablation or liver transplantation); uncompromised pulmonary function; adequate hematologic parameters (i.e., granulocyte count 1.5  109/L, platelets 50  109/L), renal function (creatinine <2.0 mg/dL), and liver function (i.e. bilirubin 62.0 mg/dL). Patients were excluded from radioembolization if there was: evidence of any uncorrectable flow to the gastrointestinal (GI) tract observed on angiography or Technetium-99m macroaggregated albumin (99mTc-MAA) scan; estimated radiation dose greater than 30 Gy (16.5 mCi) delivered to the lungs in a single administration or 50 Gy on multiple administrations; abnormal organ or bone marrow function (total bilirubin level >2.0 mg/dL in the absence of a reversible cause; serum albumin <3.0 g/dL); limited hepatic reserve; or ascites or other clinical signs of liver failure on physical examination. The radioembolization procedure has previously been described [25].

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JOURNAL OF HEPATOLOGY Follow-up All adverse events were graded using the National Cancer Institute Common Toxicity Criteria Adverse Events Version (CTCAE) 3.0. The nature and severity of all procedure-related events (fatigue, nausea and vomiting, abdominal pain, and fever) were evaluated from day 1 to day 7, laboratory changes from day 1 to month 3 and radiation-related events (long-term fatigue, GI ulceration, and pneumonitis) from day 8 to month 3 post-radioembolization. Statistical analysis All statistical analyses were conducted using SAS (SAS Institute Inc., Cary NC) version 9.2 XP Pro statistical analyses software. The Kaplan-Meier product-limit method was used to compute non-parametric estimates of survival. The p-values for continuous baseline variables were assessed by one-way ANOVA; the p-values for dichotomous variables by the Fisher’s exact test, and p-values for nominal categorical variables by the Chi-Square general association test. The CochranMantel-Haenszel was used to compare the CTCAE distribution between cohorts.

Results Patient characteristics One hundred and twenty-eight elderly patients (39.4%; mean age: 74; range: 70–87 years) and 197 patients <70 years (60.6%;

mean age: 58; range: 22–69.8 years) were included in this analysis (Table 1); details of a further sub-analysis of a small cohort of 49 very elderly patients who were at least 75 years old (mean age: 78.4; range 75–87 years) are provided in Supplementary Table 1. All patients (whether elderly or younger) chosen for radioembolization had similar baseline liver function tests (total bilirubin >1.5 mg/dL: 13.3% vs. 19.5%), Child-Pugh class A (85.2% vs. 80.7%), underlying cirrhosis (81.3% vs. 76.6%) and performance status (ECOG 0–1: 89.8% vs. 86.2%), respectively. A few patients beyond the inclusion criteria for radioembolization were treated at the discretion of the physician and evaluated, including 3 patients from one center with an ECOG performance status of 3. A greater proportion of younger patients presented with hepatitis B virus (HBV) infection, as compared to the elderly (7.8% vs. 16.3%: p = 0.028), whereas the rates of hepatitis C virus (HCV) infection were similar between the two groups (43.1% vs. 46.1%: p = 0.648). Prior procedures, such as surgery, ablation or TACE/TAE, were performed in similar proportions between the two groups (any prior procedure: 45.3% vs. 39.1%). In addition, both age groups had similar proportions of BCLC stage A and B patients. BCLC stage A patients who elected to receive radioembolization were either on the transplant waiting list or had tumors not amenable to resection or ablation; while

Table 1. Baseline patient, disease and treatment characteristics among elderly (P70 years) and younger patients (<70 years).

Characteristic

Parameter

Sex Age, yr ECOG performance statusi

Prior procedures

Cirrhosis Etiology Child-Pugh class Tumor burden (nodules)

Bilobar Extra-hepatic metastases Portal vein occlusion

Ascites Encephalopathy BCLC stage

Male Female Mean ± SD Range 0 1 2 3 Surgical (resection, transplant) Vascular (TACE/TAE) Ablation (PEI, RFA) Any prior procedure Yes Hepatitis B Hepatitis C A B 1 2-5 >5 Yes Yes (lymph, bone, adrenal, pulmonary) Patent Branch Main Yes Yes

Age ≥70 yr (n = 128) 102 (79.7%) 26 (20.3%) 74.3 ± 3.97 70.0-87.0 70 (54.7%) 45 (35.2%) 13 (10.2%) 0 25 (19.5%) 39 (30.5%) 15 (11.7%) 58 (45.3%) 104 (81.3%) 10 (7.8%) 59 (46.1%) 109 (85.2%) 19 (14.8%) 34 (26.6%) 50 (39.1%) 44 (34.4%) 65 (51.2%)i 8 (6.3%) 104 (81.3%) 16 (12.5%) 8 (6.3%) 12 (10.5%)ix 2 (1.8%)ix

Age <70 yr (n = 197) 163 (82.7%) 34 (17.3%) 58.1 ± 8.86 22.0-69.8 106 (54.1%) 63 (32.1%) 24 (12.2%) 3 (1.5%)i 31 (15.7%) 50 (25.4%) 14 (7.1%) 77 (39.1%) 151 (76.6%) 32 (16.3%)i 85 (43.1%) 159 (80.7%) 38 (19.3%) 44 (22.4%) 71 (36.2%) 81 (41.3%)i 107 (54.3%) 22 (11.2%) 145 (73.6%) 28 (14.2%) 24 (12.2%) 25 (14.1%)xi 5 (2.8%)xi

A B C D

21 (16.4%) 35 (27.3%) 72 (56.3%) 0

31 (15.7%) 52 (26.4%) 111 (56.3%) 3 (1.5%)

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p value between sub-groups 0.559 <0.001 0.486

0.452 0.373 0.167 0.300 0.338 0.028 0.648 0.371 0.212

0.648 0.170 0.172

0.471 0.708 0.660

755

Research Article Table 1 (continued)

>400

Age ≥70 yr (n = 128) 38 (30.6%)iv

Age <70 yr (n = 197) 71 (37.8%)vi

p value between sub-groups 0.225

ALT, IU/L

Mean ± SD >1.5 mg/dl Mean ± SD <3.5 g/dl Mean ± SD >1.2 Mean ± SD

1.1 ± 0.45 17 (13.3%) 3.6 ± 0.51 51 (43.6%)viii 1.2 ± 0.25ii 27 (21.3%)i 57.0 ± 46.36

1.1 ± 0.65ii 38 (19.5%)ii 3.6 ± 1.19 75 (41.9%)x 1.2 ± 0.25iii 48 (24.7%)iii 64.3 ± 50.78v

0.419 0.174 0.973 0.810 0.666 0.502 0.194

Creatinine, mg/dl

Mean ± SD

1.0 ± 0.25i

0.9 ± 0.37vii

0.033

Occlusion of non-target arteries (GDA, etc)

76 (59.4%)

122 (61.9%)

0.644

Activity, GBq, administered

1.5 0.5-4.0 62 (48.4%) 44 (34.4%) 9 (7.0%) 13 (10.2%) 127 (99.2%) 1 (0.8%) 167.2 3.0-1908 1340 98-3816 1610 (898-3816) 119 (93.0%) 7 (5.5%) 2 (1.6%)

1.7 0.3-3.9 94 (47.7%) 75 (38.1%) 19 (9.6%) 9 (4.6%) 195 (99.0%) 2 (1.0%) 250.0 2.2-4000 1470 240-5566 1874 (859-5566) 180 (91.4%) 16 (8.1%) 1 (0.5%)

0.078

Characteristic

Parameter

α-fetoprotein, ng/ml Total bilirubin, mg/dl Albumin, g/dl INR

Target treatment

Treatment approach Target tumor volume, ml Target liver volume, ml Whole liver volume, ml Number of treatments

Median Range Whole liver Right lobe Left lobe Segmental Single session Sequential lobar Median Range Median Range Median Range 1 2 3

0.214

1.000 0.006 0.008 <0.001 0.880

Percentages calculated on available data. Missing baseline data on i1 patient; ii2 patients; iii3 patients; iv4 patients; v5 patients; vi9 patients; vii10 patients; viii11 patients; ix14 patients; x18 patients; xi20 patients. p Value for continuous variables by one-way ANOVA, p values for dichotomous variables by Fisher’s exact test, and p value for nominal categorical variables by Chi-Square general association test.

BCLC stage B patients received radioembolization if they were considered either poor candidates for radical therapy or TACE (due to bilobar and/or multiple [>5] tumors) or had disease progression following TACE. Assessment prior to radioembolization found that many elderly and younger patients alike had multinodular (73.4% vs. 77.6%), advanced BCLC stage C disease (56.3% vs. 56.3%) invading both lobes (51.2% vs. 54.3%). Elderly patients had a lower tumor burden in the liver (median target tumor volume: 167.2 vs. 250.0 mL; p = 0.006), a smaller median target liver volume (1340 vs. 1470 mL; p = 0.008), a smaller whole liver volume (1610 vs. 1874 mL; p <0.001) and may have been more likely to receive segmental treatment (10.2% vs. 4.6%; p = 0.069 for segmental compared with other treatment approaches), and these findings were also reflected in the very elderly cohort (Supplementary Table 1). Radioembolization was mostly performed as a single procedure in both elderly and younger cohorts (93.0% vs. 91.4%, respectively). Safety and tolerability Radioembolization was equally well tolerated in all cohorts (Table 2 and Supplementary Table 2). Common procedure756

related adverse events (fatigue, nausea and/or vomiting, abdominal pain, fever, and raised bilirubin) were predominantly of mild-to-moderate intensity and of short duration. Of the common procedure-related events which occurred in the elderly, none were grade P3 in the very elderly cohort (P75 years, n = 49) except one patient with grade 3 fatigue and 2 patients with grade 4 changes in bilirubin. Gastrointestinal (GI) ulceration was predominantly of mild or moderate severity in both the younger and elderly patients (p = 0.320). Severe GI ulcers (grade P3) were less common in elderly than younger patients (0.8% vs. 2.7%). Severe increases in total bilirubin (to grade P3) at 3 months compared to baseline were observed in 4.3% and 6.9% of the elderly and younger populations, respectively (p = 0.432) (Table 3) and 4.2% of the very elderly (Supplementary Table 3). A greater number of elderly patients experienced hypoalbuminemia (p = 0.018) and elevated alanine transaminase (ALT) (p = 0.015) at 3 months, although these changes were restricted to grade 1–2. Of the 201 deaths recorded in the overall cohort of 325 patients during a median follow-up of 10.0 months (range 0.2– 48.0), 3 (0.9%) were considered to be definitely related and 11 (3.4%) were considered to be probably related to the procedure.

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JOURNAL OF HEPATOLOGY Table 2. Main procedure-related clinical adverse events in the elderly (P70 years) and younger patients (<70 years) in the first 3 months post-treatment by severity (CTCAE v3).

CTCAE Study sub-group

N

Fatigue Age ≥70 yr 128 Age <70 yr 197 Nausea and/or vomiting Age ≥70 yr 128 Age <70 yr 197 Abdominal pain Age ≥70 yr 128 Age <70 yr 197 Fever Age ≥70 yr 128 Age <70 yr 197 GI ulceration Age ≥70 yr 128 Age <70 yr 197

All Grades

Grade 1

CTCAE v3: number (%) of patients Grade 2 Grade 3 Grade 4

Grade 5

p value between sub-groups†

68 (53.1%) 58 (45.3%) 109 (55.3%) 94 (47.7%)

8 (6.3%) 9 (4.6%)

2 (1.6%) 6 (3.0%)

0 0

0 0

0.658

41 (32.0%) 63 (32.0%)

36 (28.1%) 53 (26.9%)

5 (3.9%) 9 (4.6%)

0 1 (0.5%)

0 0

0 0

0.806

31 (24.2%) 57 (28.9%)

26 (20.3%) 44 (22.3%)

5 (3.9%) 8 (4.1%)

0 5 (2.5%)

0 0

0 0

0.165

19 (14.8%) 21 (10.7%)

17 (13.3%) 19 (9.6%)

2 (1.6%) 2 (1.0%)

0 0

0 0

0 0

0.269

3 (2.3%) 9 (4.6%)

0 3 (1.5%)

2 (1.6%) 1 (0.5%)

1 (0.8%) 4 (2.0%)

0 0

0 1 (0.7%)

0.320

CTCAE v3: Common Terminology Criteria for Adverse Events version 3.0.   p Value for CTCAE distribution comparison between cohorts by Cochran-Mantel-Haenszel row mean score test statistic.

Table 3. Comparison of laboratory toxicities in the elderly (P70 years) and younger patients (<70 years) by severity (CTCAE v3) between baseline and month 3.

CTCAE Study sub-group Total bilirubin Age ≥70 yr Age <70 yr Albumin Age ≥70 yr Age <70 yr ALT Age ≥70 yr Age <70 yr INR Age ≥70 yr Age <70 yr Creatinine Age ≥70 yr Age <70 yr Platelets Age ≥70 yr Age <70 yr

N

Pre-radioembolization All grades Grade ≥3‡

Month 3 All grades Grade ≥3‡

Change of CTCAE grade at month 3 p value between † Decreased Same Increased sub-groups

117 175

20.5% 24.0%

0 0

50.4% 47.4%

4.3% 6.9%

2.6% 6.3%

59.0% 59.4%

38.5% 34.3%

0.432

97 140

38.1% 37.9%

0 0

45.4% 35.7%

1.0% 0.7%

10.3% 13.6%

62.9% 72.9%

26.8% 13.6%

0.018

109 163

53.2% 63.8%

1.8% 1.8%

57.8% 57.1%

2.8% 3.7%

11.0% 18.4%

67.9% 70.6%

21.1% 11.0%

0.015

113 164

23.0% 22.0%

0 0

33.6% 29.9%

0 3.0%

3.5% 4.3%

82.3% 80.5%

14.2% 15.2%

0.911

115 161

8.7% 8.1%

0 0.6%

13.0% 10.6%

0 2.5%

2.6% 1.2%

89.6% 91.9%

7.8% 6.8%

0.906

102 166

47.1% 42.8%

1.0% 3.0%

52.0% 53.0%

1.0% 4.8%

9.8% 9.0%

74.5% 71.1%

15.7% 19.9%

0.408

CTCAE: Common Terminology Criteria for Adverse Events version 3.0;   Differences in CTCAE grade from baseline to month 3 (month 3 minus baseline) between cohorts were assessed by the Wilcoxon rank sum test. à Differences in laboratory values between baseline and month 3 were also assessed by McNemar test regarding Grade 3–4 CTCAE (Yes/No) at month 3 vs. Grade 3–4 CTCAE at month 0, and were statistically significant (p <0.05) for total bilirubin in the age <70 year cohort (p <0.001), and showed a trend for total bilirubin in the age P70 year cohort (p = 0.063).

All-cause mortality did not differ significantly between the young and elderly on day 30 (2 ([1.0%]) vs. 0 (0.0%); p = 0.521), day 60 (8 [4.1%] vs. 5 [3.9%]; p = 1.000) or day 90 after the procedure (13 [6.6%] vs. 9 [7.0%]; p = 1.000).

Overall survival Kaplan-Meier analysis revealed no significant difference in survival following radioembolization between elderly and younger

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Research Article Table 4. Comparison of survival by age in the elderly (P70 years) and younger patients (<70 years).

Characteristic

All patients ECOG performance status

Child-Pugh class Tumor burden (nodules) Bilobar Extra-hepatic metastases Portal vein occlusion Ascites BCLC stage

α-fetoprotein Total bilirubin INR ALT

0 1-2 3 A B 1-5 >5

N 128 70 58 0 109 19 84 44

Median overall survival (mOS), months (95% CI)† Age ≥70 yr (n = 128) Age <70 yr (n = 197) mOS (95% CI) p value N mOS (95% CI) p value 14.5 (10.6-16.8) n.a. 197 12.8 (10.8-17.9) n.a. 16.6 (12.4-33.7) 0.070 106 18.4 (12.8-22.8) <0.001 10.7 (8.2-15.3) 87 8.3 (6.6-11.4) n.a. 3 5.2 (2.2-n.r.) 15.3 (10.9-18.4) 0.015 159 13.6 (11.4-18.8) 0.088 7.4 (4.4-15.7) 38 10.3 (5.5-19.4) 16.8 (10.9-24.5) 0.012 115 15.9 (12.4-22.1) 0.001 10.7 (6.0-13.1) 81 9.5 (7.2-11.8)

No Yes No Yes Patent Branch/main No Yes A B C D ≤400 ng/ml >400 ng/ml ≤1.5 mg/dl >1.5 mg/dl ≤1.2 >1.2 ≤Median >Median

62 65 120 8 104 24 102 12 21 35 72 0 86 38 111 17 100 27 64 64

15.8 (10.0-19.8) 12.4 (8.3-16.6) 15.1 (10.7-17.1) 8.3 (1.1-13.1) 15.7 (10.9-18.6) 8.3 (5.3-10.9) 16.8 (10.9-19.8) 6.6 (3.9-14.5) 23.7 (15.1-38.1) 16.9 (10.6-n.r.) 10.3 (7.4-13.1) n.a. 18.4 (12.6-24.5) 8.2 (6.8-13.1) 15.7 (10.7-18.4) 8.3 (3.1-15.3) 12.6 (10.0-16.8) 18.6 (7.4-31.7) 18.6 (10.7-31.7) 10.9 (7.4-14.9)

Parameter

0.427 0.061 0.008 <0.001 0.002

0.001 0.048 0.466 0.073

90 107 175 22 145 52 152 25 31 52 111 3 117 71 157 38 146 48 98 94

17.9 (11.9-29.5) 11.2 (8.6-13.8) 13.6 (11.2-18.8) 7.2 (4.3-17.9) 13.6 (10.9-19.4) 10.8 (7.7-13.8) 13.6 (11.2-18.4) 6.1 (3.4-8.6) 27.4 (19.4-46.8) 18.4 (12.8-22.8) 9.7 (7.5-11.7) 5.2 (2.2-n.r.) 18.8 (12.8-22.1) 10.3 (7.2-11.9) 14.1 (11.2-19.1) 9.5 (5.3-13.8) 18.4 (13.6-22.1) 7.7 (5.6-9.5) 15.4 (11.9-19.4) 10.8 (8.6-15.5)

0.002 0.008 0.076 <0.001 <0.001

0.017 0.023 <0.001 0.106

 

Median survival calculated by Kaplan-Meier analysis. 95% CI, 95% confidence interval; n.a., not applicable; n.r., not reached.

patients (median 14.5 [95% CI 10.6–16.8] months vs. 12.8 [95% CI 10.8–17.9] months, respectively; p = 0.942) (Table 4 and Fig. 1). Further analysis by patient age revealed that median survival in the very old (P75 years; n = 49) and in patients <75 years (n = 276) was 14.9 (95% CI 8.3–23.7) months and 12.8 (95% CI 10.9–15.8) months, respectively (Supplementary Table 4); and in patients P65 years (n = 183) and <65 years (n = 142), median survival was 13.6 (95% CI 10.9–16.8) months and 12.8 (95% CI 10.4–17.9) months, respectively. Median overall survival of elderly and younger patients was similar in patients with early, BCLC stage A disease (23.7 [15.1–38.1] vs. 27.4 [19.4–46.8] months), intermediate, BCLC stage B disease (16.9 [10.6–not reached] vs. 18.4 [12.8–22.8] months) or advanced BCLC stage C disease (10.3 [7.4–13.1] months vs. 9.7 [7.5–11.7] months), respectively. Broadly equivalent trends were observed in the very elderly, elderly, and the young for each prognostic variable, with no significant differences between the two cohorts (Table 4 and Supplementary Table 4).

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Discussion A worldwide trend towards increased age in patients who are diagnosed with HCC has been observed [2,4,5,29] in developed countries, where HCV and alcohol account for most cases of HCC. The median age of patients at diagnosis is now over 60 years [30], and the proportion of elderly patients is expected to increase, due to a number of epidemiological phenomena: (1) the spread of HCV, which is more common in the elderly patients, counterbalanced by the decreasing incidence of HBV infection due to vaccination campaigns [4]; (2) the rising incidence of cirrhosis due to alcohol abuse and metabolic disorders such as ‘cryptogenic’ and non-alcoholic steatohepatitis (NASH)-related cirrhosis [3,4,6,29]; and (3) the ‘delaying’ effect of anti-viral therapy on the primary as well as secondary occurrence of HCC in HBV and HCV infected cases is well documented [31]. Therefore, compared with younger patients, HCC in elderly patients is associated with different underlying liver disease with lower rates of HBV [11,32], but a higher incidence of HCV-infection, alcohol

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1.00

Parameter n

0.75

Age <70 yr 197 12.8 mo Age ≥70 yr 128 14.5 mo

Median survival (95% CI) (10.8-7.9) (10.6-6.8)

p = 0.942

0.50

n

=

38 = n

= n

n

11 6

32 5

0.00

13

0.25

=

Survival distribution function

JOURNAL OF HEPATOLOGY

0 6 12 18 24 30 36 42 48 54 Time from radioembolization (mo) Fig. 1. Kaplan-Meier analysis of overall survival by age.

abuse and/or genetic susceptibility to the development of HCC [4,6,32,33]. Our results confirm a significantly lower proportion of elderly patients with hepatitis B whereas the rate of HCV-associated HCC was similar in both groups. Regarding gender, contrary to the literature indicating a gradual increase in the proportion of the female population affected by HCC with increasing age [9,32,34,35], our results did not show any gender prevalence between the elderly and non-elderly groups. The exact reason for this discordance of the sex ratio in our findings, compared with previous studies, is unclear. Evaluating the distribution of prior treatments (received by >40% of patients in this study), no statistical difference was found in the number of vascular procedures (TACE/TAE), ablations and resections previously performed in the elderly and non-elderly groups. This suggests that, although the elderly group was presumed to poorly tolerate more intensive or invasive treatments, in reality, other factors such as performance status may come into play in the decision making. The Italian survey by Mirici Cappa and colleagues [6] indicated a trend towards the less frequent use of aggressive therapies in the elderly, but for those patients who were treated with TACE and RFA, the treatment was welltolerated regardless of age. These finding are in agreement with other studies [5,33] reporting that an age beyond 70 years does not influence the outcome of radical and/or effective HCC treatments, providing that the correct selection of patients is adopted. As expected, a patient’s underlying clinical state was the major determinant when choosing the therapeutic modality. Of interest, we found that elderly patients had a significantly lower median tumor burden in the liver, which more frequently allowed segmental treatment as compared to the younger patients. This difference could be related to a significantly smaller median target liver volume, which reflected the difference in whole liver volume. A negative correlation between age and liver volume has been previously reported and confirms that elderly patients have smaller livers, as a consequence of ageing [36]. In addition, delayed tumor growth (less aggressive tumors) in elderly patients may have also been a factor, since we found that younger patients tended to have more advanced disease, with more frequent extrahepatic metastasis, portal occlusion, an increased number of nodules and higher tumor burden; although there was no significant difference in survival by BCLC stage between the elderly and younger cohorts. In our series, the number of radioembolization treatments was similar in both groups and was equally well tolerated. Considering that the study we performed was not a clinical trial and therefore the policies may be different across centers, we considered only patients with liver-only or liver-dominant

tumors, which had either progressed following surgical resection or loco-regional treatment and/or patients who were considered poor candidates for TACE because of presence of portal vein invasion or thrombosis or extensive tumor burden. These data are described in Table 1, which clearly demonstrated that the distribution of prior treatments is similar in both age groups. Common procedure-related AEs (fatigue, nausea and/or vomiting, abdominal pain and fever) were predominantly grade 1–2 and of short duration. A significantly greater number of elderly patients experienced grade 1–2 hypoalbuminemia and elevated ALT at 3 months; although these changes were clinically irrelevant. Safety and tolerability in our study population were similar to previous experiences with radioembolization [23,24], where the incidence of fatigue was reported to be 54% to 61% together with abdominal pain (23–56%), nausea and/or vomiting (20–30%), and low-grade fever (3–12%). Overall, these adverse events appear to be significantly milder than the post-embolization syndrome observed after conventional TACE. In our series, an increase in total bilirubin (to grade P3) at 3 months compared to baseline was observed in a similar number of elderly and younger patients. Nearly 6% of the whole patient population (almost half of them treated with wholeliver approach) had grade 3 or higher CTCAE bilirubin levels at 3 months after therapy [25]. This is lower than the rate of 14% reported up to 3 months after radioembolization with 90 Y-glass microspheres (mostly treated in a lobar approach) in the other large study from Chicago [23]. The current opinion is that this early increase in bilirubin levels reflects some degree of radioembolization-induced liver disease (REILD). REILD has been described in some non-cirrhotic patients as a form of sinusoidal obstruction syndrome appearing 4–8 weeks after radioembolization, with signs of jaundice, mild ascites and a moderate increase in gamma-glutamyl transpeptidase (GGTP) and alkaline phosphatase, and as such is not true liver decompensation [37,38]. Cirrhotic patients have been shown to develop a similar syndrome for which the histological background is still unknown [39]. This opinion is further supported by the fact that the increase in bilirubin observed after radioembolization is distinct from other changes reflecting impaired liver function such as decreased albumin levels or prothrombin activity [25]. In fact, a worsening of CTCAE grade (mostly 1 or 2) of albumin after radioembolization was observed in 27% and 14% of elderly and young patients (p = 0.018), but relevant changes (grade 3 or higher) were observed in a similar proportion of elderly and young patients alike (1.0% and 0.7% of patients, respectively). In order to assess further whether advancing age was a factor in the development of clinically significant liver function changes after radioembolization, additional analyses were conducted in patients 75 years or older. These data reveal that there was no significant increase from baseline in the incidence of grade P3 ALT 3 months after radioembolization (from 2 [4.5%] patients to 3 [6.8%] patients; p = 1.00) and bilirubin (from 0 to 2 [4.2%] patients; p = 0.500), and there were no patients P75 years with grade P3 changes in albumin. Similarly, increases in INR CTCAE grade occurred in 14% and 15% of the elderly (P70 years) and young patients, without any grade 3 or higher increases in prothrombin adverse events even in patients P75 years old. These findings emphasize the

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Research Article good safety profile of radioembolization in both the elderly and young. Concerning efficacy, our study demonstrated similar median survival, regardless of age following radioembolization in the elderly and non-elderly groups. Our data confirm that, similar to other treatments [6,12,34], prognosis after radioembolization largely depends on pre-treatment liver function and tumor burden but not on patients’ age. Assessment of patients by disease stage found that median overall survival did not significantly differ between the elderly (including very elderly) and younger cohorts with advancing BCLC stage disease (Table 4 and Supplementary Table 4). Assessment of each prognostic variable found no significant differences in overall survival between the two cohorts (Table 4 and Supplementary Table 4) and confirmed that disease stage, rather than age, was the main driver of overall survival. A large European retrospective analysis of HCC patients has recently found that life expectancy of patients with HCC is unaffected by age, despite a higher prevalence of comorbidities and a mean difference in age between the elderly and young group of 14 years; thereby indicating that the occurrence of HCC (with a low survival [<20%] at 5 years) outweighs the impact of both comorbidity and age per se on life expectancy [6]. Only disease stage was found to be an independent predictor of survival. When elderly and younger groups were matched for the main confounding factors, the prognosis for each type of treatment (RFA, PEI or TACE) was similar in elderly and younger patients, indicating that the treatment did not adversely impact outcome; although elderly individuals were more likely to receive percutaneous procedures and less likely to receive hepatic resections or TACE [6]. When compared to TACE and sorafenib, radioembolization in the present series provides similar survival rates across tumor stages [24,25,40,41]. However, the mildness of procedure-related events after radioembolization compared with TACE, together with a longer time-to-progression and similar survival times, suggests that radioembolization could replace TACE in the elderly or in more fragile HCC patients [41]. In our opinion, an effective single procedure such as radioembolization may be more acceptable to elderly patients than multiple procedures with TACE. While sorafenib also represents a good treatment option for elderly patients, the increased frequency of adverse events with age (beyond 75 years), without dose-modification, may impact the outcome of very old patients [8]. The main limitation of our study was that analyses were retrospective, although many patients were followed prospectively. The study therefore only gives information on the patients treated. While it is difficult to provide a retrospective assessment of the number of patients who did not meet the strict patient selection criteria for radioembolization, we have estimated that of those referred to our tertiary care centers as potential candidates for radioembolization, approximately 12–15% could not be treated with radioembolization after detailed pretreatment work-up due to factors including excessive hepato-pulmonary shunting or uncorrectable vascular abnormalities, and this proportion of patients did not differ by age. The findings of our analyses are consistent across the age groups suggesting that even in this retrospective analysis, the recommendations from the manufacturer and expert consensus [42] were largely followed (with only a few treated patients with compromised liver function or ECOG performance status >2).

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Our data clearly support the need for further studies using a prospective randomized design to better delineate the survival benefits in younger and older HCC patients, eventually by using a propensity score analysis to determine prognostic predictors of survival in both groups. In conclusion, for patients with unresectable HCC that meet the eligibility criteria and do not have concomitant disorders that would otherwise preclude treatment, radioembolization appears to be a well-tolerated and effective treatment option for the elderly patients, for whom tolerability and time in hospital may be important considerations.

Conflict of interest RG, JIB, FTK, TFJ, and RTH have received honoraria for scientific presentations from Sirtex Medical Ltd, Sydney, Australia.

Addendum The European Network on Radioembolization with Y90 Microspheres (ENRY) Study Collaborators: Cinzia Pettinato, Bruna Angelelli, Fabio Monari, Matteo Renzulli, Cristina Mosconi, Maria Cristina Galaverni, Renzo Mazzarotto, Gilberto Gavaruzzi, Stefano Fanti (Azienda Ospedaliero-Universitaria, Policlinico S. Orsola-Malpighi, Bologna, Italy); Giovanni Vennarecci, Roberto Santoro (General Surgery and Transplantation San Camillo Hospital, Rome, Italy); Giuseppe Pelle, Luca Filippi (Ospedale Santa Maria Goretti, Latina, Italy); Giudo Ferretti (Azienda Ospedaliera Santa Maria della Misericordia, Udine, Italy); Christiane Kuhl (Uniklinik Bonn, Germany); Peter Bartenstein, Maximilian F. Reiser, Frank Thomas Kolligs, Ralf Thorsten Hoffmann (LMU Klinikum der Universität München, Munich, Germany).

Acknowledgements The authors wish to thank their colleagues within the European Network on Radioembolization with Yttrium-90 resin microspheres (ENRY) group who gave their support to the realization of this study: Pamplona: Javier Arbizu, Alberto Benito, Jose I. Bilbao, Delia D’Avola, Mercedes Iñarrairaegui, Macarena Rodriguez, Bruno Sangro; Rome: Livio Carpanese, Giuseppe M. Ettorre, Carlo L. Maini, Michele Milella, Giuseppe Pizzi, Rosa Sciuto, Giovanni Vennarecci; Bologna: Bruna Angelelli, Alberta Cappelli, Emanuela Giampalma, Rita Golfieri, Cristina Mosconi, Matteo Renzulli, Cinzia Pettinato, Fabio Monari, Renzo Mazzarotto; Udine: Guido Ferretti, Daniele Gasparini, Onelio Geatti, Orfea Manazzone, Giorgio Soardo, Pierluigi Toniutto, Alessandro Vit; Latina: Oreste Bagni, Roberto Cianni, Antonio D’Agostini, Ermanno Notarianni, Adelchi Saltarelli, Rita Salvatori, Carlo Urigo; Napoli: Vittorio Albino, Luigi Aloy, Cecilia Arrichiello, Roberto D’Angelo, Francesco Fiore, Francesco Izzo, Secondo Lastoria; Bonn: Hojjat Ahmadzadehfar, Samer Ezziddin, Carsten Meyer, Holger Palmedo, Hans Heinz Schild, Volker Schmitz, Kai Wilhelm; Munich: Peter Bartenstein, A Haug, Ralf T. Hoffmann, Tobias F. Jakobs, Frank T. Kolligs, Philipp M. Paprottka, Christoph Trumm.

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JOURNAL OF HEPATOLOGY Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jhep.2013. 05.025.

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