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Transarterial chemoembolization and sorafenib in hepatocellular carcinoma Expert Rev. Anticancer Ther. 14(7), 831–845 (2014)
Giuseppe Cabibbo1*, Silvia Tremosini2, Giovanni Galati3, Giancarlo Mazza4, Gennaro GadaletaCaldarola5, Giuseppe Lombardi6, Michela Antonucci7 and Rodolfo Sacco8 1 Section of Gastroenterology, DIBIMIS, University of Palermo, 90127 Palermo, Italy 2 Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic Barcelona, IDBAPS, University of Barcelona, Spain 3 Hepatology Unit, Campus Bio Medico University, 00128 Rome, Italy 4 Department of Radiology, Civil Hospital of Brescia, 25123 Brescia, Italy 5 Medical Oncology Unit “Mons. R. Dimiccoli” Hospital, Barletta, Italy 6 Medical Oncology 1, Venetian Oncology Institute – IRCCS, Padua, Italy 7 Section of Radiology, Di.Bi.Me.F. University of Palermo, Palermo, Italy 8 Gastroenterology and Metabolic Diseases Unit, Pisa University Hospital, Pisa, Italy *Author for correspondence: Tel.: +39 091 655 2280 Fax: +39 091 655 2156 [email protected]
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Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients. KEYWORDS: combination therapy • HCC • intermediate stage • sorafenib • TACE
Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance and one of the most frequent cause of cancer-related mortality worldwide. Given the complexity of the disease and the lack of effective treatment options, the mortality rate associated with HCC is high and the prognosis is poor, especially in case of advanced disease, symptomatic patients or presence of liver function impairment. Systematic screening and early detection are therefore the primary objectives in HCC treatment, as the stage of cancer dictates the therapeutic choice [1]. Patients affected by HCC can be classified according to the Barcelona Clı´nic Liver Cancer (BCLC) staging system, which is recommended by the guidelines of the European Association for the Study of Liver (EASL) for prognostic prediction and treatment allocation. The BCLC classification divides HCC patients into five stages (0, A, B, C and D) and is based on prognostic and treatment-related variables including tumor status, liver function and health performance status (PS) [2]. A flow chart of HCC patients classification according to the BCLC staging system, patients’ characteristics and most appropriate therapies is depicted in FIGURE 1 [3]. Transarterial chemoembolization (TACE) is currently recommended as first-line therapy in
10.1586/14737140.2014.920694
the treatment of patients at intermediate stage of the disease (BCLC-B class), characterized by multinodular asymptomatic tumors without an invasive pattern [2,4,5]. According to the results of two meta-analyses [6,7] of the pooled data from randomized controlled trials, TACE has been established as the standard locoregional therapy in this class of patients, who can benefit from a relevant increase in survival, from a median of 16 months up to 19–20 months [8]. Sorafenib, an oral multityrosine kinase inhibitor, is the only drug approved as systemic therapy in patients with HCC [9]. Results from a doubleblind placebo-controlled Phase III study (SHARP trial) demonstrated that sorafenib significantly prolongs overall survival (OS) and time to progression (TTP) in patients with HCC [10]. These results were confirmed in another Phase III trial conducted in an Asia-Pacific population [11]. Current guidelines and report opinions recommend the use of sorafenib in patients with intermediatestage HCC (BCLC-B) with progressing tumors, who failed to respond or are not eligible to TACE therapy [2,12]. Although conventional TACE is frequently used for the treatment of patients with intermediate-stage HCC, there is still a lack of standardization in treatment methodology, and
2014 Informa UK Ltd
ISSN 1473-7140
831
Review
Cabibbo, Tremosini, Galati et al.
HCC Stage A–C Okuda 1–2, PS 0–2, Child-Pugh A–B
Very early Early stage (A) stage (0) Single or 3 nodules Single 100 μm
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O2
Aorta
Transarterial Chemoembolization TACE Hepatic arthery Hypoxia
VEGFR
Tumor cell
Sorafenib VEGF HIFα
PDGFR
HIFα Pro
Pro
HIFα Pro
PDGF Endothelial cell Transcription of HIF target genes VEGF, Ang2 NOS, PDGFb
Figure 2. Post-transarterial chemoembolization hypoxia and tumor necrosis cause the activation of hypoxia-induced factor target genes, such as VEGF and PDGF, which promote angiogenesis and tumor growth and whose activity is blocked by the presence of sorafenib. Ang2: Angiopoietin-2; HIF: Hypoxia-induced factor; NOS: Nitric oxide synthase; TACE: Transarterial chemoembolization; PDGFR: PDGF receptor; VEGFR: VEGF receptor.
treated HCC. For example, the hypoxic change induced by TACE in the hepatic hilus (S1) is usually stronger than that generated in other areas, possibly inducing a more substantial expression of VEGF. In these cases, the OS and TTP achieved with the combination therapy would be underestimated. Several studies, which investigate the efficacy and safety of the combination of TACE and sorafenib in patients with intermediate-stage HCC, have been published to date, and a number of trials using the same strategy are ongoing. We conducted a systematic review to present and critically discuss available evidence on the use of TACE in combination with sorafenib in HCC patients. Studies are evaluated according to the characteristics and the classification of patients (intermediate- or advanced-stage HCC) and the type of treatment provided: either combination or sequential use of TACE and sorafenib. informahealthcare.com
Search strategy & data presentation
With the aim to identify the key publications specifically addressing the efficacy and safety of the combination of TACE and sorafenib in HCC patients, a literature search was conducted from the MEDLINE database using the search terms ‘hepatocellular carcinoma’, ‘liver cancer’ and ‘primary liver carcinoma’, either individually or in combination with the terms ‘randomized’, ‘controlled clinical trials’, ‘clinical trials’, ‘Phase III studies’, ‘meta-analysis’, ‘combined therapy’, ‘treatment’, ‘liver cancer’, ‘TACE’, ‘TAE’, ‘chemoembolization’, ‘embolization’, ‘locoregional treatments’, ‘sorafenib’ and ‘systemic therapy’, as well as by a manual search and review of reference lists. We also browsed the abstract collection of major oncology and hepatology congresses (ASCO, ESMO, EASL, AASLD, ILCA), but studies reported only in abstract form 833
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were considered for inclusion only if published in the last 2 years. The search was limited to studies published in English, without any limitation on the publication date. Studies not directly evaluating the strategy under investigation were discarded; we did not include studies that were the combination of TACE, and sorafenib was associated to other local therapies such as surgery, local ablation or radioembolization. Clinical trial databases (e.g., clinicaltrial.gov) were also searched to identify ongoing studies. The search was last updated on the 3 March 2014. For published studies, data are presented according to the type of TACE used in the study: conventional or DB-TACE. Due to the heterogeneity of the populations and outcomes analyzed in each study, a pooled statistical analysis of the results was not performed. Identified studies
Our MEDLINE query resulted in 42 papers. Of these, 10 were studies addressing the combination of conventional TACE (c-TACE) and sorafenib [30–39], whereas three addressed DBTACE in combination with sorafenib [40–42]. Among the studies on c-TACE, eight investigated a concomitant treatment strategy either on intermediate- (n = 6) or advanced-stage (n = 2) HCC patients [30–37], while two evaluated the sequential treatment of c-TACE and sorafenib [38,39]. All studies, with one exception [35], have a prospective design; only three studies were randomized trials [38,39,42], and the sample size ranged from 14 [30] to 458 [38]. Key information on the studies are shown in TABLE 1. TACE combined with sorafenib: efficacy & safety Studies on c-TACE & sorafenib in intermediate-stage HCC patients
The first report describing the combination of conventional TACE with sorafenib dates back to 2010, when Dufour et al. conducted an open-label, Phase I study on 14 patients classified as intermediate-stage HCC, mainly BCLC-B (only five patients were BCLC-C), with PS score of 1 or 2 and Child-Pugh class A or B. Patients were treated with sorafenib (200 or 400 mg b.i.d.) starting 7 days prior to TACE with doxorubicin (50 mg) therapy [30]. In total, 11 patients were administered sorafenib 400 mg b.i.d. and only 3 patients with sorafenib 200 mg b.i.d., given that no dose-limiting toxicities were reported in the first three patients who received sorafenib 200 mg b.i.d. Overall, TACE was delivered 27=times in total (twice for each patient in media), and the median duration of sorafenib therapy was 246 days (range: 14– 547 days). The most common sorafenib-related adverse events (AEs) of grade ‡3 were hand–foot skin reaction (HFSR) (21%), weight loss (14%), diarrhea (7%), abdominal pain (7%) and thrombocytopenia (21%). The results of the study reported a significant decrease in the concentration of plasma VEGF from 93 to 67 ng/l after treatment with sorafenib and TACE, thus suggesting that sorafenib may play an important role in blocking tumor growth, by preventing the increase in the circulating levels of VEGF generated by TACE [30]. Another pilot study conducted on a small (n = 15) but heterogeneous group of patients (mainly BCLC-B class, with ChildPugh A and PS 0) evaluated the combination of sorafenib 834
400 mg b.i.d. starting 2 weeks before the first TACE session, up to withdrawal or discontinuation [31]. The study was stopped early for safety concerns as many AEs such as abdominal pain (93%), weight loss (86%), alopecia (80%), fatigue (80%) and hyperbilirubinemia (73%) were registered, together with unscheduled hospitalization and death. However, an overall OS of 10.6 months was documented (95% CI: 5.2–16 months) [31]. Further studies were conducted on a larger number of patients: Park et al. enrolled 50 patients with intermediate-stage HCC (BCLC-B class in 82% of the cases, Child-Pugh class A and PS score 0–1) in a prospective, single-arm, Phase II trial [32]. Patients were administered sorafenib on day 3 after the first or every session of TACE with doxorubicin 20–60 mg for up to 24 weeks. Each patient received a different number of TACE sessions (media 1, range 2–4), and repeated TACE was performed on demand. Sorafenib was administered on a median of 5 days (range: 3–20 days) after each session of TACE, with a median daily dose of 600 mg (range: 200–800 mg). Seventeen patients discontinued sorafenib due to disease progression, while dose reduction was required in 70% of the cases due to HFSR and thrombocytopenia. Other grades 3 and 4 AEs were HFSR (42%), increase of liver enzymes (36%), leukocytopenia/ neutropenia (14%) and thrombocytopenia (10%). The overall median TTP was 7.1 months (95% CI: 4.8–7.5 months), the 6-month PFS rate was 52% (95% CI: 37.3–66.1) and the median OS was 20.8 months. The authors of the study concluded that concurrent treatment with c-TACE and sorafenib in patients with unresectable HCC may be associated with longer TTP and significant antitumor activity than c-TACE alone [32]. The interim analysis of the Phase II, open-label START trial, conducted in Asia, investigated the combination of TACE and sorafenib on 151 intermediate-stage HCC patients, mainly classified as BCLC-B (80.9%), with PS of 0–1 and Child-Pugh score £7 (A or B). Patients were treated with c-TACE, performed by transarterial injection of doxorubicin 30–60 mg, followed by administration of sorafenib 400 mg b.i.d. after 4–7 days [33]. Each TACE/sorafenib cycle was repeated every 6–8 weeks, and the mean number of cycles undertaken was 2.1 (range: 1–5). The disease control rate was 91.2%, while the overall response rate was 52.4% with complete response, partial response and stable disease achieved by 28, 25 and 39% of patients, respectively. The combination therapy resulted in a median TTP of 280 days and OS probability of >90% over the same time period. There were no unexpected safety issues; the most common AEs were of mild–moderate grade and were gastrointestinal disorders (62.6%) and skin reactions (57.8%) [33]. Similar results were reported by an interim analysis of the same trial, which analyzed a subgroup of 62 Chinese patients mainly classified as BCLC-B (94%) and with Child-Pugh £7 [34]. The median TTP and OS were 10.6 and 16.5 months, respectively, while the objective response and stable disease rates were 44.3 and 42.6%, respectively. Patients experienced several AEs such as pyrexia (37.1%), diarrhea (27.4%), skin reactions (22.6%), alopecia (19.4%) and abnormal hepatic function (16.1%). However, most of the adverse reactions were of mild Expert Rev. Anticancer Ther. 14(7), (2014)
Study design
Patients characteristics
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Phase I pilot study
Single-center, prospective, open-label, Phase II, singlearm study;
Prospective Phase II, openlabel study
Prospective Phase II, openlabel study (interim subgroup analysis)
Retrospective cohort study
Sieghart et al. (2012)
Park et al. (2012)
Chung et al. (2013)
Han et al. (2013)
Muhammad et al. (2013)
[34]
Grade ‡3 AEs: Abnormal hepatic function (6.5%), diarrhea (3.2%) TTP: 10.6 m OS: 16.5 m RR: 44.3% SD: 42.6%
OS: 20.6 m
c-TACE (doxorubicin 30–60 mg) + sorafenib 400 mg b.i.d. sorafenib 4–7 days after c-TACE
c-TACE + sorafenib
c-TACE alone
n = 62 BCLC: A (3.5%), B (93%) and C (3.5%) Child-Pugh £7 PS: 0 (70%), 1 (30%) n = 13 BCLC: A (46.1%), B (15.4%), C (38.4%) n = 30 BCLC: A (73%), B (27%)
OS: 18.3 m
[33]
Grades 1–5 AEs: Gastrointestinal disorders (62.6%), skin reactions (57.8%) TTP: 9.2 m PFS: 8.9 m OS (9.2 m) >90% CR: 28% PR: 25% SD: 39%
c-TACE (doxorubicin 30–60 mg) + sorafenib 400 mg b.i.d. sorafenib 4–7 days after c-TACE
n = 151 BCLC: A (17%), B (81%) and C (2%) Child-Pugh: A (92%), B (8%) PS: 0 (82%), 1 (18%)
Grades 1–4 AEs: Abdominal pain (20%), nausea and vomiting (10%)
[35]
[32]
Grade ‡3 AEs: HFSR (42%), elevated liver enzymes (36%), leukocytopenia/ neutropenia (14%), thrombocytopenia (10%) TTP: 7.1 m (95% CI: 4.8–7.5 m) PFS: 52% (95% CI: 37.3–66.1) OS: 20.8 m
c-TACE (doxorubicin 20–60 mg) + sorafenib 600 mg (200–800 mg) daily sorafenib 3 days after c-TACE
n = 50 BCLC: B (82%), C (18%) Child-Pugh: A (94%), B (6%) PS: 0 (44%), 1 (56%)
Grades 1–4 AEs: HFSR (15%), Elevated liver enzymes (15%)
[31]
Grades 1–4 AEs: Abdominal pain (93%), weight loss (86%), alopecia (80%), fatigue (80%), hyperbilirubinaemia (73%)
OS: 10.6 m
n = 14 BCLC: B (64%), C (36%) Child-Pugh: A (93%), B (7%) PS: 0 (93%), 1 (7%) c-TACE (doxorubicin 75-50-25 mg/m2) + sorafenib 400 mg b.i.d. sorafenib 2 weeks before c-TACE
[30]
Ref.
n = 15 BCLC: A (6%), B (60%) and C (34%) Child-Pugh: A (80%), B (20%) PS: 0 (93%), 2 (7%)
Grade ‡3 AEs: HFSR (21%), thrombocytopenia (21%), weight loss (14%), Diarreha (7%), Abdominal pain (7%),
Safety
Reduction in VEGFR from 93 ng/l to 67 ng/l
Results
c-TACE (doxorubicin 50 mg) + sorafenib 200-400 mg b.i.d. sorafenib 7 days before c-TACE
Treatment characteristics
AEs: Adverse events; AST: Aspartate aminotransferase; BCLC: Barcelona clı´nic liver cancer; CR: Complete response; c-TACE: Conventional TACE; DB-TACE: Drug-eluting beads TACE; DC: Disease control; HFSR: Hand–foot skin reaction; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PS: Performance status score; RR: Response rate (CR + PR); SD: Stable disease; TACE: Transarterial chemoembolization; TTP: Time to progression.
Phase I, openlabel study
Dufour et al. (2010)
Concomitant combination sorafenib + c-TACE
Study (year)
Table 1. Design and key results of the studies investigating the efficacy and safety of the combination of transarterial chemoembolization and sorafenib in patients with hepatocellular carcinoma.
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836 Patients characteristics
Prospective nonrandomized controlled trial
Bai et al. (2013)
Randomized Phase III Study
TTP: 3.7 m (95% CI, 3.5–4.0 m) PFS (6 m): 33.5%, OS: (1y) 94.1% – (2y) 73.8%
c-TACE alone
n = 229 Child-Pugh: A PS: 0 (88%), 1 (12%)
OS: 5.5 m PFS: 3 m
Sorafenib 400 mg b.i.d. + c-TACE or HAIC and/or EBR
TTP: 5.4 m (95% CI: 3.8–7.2 m) PFS (6 m): 45.7% OS: (1y) 94.6% – (2y) 72.1%
TTP: 4.3 m OS: 5.1 m PR: 3.4 % SD: 41% DC: 44%
c-TACE alone
c-TACE (epirubicin + cisplatin + doxorubicin + mitomycin) - 1 (295 pts) or 2 (163 pts) sessions + sorafenib 400 mg b.i.d. sorafenib 1–3 months after TACE
TTP: 6.3 m OS: 7.5 m PR: 9.7% SD: 49% DC: 58%
c-TACE (mitomycin 2–10 mg + doxorubicin 10–40 mg) + sorafenib 400 mg b.i.d. sorafenib £14 days after c-TACE
n = 82 BCLC: B (23%), C (77%) Child-Pugh: A (77%), B (23%) PS: 0 (36.5%), 1 (46.5%), ‡2 (17%)
n = 229 Child-Pugh: A PS: 0 (88%), 1 (12%)
Grade ‡3 AEs: diarrhea (4.9%), HFSR (2.4%), hypertension (1.2%), fatigue (1.2%)
OS: 17 m (95% CI: 8.9–25.0)
c-TACE alone
n = 45 BCLC: B (37%), C (63%) Child-Pugh: A (78%), B (22%) PS: 0 (91%), 1 (9%)
Grade ‡3 AEs: elevated lipase (3%), hypophosphatemia (3%), elevated AST (3%)
Grade ‡3 HFSR (35%), elevated lipase (28%), hypophosphatemia (16%), hypertension (15%)
Grade ‡2 AEs: HFSR (23.4%), diarrhea (15.6%), skin reaction (10.9%)
Grades 1–4 AEs: Gastrointestinal bleeding (11%), hyperbilirubinemia (5.5%)
Grades 1–3 AEs: nausea/vomiting, tenderness in the right upper abdomen, fever
OS: 27 m (95% CI: 21.9–32.1)
c-TACE (oxaliplatin 100– 200 mg ± fluorouracil glycosides 500–1000 mg + epirubicin 30–60 mg) + sorafenib 400 mg b.i.d.
Grades 1–3 AEs: fatigue, skin reaction, hear loss, nausea/anorexia, diarrhea, hypertension
Safety
n = 45 BCLC: B (35%), C (65%) Child-Pugh: A (73%), B (27%) PS: 0 (95%), 1 (5%)
Results
[38]
[37]
Ref.
AEs: Adverse events; AST: Aspartate aminotransferase; BCLC: Barcelona clı´nic liver cancer; CR: Complete response; c-TACE: Conventional TACE; DB-TACE: Drug-eluting beads TACE; DC: Disease control; HFSR: Hand–foot skin reaction; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PS: Performance status score; RR: Response rate (CR + PR); SD: Stable disease; TACE: Transarterial chemoembolization; TTP: Time to progression.
Kudo et al. (2011)
Sequential combination
Retrospective study
Qu et al. (2012)
Treatment characteristics
[36]
Study design
Concomitant combination sorafenib + c-TACE (cont.)
Study (year)
Cabibbo, Tremosini, Galati et al.
Table 1. Design and key results of the studies investigating the efficacy and safety of the combination of transarterial chemoembolization and sorafenib in patients with hepatocellular carcinoma (cont.).
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Study design
Prospective, single-center, placebocontrolled, randomized, doubleblind Phase II study
TTP: 9.2 m
TTP: 4.9 m
c-TACE alone
n = 31 BCLC: B Child-Pugh: A PS: 0 (77%), 1 (23%)
Prospective single-center Phase II study
Randomized, double-blind, Phase II study
Cabrera et al. (2011)
Lencioni et al. (2012)
n/a
TTP: 169 d (5.55 m)
TTP: 166 d (5.45 m)
DB-TACE (doxorubicin 150 mg) + sorafenib 400 mg b.i.d. DB-TACE: 3–7 days after sorafenib DB-TACE Alone
n = 154 BCLC:B Child-Pugh: A PS: 0 n = 153 BCLC:B Child-Pugh: A PS: 0
n/a
[41]
Grade ‡3 AEs: HFSR (26%), fatigue (13%), Post-TACE syndrome (23%) PR: 29% CR: 27% DC (6 m): 68% OS: 18.5 m
DB-TACE (doxorubicin 75–150 mg) + sorafenib 400 mg b.i.d. sorafenib 2–4 weeks before TACE
n = 47 BCLC: B (81%), C (19%) Child-Pugh: A (72%), B (28%) PS: 0 (75), 1 (25%)
[42]
[40]
Grades 1–4 AEs: fatigue (94%), anorexia (67%), liver enzymes alteration (64%), dermatologic events (48%)
DC: 95% RR: 58%
DB-TACE (doxorubicin 75–60 -49 mg, decreasing each cycle) + sorafenib 400 mg b.i.d. sorafenib 1 week before TACE
[39]
Ref.
n = 35 BCLC: B (34%), C (66%) Child-Pugh: A(89%), B (11%) PS: 0(46%), 1 (54%)
Grade ‡3 AEs: Anorexia (2.5%), hypertension (2.5%)
Grade ‡3 AEs: HFSR (10%), rash/ desquamation (10%), hematological event (7.5%), fatigue (7.5%)
Safety
AEs: Adverse events; AST: Aspartate aminotransferase; BCLC: Barcelona clı´nic liver cancer; CR: Complete response; c-TACE: Conventional TACE; DB-TACE: Drug-eluting beads TACE; DC: Disease control; HFSR: Hand–foot skin reaction; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PS: Performance status score; RR: Response rate (CR + PR); SD: Stable disease; TACE: Transarterial chemoembolization; TTP: Time to progression.
Prospective single-center Phase II study
Pawlik et al. (2011)
Results
c-TACE (doxorubicin 30 mg + mitomycin 10 mg) + sorafenib 400 mg b.i.d. sorafenib 30 days after TACE
Treatment characteristics
n = 31 BCLC: B Child-Pugh: A PS: 0 (86%), 1 (24%)
Patients characteristics
Concomitant combination sorafenib + DB-TACE
Sansonno et al. (2012)
Sequential combination (cont.)
Study (year)
Table 1. Design and key results of the studies investigating the efficacy and safety of the combination of transarterial chemoembolization and sorafenib in patients with hepatocellular carcinoma (cont.).
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grade, and grades 3–4 events, such as abnormal hepatic function (6.5%) and diarrhea (3.2%), were slightly rare. The overall positive findings of these studies were not in line with those reported in a retrospective analysis conducted by Muhammad et al. [35]. This study evaluated 43 patients with early and intermediate-stage HCC and Child-Pugh of A or B, who had been previously treated either with TACE alone (30 patients) or concomitantly with TACE and sorafenib (13 patients). According to the results of the study, there was no significant difference in median survival between the two treatments: 20.6 months (95% CI: 13.4–38.4) for the TACE + sorafenib group versus 18.3 months (95% CI: 11.8– 32.9) for the TACE alone group; the hazard ratio (HR) for OS was 0.56 (95% CI: 0.21–1.47; p = 0.24). In addition, the PFS was not statistically different between the two treatments: HR for PFS was 0.70 (95% CI: 0.3–1.6; p = 0.41). The most common AE observed in the TACE alone group were abdominal pain (20%) and nausea and vomiting (10%), while 15% of patients in the combination group suffered from HFSR and elevated liver enzymes. However, there was no statistically significant difference in treatment-related toxicities (p = 0.554). Even if the retrospective design of the analysis should be taken into consideration, in the authors’ opinion, there was no difference in terms of safety and efficacy between TACE therapy alone and its concomitant combination with sorafenib; conversely, they suggested that Child–Turcotte–Pugh classification and BCLC staging are significant predictors of OS [35]. Studies on c-TACE & sorafenib in advanced-stage HCC patients
The combination of TACE and sorafenib has also been investigated in patients with advanced-stage HCC. A study conducted on a total of 45 Chinese patients supported the concomitant use of sorafenib (400 mg b.i.d.) and TACE (oxaliplatin 100–200 mg and/or fluorouracil glycosides 500–1000 mg followed by epirubicin 30–60 mg) in advanced-stage HCC patients [36]. The majority of patients in this study were classified as BCLC-C (64%), presented Child-Pugh A or B and PS 0–1. Overall, the combination treatment resulted in a median OS of 27 months (95% CI: 21.9–32.1) if compared to 17 months (95% CI: 8.9–25.0) reported in historical controls treated with TACE alone (p = 0.001). The most common AEs were of grades 1–3, especially HFSR, hypertension, rash and diarrhea [36]. Comparable results were obtained by Bai et al. in a prospective nonrandomized controlled trial on 82 patients, characterized by BCLC-C (77%), Child-Pugh £7 (A or B) and PS £2, who were treated concurrently with sorafenib 400 mg b.i.d., initiated within 14 days after TACE therapy with mitomycin 2–10 mg and doxorubicin 10–40 mg [37]. These patients were matched at a 1:2 ratio with 164 patients who received TACE alone; propensity score matching was employed to minimize selection bias. The response to treatment was measured by considering TTP and OS during a median follow-up period of 21.4 weeks (range: 0.5–103 weeks). The combination of TACE and sorafenib prolonged both TTP (6.3 vs 4.3 months; HR: 0.60; 95% CI: 838
0.422–0.853; p = 0.004) and OS (7.5 vs 5.1 months; HR: 0.61; 95% CI: 0.423–0.884; p = 0.009) compared with TACE alone. In addition, according to the statistical analysis performed, several factors including the use of sorafenib, BCLC-B stage, metastasis/vascular invasion and Child-Pugh score were identified as significant prognostic factors for OS [37]. Sequential treatment of c-TACE & Sorafenib
The combination of c-TACE and sorafenib was evaluated in intermediate HCC patients also when administered within a sequential strategy, which means that TACE sessions and sorafenib administration were carried out one after the other and not concurrently as in the combination therapy [24]. There is no standard schedule for the sequential treatment; however, the first administration of sorafenib (400 mg b.i.d.) usually starts 30 days after the end of TACE therapy [40]. Kudo et al. conducted a study on 458 patients, with unresectable HCC, Child-Pugh class A cirrhosis and PS 1 or 2, who had previously undergone 1 or 2 sessions of TACE responding after 1–3 months with ‡25% tumor necrosis/ shrinkage [38]. Eligible patients were randomized to either sorafenib 400 mg b.i.d. or placebo until progression/recurrence or unacceptable toxicity. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively, while dose reductions and dose interruptions were observed in 73 and 91% of the patients, respectively. However, no unexpected AEs were registered. Results of the study showed that sorafenib administration did not significantly prolong TTP and OS compared with the placebo group: HR (sorafenib/placebo) was 0.87 for TTP (95% CI: 0.70–1.09; p = 0.252) and 1.06 for OS (95% CI: 0.69–1.64; p = 0.790). However, exploratory subgroup analyses suggested that the administration of sorafenib after TACE failure may have clinical benefits in certain patient subsets including males, patients
Review
Transarterial chemoembolization and sorafenib in hepatocellular carcinoma Expert Rev. Anticancer Ther. 14(7), 831–845 (2014)
Giuseppe Cabibbo1*, Silvia Tremosini2, Giovanni Galati3, Giancarlo Mazza4, Gennaro GadaletaCaldarola5, Giuseppe Lombardi6, Michela Antonucci7 and Rodolfo Sacco8 1 Section of Gastroenterology, DIBIMIS, University of Palermo, 90127 Palermo, Italy 2 Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic Barcelona, IDBAPS, University of Barcelona, Spain 3 Hepatology Unit, Campus Bio Medico University, 00128 Rome, Italy 4 Department of Radiology, Civil Hospital of Brescia, 25123 Brescia, Italy 5 Medical Oncology Unit “Mons. R. Dimiccoli” Hospital, Barletta, Italy 6 Medical Oncology 1, Venetian Oncology Institute – IRCCS, Padua, Italy 7 Section of Radiology, Di.Bi.Me.F. University of Palermo, Palermo, Italy 8 Gastroenterology and Metabolic Diseases Unit, Pisa University Hospital, Pisa, Italy *Author for correspondence: Tel.: +39 091 655 2280 Fax: +39 091 655 2156 [email protected]
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Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients. KEYWORDS: combination therapy • HCC • intermediate stage • sorafenib • TACE
Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance and one of the most frequent cause of cancer-related mortality worldwide. Given the complexity of the disease and the lack of effective treatment options, the mortality rate associated with HCC is high and the prognosis is poor, especially in case of advanced disease, symptomatic patients or presence of liver function impairment. Systematic screening and early detection are therefore the primary objectives in HCC treatment, as the stage of cancer dictates the therapeutic choice [1]. Patients affected by HCC can be classified according to the Barcelona Clı´nic Liver Cancer (BCLC) staging system, which is recommended by the guidelines of the European Association for the Study of Liver (EASL) for prognostic prediction and treatment allocation. The BCLC classification divides HCC patients into five stages (0, A, B, C and D) and is based on prognostic and treatment-related variables including tumor status, liver function and health performance status (PS) [2]. A flow chart of HCC patients classification according to the BCLC staging system, patients’ characteristics and most appropriate therapies is depicted in FIGURE 1 [3]. Transarterial chemoembolization (TACE) is currently recommended as first-line therapy in
10.1586/14737140.2014.920694
the treatment of patients at intermediate stage of the disease (BCLC-B class), characterized by multinodular asymptomatic tumors without an invasive pattern [2,4,5]. According to the results of two meta-analyses [6,7] of the pooled data from randomized controlled trials, TACE has been established as the standard locoregional therapy in this class of patients, who can benefit from a relevant increase in survival, from a median of 16 months up to 19–20 months [8]. Sorafenib, an oral multityrosine kinase inhibitor, is the only drug approved as systemic therapy in patients with HCC [9]. Results from a doubleblind placebo-controlled Phase III study (SHARP trial) demonstrated that sorafenib significantly prolongs overall survival (OS) and time to progression (TTP) in patients with HCC [10]. These results were confirmed in another Phase III trial conducted in an Asia-Pacific population [11]. Current guidelines and report opinions recommend the use of sorafenib in patients with intermediatestage HCC (BCLC-B) with progressing tumors, who failed to respond or are not eligible to TACE therapy [2,12]. Although conventional TACE is frequently used for the treatment of patients with intermediate-stage HCC, there is still a lack of standardization in treatment methodology, and
2014 Informa UK Ltd
ISSN 1473-7140
831
Review
Cabibbo, Tremosini, Galati et al.
HCC Stage A–C Okuda 1–2, PS 0–2, Child-Pugh A–B
Very early Early stage (A) stage (0) Single or 3 nodules Single 100 μm
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O2
Aorta
Transarterial Chemoembolization TACE Hepatic arthery Hypoxia
VEGFR
Tumor cell
Sorafenib VEGF HIFα
PDGFR
HIFα Pro
Pro
HIFα Pro
PDGF Endothelial cell Transcription of HIF target genes VEGF, Ang2 NOS, PDGFb
Figure 2. Post-transarterial chemoembolization hypoxia and tumor necrosis cause the activation of hypoxia-induced factor target genes, such as VEGF and PDGF, which promote angiogenesis and tumor growth and whose activity is blocked by the presence of sorafenib. Ang2: Angiopoietin-2; HIF: Hypoxia-induced factor; NOS: Nitric oxide synthase; TACE: Transarterial chemoembolization; PDGFR: PDGF receptor; VEGFR: VEGF receptor.
treated HCC. For example, the hypoxic change induced by TACE in the hepatic hilus (S1) is usually stronger than that generated in other areas, possibly inducing a more substantial expression of VEGF. In these cases, the OS and TTP achieved with the combination therapy would be underestimated. Several studies, which investigate the efficacy and safety of the combination of TACE and sorafenib in patients with intermediate-stage HCC, have been published to date, and a number of trials using the same strategy are ongoing. We conducted a systematic review to present and critically discuss available evidence on the use of TACE in combination with sorafenib in HCC patients. Studies are evaluated according to the characteristics and the classification of patients (intermediate- or advanced-stage HCC) and the type of treatment provided: either combination or sequential use of TACE and sorafenib. informahealthcare.com
Search strategy & data presentation
With the aim to identify the key publications specifically addressing the efficacy and safety of the combination of TACE and sorafenib in HCC patients, a literature search was conducted from the MEDLINE database using the search terms ‘hepatocellular carcinoma’, ‘liver cancer’ and ‘primary liver carcinoma’, either individually or in combination with the terms ‘randomized’, ‘controlled clinical trials’, ‘clinical trials’, ‘Phase III studies’, ‘meta-analysis’, ‘combined therapy’, ‘treatment’, ‘liver cancer’, ‘TACE’, ‘TAE’, ‘chemoembolization’, ‘embolization’, ‘locoregional treatments’, ‘sorafenib’ and ‘systemic therapy’, as well as by a manual search and review of reference lists. We also browsed the abstract collection of major oncology and hepatology congresses (ASCO, ESMO, EASL, AASLD, ILCA), but studies reported only in abstract form 833
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were considered for inclusion only if published in the last 2 years. The search was limited to studies published in English, without any limitation on the publication date. Studies not directly evaluating the strategy under investigation were discarded; we did not include studies that were the combination of TACE, and sorafenib was associated to other local therapies such as surgery, local ablation or radioembolization. Clinical trial databases (e.g., clinicaltrial.gov) were also searched to identify ongoing studies. The search was last updated on the 3 March 2014. For published studies, data are presented according to the type of TACE used in the study: conventional or DB-TACE. Due to the heterogeneity of the populations and outcomes analyzed in each study, a pooled statistical analysis of the results was not performed. Identified studies
Our MEDLINE query resulted in 42 papers. Of these, 10 were studies addressing the combination of conventional TACE (c-TACE) and sorafenib [30–39], whereas three addressed DBTACE in combination with sorafenib [40–42]. Among the studies on c-TACE, eight investigated a concomitant treatment strategy either on intermediate- (n = 6) or advanced-stage (n = 2) HCC patients [30–37], while two evaluated the sequential treatment of c-TACE and sorafenib [38,39]. All studies, with one exception [35], have a prospective design; only three studies were randomized trials [38,39,42], and the sample size ranged from 14 [30] to 458 [38]. Key information on the studies are shown in TABLE 1. TACE combined with sorafenib: efficacy & safety Studies on c-TACE & sorafenib in intermediate-stage HCC patients
The first report describing the combination of conventional TACE with sorafenib dates back to 2010, when Dufour et al. conducted an open-label, Phase I study on 14 patients classified as intermediate-stage HCC, mainly BCLC-B (only five patients were BCLC-C), with PS score of 1 or 2 and Child-Pugh class A or B. Patients were treated with sorafenib (200 or 400 mg b.i.d.) starting 7 days prior to TACE with doxorubicin (50 mg) therapy [30]. In total, 11 patients were administered sorafenib 400 mg b.i.d. and only 3 patients with sorafenib 200 mg b.i.d., given that no dose-limiting toxicities were reported in the first three patients who received sorafenib 200 mg b.i.d. Overall, TACE was delivered 27=times in total (twice for each patient in media), and the median duration of sorafenib therapy was 246 days (range: 14– 547 days). The most common sorafenib-related adverse events (AEs) of grade ‡3 were hand–foot skin reaction (HFSR) (21%), weight loss (14%), diarrhea (7%), abdominal pain (7%) and thrombocytopenia (21%). The results of the study reported a significant decrease in the concentration of plasma VEGF from 93 to 67 ng/l after treatment with sorafenib and TACE, thus suggesting that sorafenib may play an important role in blocking tumor growth, by preventing the increase in the circulating levels of VEGF generated by TACE [30]. Another pilot study conducted on a small (n = 15) but heterogeneous group of patients (mainly BCLC-B class, with ChildPugh A and PS 0) evaluated the combination of sorafenib 834
400 mg b.i.d. starting 2 weeks before the first TACE session, up to withdrawal or discontinuation [31]. The study was stopped early for safety concerns as many AEs such as abdominal pain (93%), weight loss (86%), alopecia (80%), fatigue (80%) and hyperbilirubinemia (73%) were registered, together with unscheduled hospitalization and death. However, an overall OS of 10.6 months was documented (95% CI: 5.2–16 months) [31]. Further studies were conducted on a larger number of patients: Park et al. enrolled 50 patients with intermediate-stage HCC (BCLC-B class in 82% of the cases, Child-Pugh class A and PS score 0–1) in a prospective, single-arm, Phase II trial [32]. Patients were administered sorafenib on day 3 after the first or every session of TACE with doxorubicin 20–60 mg for up to 24 weeks. Each patient received a different number of TACE sessions (media 1, range 2–4), and repeated TACE was performed on demand. Sorafenib was administered on a median of 5 days (range: 3–20 days) after each session of TACE, with a median daily dose of 600 mg (range: 200–800 mg). Seventeen patients discontinued sorafenib due to disease progression, while dose reduction was required in 70% of the cases due to HFSR and thrombocytopenia. Other grades 3 and 4 AEs were HFSR (42%), increase of liver enzymes (36%), leukocytopenia/ neutropenia (14%) and thrombocytopenia (10%). The overall median TTP was 7.1 months (95% CI: 4.8–7.5 months), the 6-month PFS rate was 52% (95% CI: 37.3–66.1) and the median OS was 20.8 months. The authors of the study concluded that concurrent treatment with c-TACE and sorafenib in patients with unresectable HCC may be associated with longer TTP and significant antitumor activity than c-TACE alone [32]. The interim analysis of the Phase II, open-label START trial, conducted in Asia, investigated the combination of TACE and sorafenib on 151 intermediate-stage HCC patients, mainly classified as BCLC-B (80.9%), with PS of 0–1 and Child-Pugh score £7 (A or B). Patients were treated with c-TACE, performed by transarterial injection of doxorubicin 30–60 mg, followed by administration of sorafenib 400 mg b.i.d. after 4–7 days [33]. Each TACE/sorafenib cycle was repeated every 6–8 weeks, and the mean number of cycles undertaken was 2.1 (range: 1–5). The disease control rate was 91.2%, while the overall response rate was 52.4% with complete response, partial response and stable disease achieved by 28, 25 and 39% of patients, respectively. The combination therapy resulted in a median TTP of 280 days and OS probability of >90% over the same time period. There were no unexpected safety issues; the most common AEs were of mild–moderate grade and were gastrointestinal disorders (62.6%) and skin reactions (57.8%) [33]. Similar results were reported by an interim analysis of the same trial, which analyzed a subgroup of 62 Chinese patients mainly classified as BCLC-B (94%) and with Child-Pugh £7 [34]. The median TTP and OS were 10.6 and 16.5 months, respectively, while the objective response and stable disease rates were 44.3 and 42.6%, respectively. Patients experienced several AEs such as pyrexia (37.1%), diarrhea (27.4%), skin reactions (22.6%), alopecia (19.4%) and abnormal hepatic function (16.1%). However, most of the adverse reactions were of mild Expert Rev. Anticancer Ther. 14(7), (2014)
Study design
Patients characteristics
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Phase I pilot study
Single-center, prospective, open-label, Phase II, singlearm study;
Prospective Phase II, openlabel study
Prospective Phase II, openlabel study (interim subgroup analysis)
Retrospective cohort study
Sieghart et al. (2012)
Park et al. (2012)
Chung et al. (2013)
Han et al. (2013)
Muhammad et al. (2013)
[34]
Grade ‡3 AEs: Abnormal hepatic function (6.5%), diarrhea (3.2%) TTP: 10.6 m OS: 16.5 m RR: 44.3% SD: 42.6%
OS: 20.6 m
c-TACE (doxorubicin 30–60 mg) + sorafenib 400 mg b.i.d. sorafenib 4–7 days after c-TACE
c-TACE + sorafenib
c-TACE alone
n = 62 BCLC: A (3.5%), B (93%) and C (3.5%) Child-Pugh £7 PS: 0 (70%), 1 (30%) n = 13 BCLC: A (46.1%), B (15.4%), C (38.4%) n = 30 BCLC: A (73%), B (27%)
OS: 18.3 m
[33]
Grades 1–5 AEs: Gastrointestinal disorders (62.6%), skin reactions (57.8%) TTP: 9.2 m PFS: 8.9 m OS (9.2 m) >90% CR: 28% PR: 25% SD: 39%
c-TACE (doxorubicin 30–60 mg) + sorafenib 400 mg b.i.d. sorafenib 4–7 days after c-TACE
n = 151 BCLC: A (17%), B (81%) and C (2%) Child-Pugh: A (92%), B (8%) PS: 0 (82%), 1 (18%)
Grades 1–4 AEs: Abdominal pain (20%), nausea and vomiting (10%)
[35]
[32]
Grade ‡3 AEs: HFSR (42%), elevated liver enzymes (36%), leukocytopenia/ neutropenia (14%), thrombocytopenia (10%) TTP: 7.1 m (95% CI: 4.8–7.5 m) PFS: 52% (95% CI: 37.3–66.1) OS: 20.8 m
c-TACE (doxorubicin 20–60 mg) + sorafenib 600 mg (200–800 mg) daily sorafenib 3 days after c-TACE
n = 50 BCLC: B (82%), C (18%) Child-Pugh: A (94%), B (6%) PS: 0 (44%), 1 (56%)
Grades 1–4 AEs: HFSR (15%), Elevated liver enzymes (15%)
[31]
Grades 1–4 AEs: Abdominal pain (93%), weight loss (86%), alopecia (80%), fatigue (80%), hyperbilirubinaemia (73%)
OS: 10.6 m
n = 14 BCLC: B (64%), C (36%) Child-Pugh: A (93%), B (7%) PS: 0 (93%), 1 (7%) c-TACE (doxorubicin 75-50-25 mg/m2) + sorafenib 400 mg b.i.d. sorafenib 2 weeks before c-TACE
[30]
Ref.
n = 15 BCLC: A (6%), B (60%) and C (34%) Child-Pugh: A (80%), B (20%) PS: 0 (93%), 2 (7%)
Grade ‡3 AEs: HFSR (21%), thrombocytopenia (21%), weight loss (14%), Diarreha (7%), Abdominal pain (7%),
Safety
Reduction in VEGFR from 93 ng/l to 67 ng/l
Results
c-TACE (doxorubicin 50 mg) + sorafenib 200-400 mg b.i.d. sorafenib 7 days before c-TACE
Treatment characteristics
AEs: Adverse events; AST: Aspartate aminotransferase; BCLC: Barcelona clı´nic liver cancer; CR: Complete response; c-TACE: Conventional TACE; DB-TACE: Drug-eluting beads TACE; DC: Disease control; HFSR: Hand–foot skin reaction; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PS: Performance status score; RR: Response rate (CR + PR); SD: Stable disease; TACE: Transarterial chemoembolization; TTP: Time to progression.
Phase I, openlabel study
Dufour et al. (2010)
Concomitant combination sorafenib + c-TACE
Study (year)
Table 1. Design and key results of the studies investigating the efficacy and safety of the combination of transarterial chemoembolization and sorafenib in patients with hepatocellular carcinoma.
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836 Patients characteristics
Prospective nonrandomized controlled trial
Bai et al. (2013)
Randomized Phase III Study
TTP: 3.7 m (95% CI, 3.5–4.0 m) PFS (6 m): 33.5%, OS: (1y) 94.1% – (2y) 73.8%
c-TACE alone
n = 229 Child-Pugh: A PS: 0 (88%), 1 (12%)
OS: 5.5 m PFS: 3 m
Sorafenib 400 mg b.i.d. + c-TACE or HAIC and/or EBR
TTP: 5.4 m (95% CI: 3.8–7.2 m) PFS (6 m): 45.7% OS: (1y) 94.6% – (2y) 72.1%
TTP: 4.3 m OS: 5.1 m PR: 3.4 % SD: 41% DC: 44%
c-TACE alone
c-TACE (epirubicin + cisplatin + doxorubicin + mitomycin) - 1 (295 pts) or 2 (163 pts) sessions + sorafenib 400 mg b.i.d. sorafenib 1–3 months after TACE
TTP: 6.3 m OS: 7.5 m PR: 9.7% SD: 49% DC: 58%
c-TACE (mitomycin 2–10 mg + doxorubicin 10–40 mg) + sorafenib 400 mg b.i.d. sorafenib £14 days after c-TACE
n = 82 BCLC: B (23%), C (77%) Child-Pugh: A (77%), B (23%) PS: 0 (36.5%), 1 (46.5%), ‡2 (17%)
n = 229 Child-Pugh: A PS: 0 (88%), 1 (12%)
Grade ‡3 AEs: diarrhea (4.9%), HFSR (2.4%), hypertension (1.2%), fatigue (1.2%)
OS: 17 m (95% CI: 8.9–25.0)
c-TACE alone
n = 45 BCLC: B (37%), C (63%) Child-Pugh: A (78%), B (22%) PS: 0 (91%), 1 (9%)
Grade ‡3 AEs: elevated lipase (3%), hypophosphatemia (3%), elevated AST (3%)
Grade ‡3 HFSR (35%), elevated lipase (28%), hypophosphatemia (16%), hypertension (15%)
Grade ‡2 AEs: HFSR (23.4%), diarrhea (15.6%), skin reaction (10.9%)
Grades 1–4 AEs: Gastrointestinal bleeding (11%), hyperbilirubinemia (5.5%)
Grades 1–3 AEs: nausea/vomiting, tenderness in the right upper abdomen, fever
OS: 27 m (95% CI: 21.9–32.1)
c-TACE (oxaliplatin 100– 200 mg ± fluorouracil glycosides 500–1000 mg + epirubicin 30–60 mg) + sorafenib 400 mg b.i.d.
Grades 1–3 AEs: fatigue, skin reaction, hear loss, nausea/anorexia, diarrhea, hypertension
Safety
n = 45 BCLC: B (35%), C (65%) Child-Pugh: A (73%), B (27%) PS: 0 (95%), 1 (5%)
Results
[38]
[37]
Ref.
AEs: Adverse events; AST: Aspartate aminotransferase; BCLC: Barcelona clı´nic liver cancer; CR: Complete response; c-TACE: Conventional TACE; DB-TACE: Drug-eluting beads TACE; DC: Disease control; HFSR: Hand–foot skin reaction; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PS: Performance status score; RR: Response rate (CR + PR); SD: Stable disease; TACE: Transarterial chemoembolization; TTP: Time to progression.
Kudo et al. (2011)
Sequential combination
Retrospective study
Qu et al. (2012)
Treatment characteristics
[36]
Study design
Concomitant combination sorafenib + c-TACE (cont.)
Study (year)
Cabibbo, Tremosini, Galati et al.
Table 1. Design and key results of the studies investigating the efficacy and safety of the combination of transarterial chemoembolization and sorafenib in patients with hepatocellular carcinoma (cont.).
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Study design
Prospective, single-center, placebocontrolled, randomized, doubleblind Phase II study
TTP: 9.2 m
TTP: 4.9 m
c-TACE alone
n = 31 BCLC: B Child-Pugh: A PS: 0 (77%), 1 (23%)
Prospective single-center Phase II study
Randomized, double-blind, Phase II study
Cabrera et al. (2011)
Lencioni et al. (2012)
n/a
TTP: 169 d (5.55 m)
TTP: 166 d (5.45 m)
DB-TACE (doxorubicin 150 mg) + sorafenib 400 mg b.i.d. DB-TACE: 3–7 days after sorafenib DB-TACE Alone
n = 154 BCLC:B Child-Pugh: A PS: 0 n = 153 BCLC:B Child-Pugh: A PS: 0
n/a
[41]
Grade ‡3 AEs: HFSR (26%), fatigue (13%), Post-TACE syndrome (23%) PR: 29% CR: 27% DC (6 m): 68% OS: 18.5 m
DB-TACE (doxorubicin 75–150 mg) + sorafenib 400 mg b.i.d. sorafenib 2–4 weeks before TACE
n = 47 BCLC: B (81%), C (19%) Child-Pugh: A (72%), B (28%) PS: 0 (75), 1 (25%)
[42]
[40]
Grades 1–4 AEs: fatigue (94%), anorexia (67%), liver enzymes alteration (64%), dermatologic events (48%)
DC: 95% RR: 58%
DB-TACE (doxorubicin 75–60 -49 mg, decreasing each cycle) + sorafenib 400 mg b.i.d. sorafenib 1 week before TACE
[39]
Ref.
n = 35 BCLC: B (34%), C (66%) Child-Pugh: A(89%), B (11%) PS: 0(46%), 1 (54%)
Grade ‡3 AEs: Anorexia (2.5%), hypertension (2.5%)
Grade ‡3 AEs: HFSR (10%), rash/ desquamation (10%), hematological event (7.5%), fatigue (7.5%)
Safety
AEs: Adverse events; AST: Aspartate aminotransferase; BCLC: Barcelona clı´nic liver cancer; CR: Complete response; c-TACE: Conventional TACE; DB-TACE: Drug-eluting beads TACE; DC: Disease control; HFSR: Hand–foot skin reaction; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PS: Performance status score; RR: Response rate (CR + PR); SD: Stable disease; TACE: Transarterial chemoembolization; TTP: Time to progression.
Prospective single-center Phase II study
Pawlik et al. (2011)
Results
c-TACE (doxorubicin 30 mg + mitomycin 10 mg) + sorafenib 400 mg b.i.d. sorafenib 30 days after TACE
Treatment characteristics
n = 31 BCLC: B Child-Pugh: A PS: 0 (86%), 1 (24%)
Patients characteristics
Concomitant combination sorafenib + DB-TACE
Sansonno et al. (2012)
Sequential combination (cont.)
Study (year)
Table 1. Design and key results of the studies investigating the efficacy and safety of the combination of transarterial chemoembolization and sorafenib in patients with hepatocellular carcinoma (cont.).
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grade, and grades 3–4 events, such as abnormal hepatic function (6.5%) and diarrhea (3.2%), were slightly rare. The overall positive findings of these studies were not in line with those reported in a retrospective analysis conducted by Muhammad et al. [35]. This study evaluated 43 patients with early and intermediate-stage HCC and Child-Pugh of A or B, who had been previously treated either with TACE alone (30 patients) or concomitantly with TACE and sorafenib (13 patients). According to the results of the study, there was no significant difference in median survival between the two treatments: 20.6 months (95% CI: 13.4–38.4) for the TACE + sorafenib group versus 18.3 months (95% CI: 11.8– 32.9) for the TACE alone group; the hazard ratio (HR) for OS was 0.56 (95% CI: 0.21–1.47; p = 0.24). In addition, the PFS was not statistically different between the two treatments: HR for PFS was 0.70 (95% CI: 0.3–1.6; p = 0.41). The most common AE observed in the TACE alone group were abdominal pain (20%) and nausea and vomiting (10%), while 15% of patients in the combination group suffered from HFSR and elevated liver enzymes. However, there was no statistically significant difference in treatment-related toxicities (p = 0.554). Even if the retrospective design of the analysis should be taken into consideration, in the authors’ opinion, there was no difference in terms of safety and efficacy between TACE therapy alone and its concomitant combination with sorafenib; conversely, they suggested that Child–Turcotte–Pugh classification and BCLC staging are significant predictors of OS [35]. Studies on c-TACE & sorafenib in advanced-stage HCC patients
The combination of TACE and sorafenib has also been investigated in patients with advanced-stage HCC. A study conducted on a total of 45 Chinese patients supported the concomitant use of sorafenib (400 mg b.i.d.) and TACE (oxaliplatin 100–200 mg and/or fluorouracil glycosides 500–1000 mg followed by epirubicin 30–60 mg) in advanced-stage HCC patients [36]. The majority of patients in this study were classified as BCLC-C (64%), presented Child-Pugh A or B and PS 0–1. Overall, the combination treatment resulted in a median OS of 27 months (95% CI: 21.9–32.1) if compared to 17 months (95% CI: 8.9–25.0) reported in historical controls treated with TACE alone (p = 0.001). The most common AEs were of grades 1–3, especially HFSR, hypertension, rash and diarrhea [36]. Comparable results were obtained by Bai et al. in a prospective nonrandomized controlled trial on 82 patients, characterized by BCLC-C (77%), Child-Pugh £7 (A or B) and PS £2, who were treated concurrently with sorafenib 400 mg b.i.d., initiated within 14 days after TACE therapy with mitomycin 2–10 mg and doxorubicin 10–40 mg [37]. These patients were matched at a 1:2 ratio with 164 patients who received TACE alone; propensity score matching was employed to minimize selection bias. The response to treatment was measured by considering TTP and OS during a median follow-up period of 21.4 weeks (range: 0.5–103 weeks). The combination of TACE and sorafenib prolonged both TTP (6.3 vs 4.3 months; HR: 0.60; 95% CI: 838
0.422–0.853; p = 0.004) and OS (7.5 vs 5.1 months; HR: 0.61; 95% CI: 0.423–0.884; p = 0.009) compared with TACE alone. In addition, according to the statistical analysis performed, several factors including the use of sorafenib, BCLC-B stage, metastasis/vascular invasion and Child-Pugh score were identified as significant prognostic factors for OS [37]. Sequential treatment of c-TACE & Sorafenib
The combination of c-TACE and sorafenib was evaluated in intermediate HCC patients also when administered within a sequential strategy, which means that TACE sessions and sorafenib administration were carried out one after the other and not concurrently as in the combination therapy [24]. There is no standard schedule for the sequential treatment; however, the first administration of sorafenib (400 mg b.i.d.) usually starts 30 days after the end of TACE therapy [40]. Kudo et al. conducted a study on 458 patients, with unresectable HCC, Child-Pugh class A cirrhosis and PS 1 or 2, who had previously undergone 1 or 2 sessions of TACE responding after 1–3 months with ‡25% tumor necrosis/ shrinkage [38]. Eligible patients were randomized to either sorafenib 400 mg b.i.d. or placebo until progression/recurrence or unacceptable toxicity. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively, while dose reductions and dose interruptions were observed in 73 and 91% of the patients, respectively. However, no unexpected AEs were registered. Results of the study showed that sorafenib administration did not significantly prolong TTP and OS compared with the placebo group: HR (sorafenib/placebo) was 0.87 for TTP (95% CI: 0.70–1.09; p = 0.252) and 1.06 for OS (95% CI: 0.69–1.64; p = 0.790). However, exploratory subgroup analyses suggested that the administration of sorafenib after TACE failure may have clinical benefits in certain patient subsets including males, patients
