Sorafenib treatment by Child–Pugh score in Latin American patients with hepatocellular carcinoma
Abstract
Aim: To evaluate sorafenib treatment in Latin American patients with unresectable hepatocellular carcinoma in the real-world GIDEON study. Patients & methods: Sorafenib administration, safety and efficacy were analyzed by Child–Pugh status. Results: Of 90 evaluable patients (37% Child–Pugh A, 46% Child–Pugh B and 3% Child–Pugh C at study entry), 97% started sorafenib at 800 mg/day. Patients with Child–Pugh B7 had the longest median treatment duration of sorafenib (33.1 weeks). Sorafenib-related adverse events occurred in 58% of patients with Child–Pugh A (21% grade 3/4) and 46% with Child–Pugh B (7% grade 3/4). Conclusion: Sorafenib had a similar safety profile across patients with Child–Pugh A and B and is a treatment option for both groups.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second major cause of tumor-related death in the world [1,2]. The incidence of HCC is heterogeneous across Latin America, partly due to local geographical differences in the incidence of hepatitis B virus and hepatitis C virus infection and alcoholic liver disease [3]; for example, hepatitis C and liver disease are the leading causes of HCC in the Latin American region overall [4], but hepatitis B is also a major factor in Brazil [3].
Patients with advanced HCC have poor long-term survival, and incidence and mortality rates are rising globally [2,5–7]; the shortcomings associated with the consequences of late-stage HCC diagnosis in the Latin American region have also been recognized [3]. Despite improvements, most HCC cases are still at an advanced stage at diagnosis, often with recurrent disease after treatment with curative intent, and usually in the setting of cirrhosis [6,8].
Sorafenib is an oral multikinase inhibitor that inhibits the VEGFR, PDGFR and Raf family kinases that drive signaling pathways to promote tumor growth and angiogenesis [9,10]. Sorafenib has been shown to prolong overall survival (OS) in Phase III randomized (SHARP and AP) studies [11,12], supporting its approval as a first-line treatment option for unresectable HCC [13]. The Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study (n = 3202) was a prospective, global, non-interventional study conducted to fulfill a post-approval commitment to the EMA, with a primary objective to evaluate the safety of sorafenib in patients with unresectable HCC in real-world practice [14,15]. Interim and final analyses of these global data indicated that the safety profile of sorafenib was similar between patients with baseline Child–Pugh A and Child–Pugh B status [15]. Regional variations were found in patient characteristics, treatment practices and outcomes in patients with HCC who received sorafenib [16]. This subgroup analysis was carried out in 90 patients from the Latin American region who participated in the GIDEON study, in order to assess the safety of sorafenib and real-world treatment/dosing practices in Latin America. The degree of liver impairment is an important consideration when making treatment decisions for patients with advanced HCC [2]; therefore, in this study, the safety and treatment patterns were assessed according to Child–Pugh status.
Patients & methods
Study design & objectives
The GIDEON study included patients who were eligible for treatment with systemic therapy and received sorafenib under real-world practice conditions (this study has been described previously [14–16]). Briefly, eligible patients were those with histologically, cytologically or radiographically confirmed unresectable HCC and a life expectancy of at least 8 weeks, who were candidates for systemic therapy. Treatment with sorafenib was based on the treating physician's decision. The primary objective of the study was to evaluate the safety of sorafenib in patients with unresectable HCC under real-life practice conditions; secondary objectives included efficacy end points of OS, progression-free survival, time to progression, response rate and stable disease rate and clinical practice patterns [14].
In the current study, the following were evaluated according to Child–Pugh score subgroup: patient demographics and baseline characteristics; incidences of all and drug-related adverse events (AEs), which were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0; Barcelona Clinic Liver Cancer (BCLC) stage; and treatment history at baseline, including the number of transcatheter arterial chemoembolization (TACE) sessions. Data on sorafenib treatment patterns/dosing and efficacy were recorded throughout the study.
In Latin America, GIDEON was conducted according to regional post-authorization surveillance regulations in accordance with Good Post-marketing Surveillance Practice, the principles of the Declaration of Helsinki and all applicable laws and regulations. Data from the Latin American subgroup were analyzed retrospectively. All patients provided written informed consent for participation before enrollment in the study ( ClinicalTrials.gov: NCT00812175). The protocol was reviewed and approved by the institutional review boards of all participating study sites.
Data collection & statistical analysis
Study data were collected as previously described [14] and safety variables were summarized descriptively in patients (safety population) who had received at least one dose of sorafenib and at least one follow-up assessment. AEs were graded and other safety variables were described in accordance with NCI-CTCAE version 3.0.
The efficacy analysis included all patients assigned to study treatment (intention-to-treat population). OS, hazard ratio and CIs were estimated using the Kaplan–Meier method.
Results
In this substudy, key data were compared descriptively in the text with published global data, where appropriate.
Patient disposition
Of the total safety population of 3202 patients in the GIDEON study, 90 patients from Latin America were evaluable for the safety analysis, of whom 77 had known Child–Pugh status (Figure 1).
†Patients may have more than one missing component.
INR: International normalized ratio; ITT: Intention-to-treat; PT: Prothrombin time.
Baseline demographics & disease characteristics
In the intention-to-treat and safety population (n = 90), 60 patients were from Mexico, 24 were from Venezuela, five were from Colombia and one was from Uruguay. Baseline variables according to Child–Pugh status are presented in Table 1. In Latin America, at the start of therapy most patients (46%) were Child–Pugh B and 37% Child–Pugh A (compared with 21% and 61%, respectively, globally [16]); only three patients (3%) were graded Child–Pugh C (Table 1), precluding meaningful evaluation of this latter group in Latin America. Furthermore, the majority of patients (40%) were BCLC B at study entry (vs 20% globally) [15,16]. The time from initial HCC diagnosis to sorafenib treatment was shorter in patients with Child–Pugh A (Table 2); however, a relatively high number of patients had stage III disease (52% in Child–Pugh A patients vs 61% in Child–Pugh B patients, compared with 36% in the global Child–Pugh A group [15]) or were BCLC stage D (9% in Child–Pugh A patients vs 2% in Child–Pugh B patients, compared with 3% in the global Child–Pugh A group [15]; Table 1). Bilirubin and albumin levels and international normalized ratio were similar to those reported across the Child–Pugh range in the global population [15]. A higher proportion of patients had non-alcoholic steatohepatitis (NASH) at the start of sorafenib treatment in the Child–Pugh B group (15% compared with 0% in the Child–Pugh A group).
| Patient or disease characteristic | Child–Pugh score† | ||||||
|---|---|---|---|---|---|---|---|
| A (<7) | B7 | B8 | B9 | B (7–9) | C (>9) | NE | |
| Patients, n (% of total) | 33 (37) | 21 (23) | 14 (16) | 6 (7) | 41 (46) | 3 (3) | 13 (14) |
| Median age, years (range) | 67 (18–87) | 63 (42–79) | 63 (48–79) | 65 (48–78) | 63 (42–79) | 67 (52–77) | 68 (47–98) |
| Gender, n (%) – Male – Female | 14 (42) 19 (58) | 14 (67) 7 (33) | 6 (43) 8 (57) | 2 (33) 4 (67) | 22 (54) 19 (46) | 2 (67) 1 (33) | 7 (54) 6 (46) |
| ECOG PS, n (%)† – 0 or 1 – ≥2 | 29 (88) 4 (12) | 20 (95) 1 (5) | 10 (71) 4 (29) | 4 (67) 2 (33) | 34 (83) 7 (17) | 2 (67) 1 (33) | 10 (77) 3 (23) |
| BCLC stage, n (%)† – A – B – C – D – NE | 7 (21) 13 (39) 8 (24) 3 (9) 2 (6) | 5 (24) 8 (38) 7 (33) 1 (5) 0 | 2 (14) 7 (50) 5 (36) 0 0 | 1 (17) 3 (50) 2 (33) 0 0 | 8 (20) 18 (44) 14 (34) 1 (2) 0 | 0 0 0 3 (100) 0 | 1 (8) 5 (38) 4 (31) 1 (8) 2 (15) |
| TNM status, n (%)† – I – II – III – IV – NE | 3 (9) 9 (27) 17 (52) 2 (6) 2 (6) | 2 (10) 1 (5) 14 (67) 2 (10) 2 (10) | 2 (14) 3 (21) 8 (57) 1 (7) 0 | 2 (33) 0 3 (50) 0 1 (17) | 6 (15) 4 (10) 25 (61) 3 (7) 3 (7) | 0 0 1 (33) 1 (33) 1 (33) | 0 0 8 (62) 2 (15) 3 (23) |
| Bilirubin (mg/dl), n (%) – <2.0 – 2.0–3.0 – >3.0 – Unknown | 30 (91) 3 (9) 0 0 | 12 (57) 8 (38) 1 (5) 0 | 4 (29) 8 (57) 2 (14) 0 | 0 5 (83) 1 (17) 0 | 16 (39) 21 (51) 4 (10) 0 | 0 2 (67) 1 (33) 0 | 7 (54) 2 (15) 3 (23) 1 (8) |
| Albumin (g/l), n (%) – >35.0 – 28.0–35.0 – <28.0 – Unknown | 29 (88) 4 (12) 0 0 | 6 (29) 13 (62) 2 (10) 0 | 2 (14) 8 (57) 4 (29) 0 | 0 6 (100) 0 0 | 8 (20) 27 (66) 6 (15) 0 | 0 1 (33) 2 (67) 0 | 2 (15) 1 (8) 1 (8) 9 (69) |
| International normalized ratio (seconds), n (%) – <1.7 – 1.7–2.3 – >2.3 – Unknown | 32 (97) 1 (3) 0 0 | 18 (86) 3 (14) 0 0 | 11 (79) 2 (14) 1 (7) 0 | 2 (33) 4 (67) 0 0 | 31 (76) 9 (22) 1 (2) 0 | 0 3 (100) 0 0 | 4 (31) 0 0 9 (69) |
| Encephalopathy, n (%) – Absent – Moderate (stage I or II) – Severe (stage III or IV) | 32 (97) 1 (3) 0 | 19 (90) 2 (10) 0 | 14 (100) 0 0 | 5 (83) 1 (17) 0 | 38 (93) 3 (7) 0 | 3 (100) 0 0 | 12 (92) 1 (8) 0 |
| Ascites, n (%) – Absent – Slight – Moderate | 26 (79) 7 (21) 0 | 12 (57) 8 (38) 1 (5) | 6 (43) 6 (43) 2 (14) | 1 (17) 4 (67) 1 (17) | 19 (46) 18 (44) 4 (10) | 0 0 3 (100) | 7 (54) 5 (38) 1 (8) |
| HCC features, n (%)† – Extrahepatic spread – Vascular invasion | 2 (6) 3 (9) | 3 (14) 2 (10) | 2 (14) 1 (7) | 0 0 | 5 (12) 3 (7) | 1 (33) 1 (33) | 2 (15) 1 (8) |
| Etiology of liver disease, n (%)‡ – Hepatitis B – Hepatitis C – NASH – Alcohol use | 1 (3) 13 (39) 0 5 (15) | 0 7 (33) 3 (14) 4 (19) | 1 (7) 5 (36) 3 (21) 2 (14) | 1 (17) 4 (67) 0 0 | 2 (5) 16 (39) 6 (15) 6 (15) | 0 1 (33) 0 1 (33) | 0 2 (15) 0 2 (15) |
| Dose administration or treatment parameter | Child–Pugh score† | ||||||
|---|---|---|---|---|---|---|---|
| A (<7) (n = 33) | B7 (n = 21) | B8 (n = 14) | B9 (n = 6) | B (7–9) (n = 41) | C (>9) (n = 3) | NE (n = 13) | |
| Initial daily dose, n (%) – 400 mg – 800 mg | 0 33 (100) | 0 21 (100) | 2 (14) 12 (86) | 0 6 (100) | 2 (5) 39 (95) | 0 3 (100) | 1 (8) 12 (92) |
| Median daily dose, mg | 800 | 800 | 800 | 800 | 800 | 800 | 800 |
| Dose reduction, n (%) | 10 (30) | 2 (10) | 3 (21) | 0 | 5 (12) | 0 | 3 (23) |
| Dose increase, n (%) | 4 (12) | 1 (5) | 1 (7) | 0 | 2 (5) | 0 | 0 |
| Median time from HCC diagnosis to initiation of sorafenib, months | n = 27 0.89 | NA | NA | NA | n = 37 2.56 | n = 3 1.58 | n = 12 0.49 |
| Median treatment duration, weeks (range) | 21.30 (2.6–156.6) | 33.10 (7.3–110.9) | 22.00 (4.0–114.7) | 21.95 (4.4–97.4) | 28.90 (4.0–114.7) | 8.60 (1.1–9.7) | 20.0 (0.6–78.9) |
| Duration of treatment, n (%) – ≤8 weeks – >8–28 weeks – >28 weeks | 4 (12) 20 (61) 9 (27) | 1 (5) 5 (24) 15 (71) | 4 (29) 4 (29) 6 (43) | 1 (17) 4 (67) 1 (17) | 6 (15) 13 (32) 22 (54) | 1 (33) 2 (67) 0 | 2 (15) 8 (62) 3 (23) |
Treatment practices prior to & after sorafenib
Of the 12 patients (13%) who had received prior TACE (vs 47% globally [16]), five (42%) were graded Child–Pugh A at the start of sorafenib therapy and five (42%) were Child–Pugh B (two patients were not evaluable); most of these patients (83%) had received only one prior TACE (vs 41% globally [16]). A total of 10/32 (31%) and 13/41 (32%) patients had prior locoregional treatment for HCC in the Child–Pugh A and B groups, respectively.
Sorafenib administration
Sorafenib dosing regimens and treatment patterns according to Child–Pugh status in patients from Latin America are presented in Table 2. In the Latin American subgroup, most patients (97%) started sorafenib at a dose of 800 mg/day (vs 70% globally [16]), with only three patients (3%; two/three were Child–Pugh evaluable and both were Child–Pugh B) starting at the lower dose of 400 mg/day. Patients in Latin America remained on treatment for a median of 23.1 weeks versus 15.0 weeks globally [16]. The median time on sorafenib treatment was consistently higher across Child–Pugh A and B groups in this subanalysis compared with the global population (range: 21.3–33.1 weeks vs 7.6–17.6 weeks globally [15]); patients with Child–Pugh B7 tended to have a longer treatment duration than those with Child–Pugh B8 and B9, while patients with Child–Pugh A had a shorter treatment duration than those with Child–Pugh B. Median duration of sorafenib treatment was 21.3 weeks and 28.9 weeks in the Child–Pugh A and B groups, respectively. Among Latin American patients, there were fewer dose reductions (20%) compared with the global population (37%) [15], despite a higher median daily dose (800 mg vs 688 mg globally [16]). In addition, in the present study, 52/53 patients (98%) with baseline bilirubin <2.0 mg/dl started at 800 mg sorafenib compared with 27/28 (96%) in those with baseline bilirubin 2.0–3.0 mg/dl and 1/8 (13%) in those with baseline bilirubin >3.0 mg/dl. It should be noted that patient numbers were low in higher baseline bilirubin groups, particularly those with baseline bilirubin >3.0 mg/dl (Supplementary Table 1). Previously reported global data showed comparable initial doses and dose modifications across bilirubin groups [15].
Safety
As indicated in Table 3, the overall safety profile of sorafenib according to Child–Pugh score shows that drug-related AEs of any grade were reported in 58% of patients with Child–Pugh A and in 46% of patients with Child–Pugh B (vs 69% and 64%, respectively, globally [15]). Grade 3/4 drug-related AEs were reported in 21% of patients with Child–Pugh A and in 7% of patients with Child–Pugh B (vs 26% and 22%, respectively, globally [15]). Analysis of the most frequent AEs according to Child–Pugh score (≥10% cutoff) in Latin American patients showed that the incidences of diarrhea, hand–foot skin reaction, alopecia, rash and liver dysfunction were all higher in those with Child–Pugh A than those with Child–Pugh B (Table 4 & Supplementary Table 2). Global data also revealed that hand–foot skin reaction was more frequent among those with Child–Pugh A than those with Child–Pugh B [15].
| Safety parameter, n (%) | Child–Pugh score† | ||||||
|---|---|---|---|---|---|---|---|
| A (<7) (n = 33) | B7 (n = 21) | B8 (n = 14) | B9 (n = 6) | B (7–9) (n = 41) | C (>9) (n = 3) | NE (n = 13) | |
| AEs (all grades) | 23 (70) | 12 (57) | 13 (93) | 3 (50) | 28 (68) | 2 (67) | 10 (77) |
| Drug-related AEs (all grades) | 19 (58) | 11 (52) | 5 (36) | 3 (50) | 19 (46) | 0 | 6 (46) |
| SAEs | 15 (45) | 6 (29) | 11 (79) | 1 (17) | 18 (44) | 2 (67) | 8 (62) |
| Drug-related SAEs | 7 (21) | 2 (10) | 2 (14) | 0 | 4 (10) | 0 | 1 (8) |
| Drug-related grade 3 or 4 AEs | 7 (21) | 2 (10) | 1 (7) | 0 | 3 (7) | 0 | 1 (8) |
| All grade 3 or 4 AEs | 2 (6) | 5 (24) | 3 (21) | 0 | 8 (20) | 0 | 2 (15) |
| AEs leading to permanent treatment discontinuation | 5 (15) | 2 (10) | 0 | 0 | 2 (5) | 2 (67) | 3 (23) |
| Deaths‡ | 11 (33) | 3 (14) | 7 (50) | 1 (17) | 11 (27) | 2 (67) | 6 (46) |
| AE, n (%) | Child–Pugh score† | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| A (<7) (n = 33) | B7 (n = 21) | B8 (n = 14) | B9 (n = 6) | B (7–9) (n = 41) | C (>9) (n = 3) | NE (n = 13) | ||||||||
| AE | Drug-related AE | AE | Drug-related AE | AE | Drug-related AE | AE | Drug-related AE | AE | Drug-related AE | AE | Drug-related AE | AE | Drug-related AE | |
| Diarrhea | 12 (36) | 12 (36) | 5 (24) | 4 (19) | 3 (21) | 2 (14) | 0 | 0 | 8 (20) | 6 (15) | 0 | 0 | 2 (15) | 2 (15) |
| HFSR | 6 (18) | 6 (18) | 2 (10) | 2 (10) | 1 (7) | 1 (7) | 1 (17) | 1 (17) | 4 (10) | 4 (10) | 0 | 0 | 1 (8) | 1 (8) |
| Anorexia | 3 (9) | 3 (9) | 2 (10) | 1 (5) | 1 (7) | 1 (7) | 1 (17) | 1 (17) | 4 (10) | 3 (7) | 0 | 0 | 0 | 0 |
| Ascites | 3 (9) | 0 | 2 (10) | 1 (5) | 2 (14) | 0 | 0 | 0 | 4 (10) | 1 (2) | 0 | 0 | 0 | 0 |
| Encephalopathy | 2 (6) | 0 | 2 (10) | 0 | 5 (36) | 0 | 0 | 0 | 7 (17) | 0 | 0 | 0 | 1 (8) | 0 |
| Hypertension | 1 (3) | 1 (3) | 2 (10) | 2 (10) | 0 | 0 | 0 | 0 | 2 (5) | 2 (5) | 0 | 0 | 0 | 0 |
| Fatigue | 3 (9) | 2 (6) | 2 (10) | 2 (10) | 0 | 0 | 1 (17) | 0 | 3 (7) | 2 (5) | 0 | 0 | 0 | 0 |
| Alopecia | 7 (21) | 7 (21) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Rash/ desquamation | 6 (18) | 6 (18) | 1 (5) | 1 (5) | 0 | 0 | 0 | 0 | 1 (2) | 1 (2) | 0 | 0 | 1 (8) | 1 (8) |
| Liver dysfunction | 5 (15) | 1 (3) | 1 (5) | 0 | 1 (7) | 0 | 0 | 0 | 2 (5) | 0 | 0 | 0 | 5 (38) | 0 |
Efficacy
OS data according to Child–Pugh subgroup are presented in Supplementary Figure 1. In the Latin American Child–Pugh A group, median OS was 13.7 months (95% CI: 6.5–not reached [NR]) compared with 13.6 months (95% CI: 12.8–14.7) in the global cohort [15]. In the Child–Pugh B and C groups, median OS was NR (95% CI: 7.2–NR) and 2.2 months (95% CI: 0.2–2.2), respectively, compared with 5.2 months (95% CI: 4.6–6.3) and 2.6 months (95% CI: 1.5–4.0) in the overall global cohort [15].
Discussion
The GIDEON study was a large, global, prospective, non-interventional, observational registry study for patients with unresectable HCC who were treated with sorafenib in real-world clinical practice, regardless of Child–Pugh score. The number of patients in Latin America who were not evaluable for Child–Pugh status at the time of sorafenib initiation was similar to those reported globally and lower than those reported in the USA [16], reflecting potential variance in adherence to accepted clinical scoring systems. The patients from Latin America were predominantly Child–Pugh B at the start of therapy, in contrast to the global population, who were mostly Child–Pugh A. Thus, although Latin American patients tended to be first diagnosed with Child–Pugh A status (46% Child–Pugh A vs 29% Child–Pugh B) [16], they were more often diagnosed at a late BCLC stage (8% BCLC D) than the global cohort and tended to have worsened Child–Pugh scores when sorafenib was initiated (37% Child–Pugh A vs 46% Child–Pugh B) [16], despite a relatively short time from initial diagnosis to treatment. It should be noted that although patients were predominantly graded Child–Pugh B at treatment initiation in this study, this represents a heterogeneous patient population in terms of BCLC stage (stages BCLC A–C). In addition, Child–Pugh determination across Latin America may have been subject to regional variance; for example, a greater number of patients in Mexico are likely to have had NASH due to a higher incidence of obesity and diabetes [17,18]. These comorbidities can make it difficult to assess ascites, and result in either under- or overestimation of Child–Pugh score. The model for end-stage liver disease provides a predictive score based on objective criteria, which may be a useful alternative or additional assessment [19].
TACE is the standard of care for patients with intermediate-stage (BCLC B) unresectable disease [20,21]. Fewer patients from Latin America had received TACE prior to sorafenib initiation versus the global cohort, and a greater proportion had received only one prior TACE, which may have influenced Child–Pugh status at study initiation. Although TACE is the most commonly provided therapy in Latin America (35% of patients with HCC) [4], the low frequency of TACE use in the Latin American region in this study may reflect a localized economic or practical restriction in one or more of the major institutions represented. A large number of patients were from Mexico, and a large proportion of patients from a single institution could introduce bias if TACE was particularly restricted at that site due to reduced availability of interventional radiologists and/or direct access to TACE. For example, only 140 active interventional radiologists have been reported in Mexico, compared with 4100 diagnostic radiologists, and only 50% of interventional radiology fellows are trained in embolization procedures [22]. Restricted access may also lead to delays resulting in TACE no longer being recommended due to advanced disease. The poor availability of other potential curative treatments in Mexico, such as transplantation or resection for earlier stage disease [23], may also be a contributory factor, particularly for late-phase cirrhotic patients. Restricted access to sorafenib at the time of the study, particularly within Mexico, may also have contributed to patients receiving the drug at a later stage of disease, particularly if a high proportion of the patients in this study were treated at an institution with this issue. Overall, these data reflect Latin American regional variation in the diagnosis and management of patients with HCC in clinical practice.
Sorafenib was well tolerated in patients with both Child–Pugh A and Child–Pugh B status, and therefore irrespective of the degree of liver impairment present. Latin American patients received a higher median dose, had fewer dose reductions and had a longer treatment duration than the global cohort. Among Latin American patients, those with Child–Pugh B7 tended to have a longer treatment duration than those with Child–Pugh B8 and B9; however, in contrast to global trends, patients with Child–Pugh A had a shorter treatment duration than those with Child–Pugh B, of whom more than half continued sorafenib beyond 28 weeks. The higher rate of drug-related serious AEs and discontinuations due to AEs in those with Child–Pugh A may be a contributory factor to the observed differences in duration of treatment, which seems to be unrelated to the degree of liver dysfunction. However, these data could reflect the practice of starting with the maximum dose of sorafenib and delayed dose reduction in responding patients. Dose escalation according to response may have prevented the discontinuation of sorafenib due to AEs in some patients with Child–Pugh B. The time from initial HCC diagnosis to sorafenib treatment was shorter in patients with Child–Pugh A, but a relatively high number had stage III disease or BCLC stage D disease compared with Child–Pugh B patients and when compared with the global Child–Pugh A group [15]. Prior treatment history, including use of TACE, was similar across those with Child–Pugh A and B and therefore does not appear to be a factor influencing median duration of sorafenib treatment between the two groups. Although a higher proportion of patients with Child–Pugh B had NASH at the start of sorafenib treatment, the effect of this and/or related comorbidities on treatment tolerance or outcome is unknown. Nonetheless, this could have contributed to a higher proportion of Child–Pugh B versus Child–Pugh A scores in patients with similar tumor burden. The increased incidence of NASH in Mexico [17] provides an additional contributory factor that may affect HCC epidemiology in the region.
A large observational study of HCC treatment and survival in South American patients, using data from Argentina, has been published [24] and a retrospective survival analysis has provided valuable data on prognostic indicators of survival benefit in South American patients treated with sorafenib [25]. An important difference between GIDEON and these other studies is that GIDEON was a prospective study that focused on safety. A key strength of this study is the safety subanalysis by Child–Pugh status, and the data provide an important complementary addition to these published survival data. A limitation of this subanalysis is the relatively small sample size compared with the overall global study, combined with the typically heterogeneous nature of the high proportion of patients classified as Child–Pugh B. In addition, the majority of evaluable patients were geographically restricted to only two Latin American countries, Mexico and Venezuela, and the cohort did not include patients from Brazil or Argentina. However, the overall safety profile of sorafenib in these patients was similar across those with Child–Pugh A and B, despite a longer treatment duration in the Child–Pugh B group, and AE rates were generally below those reported for the overall global cohort. The longer treatment duration in patients with Child–Pugh B requires further investigation, as this seems to reflect better tolerability of sorafenib in this subgroup. A future subanalysis based on Model for End-stage Liver Disease scores may potentially provide useful additional data that may help to rationalize this finding. Nonetheless, these combined data indicate that sorafenib tolerability is, at least, comparable between patients with Child–Pugh B and those with Child–Pugh A in Latin America, and is similar to that reported in the global cohort [15].
Conclusion
Overall, sorafenib has an acceptable safety profile in Latin American patients with either Child–Pugh A or B. The propensity for patients who initiated sorafenib therapy in GIDEON to have Child–Pugh B may adversely impact overall outcomes due to a probable greater degree of liver function deterioration during treatment [15,26]. Conclusions cannot be drawn based on the survival data in this observational subgroup analysis of patients from Latin America. However, the data confirm that sorafenib may be a valid treatment option for some patients in this heterogeneous group in clinical practice settings.
The incidence of hepatocellular carcinoma (HCC) is heterogeneous across Latin America, partly due to local geographical differences in the incidence of hepatitis B virus and hepatitis C virus infections and alcoholic liver disease.
HCC is often diagnosed at an advanced stage in Latin America, and patients with advanced disease have poor long-term survival.
Sorafenib has been shown to prolong overall survival in Phase III randomized studies and is approved as first-line treatment for unresectable HCC.
Global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafenib (GIDEON) was a prospective, global, non-interventional study with the primary objective to evaluate the safety of sorafenib in patients with unresectable HCC in real-world practice.
In the GIDEON study, regional variations were found in patient characteristics, treatment practices and outcomes; this subgroup analysis assessed the safety of sorafenib and real-world treatment practices among Latin American patients in GIDEON.
Given the importance of the degree of liver impairment when making treatment decisions, sorafenib safety and treatment patterns were assessed according to Child–Pugh status.
Of the safety population of the GIDEON study, 90 patients from Latin America were evaluable for this subgroup safety analysis, of whom 77 had known Child–Pugh status.
Heterogeneity was seen in disease characteristics, patient characteristics and treatment patterns across Child−Pugh score subgroups.
Patients tended to be first diagnosed with Child–Pugh A status, but were often diagnosed at a late stage and had worsened Child–Pugh scores at the time of sorafenib initiation.
Sorafenib demonstrated a similar overall safety profile across Child–Pugh A and B groups, although the incidences of diarrhea, hand–foot skin reaction, alopecia, rash and liver dysfunction were all slightly higher in patients with Child–Pugh A compared with Child–Pugh B.
A longer duration of treatment was seen in patients with Child–Pugh B, with a higher rate of drug-related serious adverse events and discontinuations due to adverse events in patients with Child–Pugh A, potentially reflecting a Latin American practice of starting sorafenib treatment at the maximum dose.
In the Child–Pugh A, B and C groups, median overall survival was 13.7 months, not reached and 2.2 months, respectively; these data were similar in the overall GIDEON population.
Sorafenib was well tolerated in Latin American patients with either Child–Pugh A or B.
Sorafenib may be a valid treatment option in clinical practice for some patients in the heterogeneous Latin American patient population.
The observed longer treatment duration in the Child–Pugh B group should be investigated further.
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-0323
Author contributions
L de Guevara, V Arruda, K Nakajima, M Kudo contributed to the conception/study design. All authors contributed to the collection and/or assembly of data. Data analysis and interpretation was carried out by V Arruda, K Nakajima, M Kudo. All authors contributed to manuscript writing and final approval. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Acknowledgments
The authors would like to thank all clinical sites that contributed to the GIDEON study.
Financial & competing interests disclosure
The GIDEON study was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, an Amgen subsidiary. L de Guevara has received consultancy fees from Galmed Pharmaceuticals and Genfit, and honoraria from Allergan, Cymabay and Genfit. L Dagher has no conflicts of interest to declare. V Arruda is an employee of Bayer. K Nakajima was an employee of Bayer, and owns Bayer stock. M Kudo has received honoraria from Bayer, Eisai and Merck Sharp & Dohme, advisory/consulting fees from Bayer, Bristol-Myers Squibb, Eisai, Merck Sharp & Dohme and Ono Pharmaceutical, and grants or other funding from AbbVie, Astellas Pharma, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, EA Pharma, Eisai, Gilead, Medico's Hirata, Otsuka, Taiho and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Medical writing support for the development of this manuscript was provided by Matthew Naylor at OPEN Health Medical Communications (Choice; London, UK), with financial support from Bayer.
Ethical conduct of research statement
This study was conducted according to regional post-authorization surveillance regulations in accordance with Good Post-marketing Surveillance Practice, the principles of the Declaration of Helsinki and all applicable laws and regulations. All patients provided written informed consent for participation before enrollment in the study and the protocol was reviewed and approved by the institutional review boards of all participating study sites.
Data sharing statement
The authors certify that this manuscript reports the secondary analysis of clinical trial data that have been shared with them, and that the use of this shared data is in accordance with the terms (if any) agreed upon their receipt. The source of this data is: NCT00812175, PMID: 27469901, DOI: 10.1016/j.jhep.2016.07.020. Availability of the data underlying this publication will be determined according to Bayer's commitment to the European Federation of Pharmaceutical Industries and Associations (EFPIA) and Pharmaceutical Research and Manufacturers of America (PhRMA) ‘Principles for responsible clinical trial data sharing’. This pertains to scope, time point and process of data access. As such, Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data and protocols from clinical trials in patients for medicines and indications approved in the USA and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the ‘Study sponsors’ section of the portal. Data access will be granted to anonymized patient-level data, protocols and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
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