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Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy
Research Article
Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy Yu-Yun Shao1,6, Chih-Horng Wu2,4, Li-Chun Lu5, Soa-Yu Chan1, Yu-Yi Ma7, Feng-Chu Yen7, Chih-Hung Hsu1,6,⇑, Ann-Lii Cheng1,3,6,⇑ 1
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 4Department of Medical Imaging, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan; 5Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan; 6Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; 7National Taiwan University Cancer Center Preparatory Office, National Taiwan University College of Medicine, Taipei, Taiwan See Editorial, pages 243–244
Background & Aims: No approved therapy is available for patients with advanced hepatocellular carcinoma (HCC) who fail first-line therapy. The prognosis of these patients, especially those eligible for clinical trials of second-line therapy, is unclear. Methods: All patients who participated in clinical trials of firstline systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included. Their clinicopathologic characteristics, when the firstline treatment failed, were analyzed and correlated with the overall survival (OS) from the date of first-line treatment failure. Results: A total of 192 patients were included. Before the start of the first-line therapy, all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program (CLIP) scores 64. After the failure of the first-line therapy, the median OS of the entire group was 4.0 months. Patients with Child-Pugh class A liver reserves, when the first-line treatment failed, had significantly better OS than patients with Child-Pugh class B or C liver reserves (median, A vs. B vs. C = 7.5 vs. 1.3 vs. 1.0 month, p <0.001). According to the key eligibility criteria of 3 published clinical trials for second-line therapy, 41%–56% of patients were
Keywords: Clinical trials; Hepatocellular carcinoma; Prognosis; Second-line therapy; Survival. Received 23 April 2013; received in revised form 15 August 2013; accepted 30 August 2013; available online 12 September 2013 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2013.10.031. ⇑ Corresponding authors. Addresses: Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan. Tel.: +886 2 23123456x67680; fax: +886 2 23711174 (C.-H. Hsu). Departments of Internal Medicine and Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan. Tel.: +886 2 23123456x67251; fax: +886 2 23711174 (A.-L. Cheng). E-mail addresses: [email protected] (C.-H. Hsu), [email protected] (A.-L. Cheng). Abbreviations: HCC, hepatocellular carcinoma; TTP, time to progression; NTUH, National Taiwan University Hospital; OS, overall survival; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG PS, Eastern Cooperative Oncology Group performance status.
potentially eligible. Compared to patients who were ineligible for clinical trials, potentially eligible patients had longer OS with a median of 7.8–8.6 months. Conclusions: Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials. Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Advanced hepatocellular carcinoma (HCC), which is defined as metastatic or locally advanced disease that is not amenable to loco-regional therapies, had no proven treatment until sorafenib was demonstrated to provide survival benefits in 2 phase III randomized clinical trials [1,2]. However, the efficacy of sorafenib is modest. The median time to progression (TTP) was 2.8– 5.5 months. Many novel compounds or combinations have been actively explored in phase II or even phase III studies [3–16]. However, none have proven to be more efficacious than sorafenib as first-line therapies. Currently, there is no proven second-line therapy for advanced HCC. Patients with advanced HCC, who fail first-line systemic therapy, are considered to have extremely poor prognosis. However, the exact course and prognosis of these patients are unclear because no report is available in literature. This information is critical for clinical trial design and practice. Because an increasing number of second-line clinical trials are being performed for advanced HCC, knowledge of the survival outcomes of potentially eligible patients is crucial for study designs and statistical considerations. In clinical practice, this information can help physicians to provide better risk stratification and cost-effective treatments to their patients. To address this issue, we used a large cohort of HCC patients, who had been enrolled in clinical trials of first-line systemic
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Research Article therapies for advanced diseases since 2005 at our center. We retrospectively reviewed their liver function reserves and laboratory findings at the time of first-line treatment failure, and analyzed them with the survival outcomes.
Patients and methods Study population and variables All patients who were enrolled in clinical trials involving first-line systemic therapy for advanced HCC from May 2005 to May 2011 at National Taiwan University Hospital (NTUH), Taipei, Taiwan were included in this study. All these clinical trials targeted HCC patients with metastatic or locally advanced disease that was not amenable to loco-regional therapies, including surgery, transcatheter (chemo-) embolization, and local ablation. The regimens used in these clinical trials included sorafenib and tegafur/uracil, thalidomide and tegafur/uracil, bevacizumab and capecitabine, bevacizumab and erlotinib, sorafenib vs. sunitinib, and sorafenib vs. brivanib [3–6,17]. The patient characteristics and laboratory examination results before the start of the first-line therapy were retrieved from the original study records. The dates of first-line treatment failure, either caused by disease progression or intolerable toxicities, were recorded according to the original clinical trial documents. We reviewed the medical records of all the enrolled patients and recorded the disease status and laboratory examination results when the firstline treatment failed. The laboratory results were acceptable for analysis if they were acquired within 1 week before or after the date of treatment failure. Overall survival (OS) was calculated from the date of the treatment failure to the date of death or the last follow-up. Statistical methods Statistical analyses were performed using SAS statistical software (version 9.1.3, SAS Institute Inc., Cary, NC, USA). In statistical testing, a two-sided p value 60.05 was considered statistically significant. For comparison of disease status and liver reserves before first-line treatment and upon treatment failure, the Wilcoxon signed-rank test was used. The Kaplan-Meier method was used to estimate OS, and the log-rank test was used to compare OS between various patient subgroups.
Results Patient characteristics before first-line therapy A total of 209 patients were enrolled in 6 clinical trials examining first-line systemic therapies, but 17 patients were excluded because no laboratory results were available when their treatment failed. Therefore, 192 patients were included in this study, with the median age of 56.9 years (Table 1). The hepatitis etiology was hepatitis B virus (HBV) in 138 (72%) patients and hepatitis C virus in 22 (11%) patients. The treatment regimens of first-line therapies included sorafenib (19%), sunitinib (10%), brivanib (10%), sorafenib with tegafur/uracil (28%), thalidomide with tegafur/uracil (17%), bevacizumab with capecitabine (10%), and bevacizumab with erlotinib (6%). Before the first-line therapy, all patients had good liver reserves that were classified as Child-Pugh class A. Extrahepatic spread (EHS) and macrovascular invasion (MVI) were found in 67% and 54% of patients, respectively (Table 2). Most (91%) of the patients had Barcelona Clinic Liver Cancer (BCLC) stage C disease. The patients had an even distribution of Cancer of the Liver Italian Program (CLIP) scores ranging from 0 to 4, and no patients had CLIP scores >4. In addition, 2 patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 2, although all other patients had ECOG PS of 0 or 1 (Table 2). 314
Patient characteristics when first-line therapy failed All 192 patients had first-line treatment failure, either due to disease progression (94%) or intolerable toxicities (6%). Compared to disease status and liver reserves prior to the first-line therapy, significantly more patients had EHS (p <0.001) and MVI (p <0.001) when first-line treatment failed (Table 2). Liver reserves significantly deteriorated when the first-line treatment failed (p <0.001). Although all patients had Child-Pugh A liver reserves before the first-line therapy, 69 (36%) patients had Child-Pugh class B (n = 66, 34%) or C (n = 3, 2%) liver reserves when the first-line therapy failed. Among patients with ChildPugh class B liver reserves, 37 patients had scores of 7, 19 patients had scores of 8, and 10 patients had scores of 9. In addition, CLIP scores significantly increased when first-line treatment failed (p <0.001). Before the first-line therapy, no patients had CLIP scores >4. When the first-line therapy failed, 31 (17%) patients had CLIP scores of 5 or 6. Furthermore, ECOG PS deteriorated (p <0.001) (Table 2). Survival after first-line therapy failed After first-line therapy failed, 77 (40%) of the patients received salvage systemic therapy, such as thalidomide (17%), 5-fluorouracil derivatives (11%), and tamoxifen (5%). Five patients were enrolled in clinical trials for second-line therapies. As of October 15, 2012, 175 (91%) patients had died. The median OS following first-line treatment failure was 4.0 months (95% confidence interval, 2.7–5.3 month) (Fig. 1A). Patients with Child-Pugh class A liver reserves had significantly longer OS than did patients with Child-Pugh class B or C liver reserves (median, 7.5 vs. 1.3 vs. 1.0 month, p <0.001; Fig. 1B). Among patients classified as Child-Pugh class A, patients with different Child-Pugh scores (i.e., 5 or 6) did not have significantly different OS (median 8.3 vs. 4.3 month, p = 0.321; Fig. 1C). Among patients classified as Child-Pugh class B, patients with different Child-Pugh scores (i.e., 7, 8, or 9) had similar OS (median, 1.3 vs. 1.6 vs. 0.7 month, p = 0.460; Fig. 1D). Patients with ChildPugh scores 7, compared to patients with Child-Pugh class A liver reserve, had significantly poorer OS (p <0.001) and were more likely to have MVI, AFP level >400 ng/ml, higher American Joint Committee on Cancer stages, higher CLIP scores, and poorer ECOG PS (Supplementary Table 1). In addition, patients with low CLIP scores or good ECOG PS had significantly better OS (p <0.001 and p <0.001, respectively; Fig. 1E and F). Patients with a-fetoprotein level >400 ng/ml upon tumor progression had poorer OS than patients with lower a-fetoprotein level (p = 0.003; Fig. 1G). TTP of first-line therapy also predicted OS (p <0.001; Fig. 1H). Shorter TTP of first-line therapy was associated with more MVI, poorer liver reserve, higher CLIP scores, and poorer performance status (Supplementary Table 2). Patients with MVI upon disease progression had poorer OS than patients with EHS only (Supplementary Fig. 1). Testing the eligibility for clinical trials following first-line treatment failure As of December 31, 2012, only 3 clinical trials of second-line therapy for advanced HCC published their results in full manuscripts. According to the key eligibility criteria of 3 clinical trials testing second-line therapies for advanced HCC, we analyzed how many
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JOURNAL OF HEPATOLOGY Table 1. Patient characteristics.
Total Age, yr. Median (range) Sex Female Male Hepatitis etiology Hepatitis B virus Hepatitis C virus Both above Alcoholism Unknown Diagnosis Histologic Clinical criteria First-line therapy Sorafenib Sunitinib Brivanib Sorafenib and tegafur/uracil Thalidomide and tegafur/uracil Bevacizumab and capecitabine Bevacizumab and erlotinib
Table 2. Patient characteristics, before first-line therapy and when first-line therapy failed.
N % 192 100 56.9 (23.6-83.1) 22 170
11 89
138 22 8 3 21
72 11 4 2 11
145 47
76 24
21 19 19 54 33 19 12
19 10 10 28 17 10 6
patients can be enrolled in clinical trials after first-line treatment failure. These 3 clinical trials comprised of the phase II study of brivanib [7], the phase III study comparing brivanib to a placebo (the phase III study of brivanib) [8], and the phase II study of tivantinib (the tivantinib study) [9]. The examined eligibility criteria are listed in Table 3. A total of 94 (49%) patients would have been ineligible for the phase II brivanib study. The most common reasons for the ineligibility included CLIP scores >3 (72%), hyperbilirubinemia (48%), and elevated levels of liver transaminases (46%). A total of 84 (44%) patients were ineligible for the phase III brivanib study. The most common reasons for the ineligibility included elevated levels of liver transaminases (51%), hyperbilirubinemia (43%), and inadequate Child-Pugh status (38%). A total of 109 (57%) patients were ineligible for the phase II tivantinib study. The most common reasons for the ineligibility included inadequate Child-Pugh status (61%), hyperbilirubinemia (50%), and elevated levels of liver transaminases (38%) (Table 3). None of the patients had elevated levels of liver transaminases due to HBV flare-ups. Among patients who were ineligible to second-line clinical trials, 25%–30% of patients actually received systemic therapy. The most common regimens included thalidomide, tamoxifen, oral fluorouracil derivatives, and hepatic arterial infusion of chemotherapy. Patients potentially eligible to the phase II brivanib study, compared to ineligible patients, had significantly longer OS (median, 8.3 vs. 1.7 month, p <0.001; Fig. 2A). Patients who were potentially eligible for the phase III brivanib study, compared to ineligible patients, had significantly longer OS (median, 7.8 vs. 1.7 month, p <0.001; Fig. 2B). Moreover, patients who were potentially eligible for the phase II tivantinib study, compared to ineligible patients, had significantly longer OS (median, 8.8 vs. 1.9 month, p <0.001; Fig. 2C).
Total Disease extent Extrahepatic spread Macrovascular invasion Either above AFP >400 ng/ml Child-Pugh score A B C AJCC stage II III IV BCLC stage B C D CLIP score 0 1 2 3 4 5 6 ECOG PS 0 1 2 3-4
N (%) Before first- Upon line treatment therapy failure 192 (100) 192 (100)
p value
128 (67) 103 (54) 176 (92) 110 (57)
144 (75) 119 (62) 181 (94) 116 (60)
<0.001 <0.001 0.059 0.201 <0.001
192 (100) 0 (0) 0 (0)
123 (64) 66 (34) 3 (2)
11 (6) 48 (25) 133 (69)
8 (4) 38 (20) 146 (76)
18 (9) 174 (91) 0 (0)
18 (9) 171 (89) 3 (2)
18 (9) 44 (23) 45 (23) 43 (22) 42 (22) 0 (0) 0 (0)
15 (8) 33 (17) 34 (18) 42 (22) 37 (19) 28 (15) 3 (2)
126 (66) 63 (33) 3 (2) 0 (0)
58 (30) 113 (59) 18 (9) 3 (2)
<0.001
0.083
<0.001
<0.001
AFP, a-fetoprotein; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG PS, Eastern Cooperative Oncology Group performance status.
Discussion Our study specifically studied the disease course and prognosis of patients with advanced HCC who failed first-line therapy. The median OS of the patients after first-line treatment failure was 4 months. Intriguingly, in well-selected patients, the median OS was approximately 8 months, as we demonstrated in the patients with Child-Pugh class A liver reserves (7.5 month), and in the patients who were potentially eligible to clinical trials for second-line systemic therapies (7.8–8.6 month). We found that patients with low CLIP scores (0 or 1) or good ECOG PS (= 0) also had favorable prognosis. The majority (83%) of our patients had viral hepatitis as the hepatitis etiology, and 72% of them had HBV. We should be cautious to apply these results to other cohorts with more patients suffering from HCV or alcoholism because some reports have found that hepatitis etiology might be a prognostic factor in patients with advanced HCC [18,19].
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Research Article A
C
All patients
Child-Pugh A patients
B
D
Child-Pugh
Child-Pugh B patients
E
CLIP scores
F
ECOG PS
G
AFP >400 ng/ml
H
TTP of first-line therapy
Fig. 1. Kaplan-Meier analysis of OS. (A) All patients; (B) all patients grouped by Child-Pugh class; (C) Child-Pugh A patients grouped by different Child-Pugh scores; (D) Child-Pugh B patients grouped by different Child-Pugh scores; (E) all patients grouped by CLIP scores; (F) all patients grouped by ECOG PS; (G) all patients grouped by serum alpha-fetoprotein levels; and (H) all patients grouped by time to progression (TTP) of first-line therapy. The p values were obtained using the Log-rank test. The months shown in the figures are the median OS (MS). (This figure appears in color on the web.)
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JOURNAL OF HEPATOLOGY Table 3. Eligibility of study patients (n = 192) according to eligibility criteria of 3 clinical trials of second-line therapy for advanced HCC.
Variable Total ECOG PS CLIP score Child-Pugh Total bilirubin (mg/dl) AST/ALT (UNL*) Albumin (mg/dl) PT INR Creatinine (mg/dl) Neutrophil (/mm3) Hemoglobin (g/dl) Platelet (/μl)
Phase II: brivanib [7] Criteria Ineligible, N (%) 94 0-2 3 (3) ≤3 68 (72) ≤2.5 45 (48) <5x 43 (46) >2.8 6 (6) ≤1.8 2 (2) ≤2.0 3 (3) >60,000 4 (4)
Second-line study Phase III: brivanib vs. placebo [8] Criteria Ineligible, N (%) 84 0-2 3 (3) A or B7 32 (38) ≤3 36 (43) <5x 43 (51) ≥2.8 5 (6) ≤2.3 0 (0) ≤2.0 3 (4) ≥1500 13 (15) ≥8.5 8 (10) ≥60,000 4 (5)
Phase II: tivantinib [9] Criteria Ineligible, N (%) 109 0-1 21 (19) A 69 (61) ≤2 57 (50) <5x 43 (38) ≥2.8 5 (4) 0.8-1.4 11 (10) ≤1.5 9 (8) ≥1500 13 (12) ≥9.0 12 (11) ≥60,000 4 (4)
⁄
Equals to 155 IU/L at our hospital. ECOG PS, Eastern Cooperative Oncology Group performance status; CLIP, Cancer of the Liver Italian Program; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio.
A
B
C
Fig. 2. Kaplan-Meier analysis showing OS of the patients who met and did not meet the eligibility criteria of clinical trials. (A) the phase II clinical trial testing brivanib as a second-line therapy for advanced HCC; (B) the phase III clinical trial comparing brivanib vs. a placebo as a second-line therapy for advanced HCC; and (C) the phase II clinical trial testing tivantinib as a second-line therapy for advanced HCC. The p values were obtained using the Log-rank test. The months shown in the figures are the median OS. (This figure appears in color on the web.)
Patients had more severe and advanced disease, when they experienced disease progression with the first-line therapy. Patients were more likely to have EHS, MVI, and high CLIP scores when they failed first-line therapy for advanced HCC. Along with disease progression, many patients suffered from deteriorated liver reserves and performance status; 36% of the patients had their liver function reserves deteriorate from Child-Pugh class A to B or C, and 11% of the patients had ECOG PS P2. When the first-line therapy failed, approximately half of the patients were potentially eligible for clinical trials based on the key eligibility criteria of 3 published clinical trials [7–9]. The most common reasons for ineligibility included high CLIP scores, ChildPugh class B or C, hyperbilirubinemia and elevated liver transaminase levels. Deteriorated liver function is the most important reason for ineligibility. For patients with advanced HCC, who failed first-line therapies, the actual enrollment rates in second-line clinical trials should be even lower than we estimated. Patients may be unwilling to participate in further clinical trials, and may become ineligible during the ‘‘washout’’ period, that is a standard design for second-line studies. To avoid inevitably low enrollment rates, some studies have attempted to enroll patients with Child-Pugh
class B status (Child-Pugh scores 7–9) with scores of 7. In our analysis, we found that Child-Pugh B patients, including patients with scores of 7, had significantly poorer OS than did Child-A patients. For clinical trials exploring second-line therapy for advanced HCC, whether or not to enroll patients with Child-Pugh scores of 7 should be well considered. The prognosis of patients with advanced HCC can be substantially heterogeneous [20]. In the phase III study that compared sorafenib to a placebo in an East Asian population, the median OS from the start of first-line therapy was 6.5 months [1]. We showed that the median OS following first-line treatment failure can be approximately 8 months in selected patients with preserved liver function. For patients with CLIP scores 61, the median OS can be longer than 10 months. Regarding this information, we should be cautious when interpreting the results of singlearm clinical trials for advanced HCC because patient selection has a significant influence on prognosis. We found that TTP of first-line therapy had strong associations with many prognostic factors. Stratification using TTP of first-line therapy should be considered in randomized trials. The results of the first phase III clinical trial for second-line therapy for advanced HCC, which compared brivanib vs. placebo,
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Research Article were recently reported [8]. Patients who received brivanib had significantly better response rates, disease control rates, and TTP than did patients who received a placebo. The primary endpoint, OS, was not significantly different between the 2 groups (p = 0.3307) although numerically the median OS of the brivanib group was longer than that of the placebo group (9.4 vs. 8.2 month). In its study design, the median OS of the patients who failed first-line therapies and received placebo therapy for advanced HCC was supposed to be 4.0 months, which was the same as the median OS of our entire patient cohort who failed first-line therapies. However, the actual median OS of the placebo group in the phase III second-line brivanib study was twice as long as intended (8.2 month), which was similar to our results for the patients who were potentially eligible for clinical trials. When designing clinical trials for second-line systemic therapies for advanced HCC, investigators should consider the survival of potentially eligible patients, but not that of the general patient population, for sample size estimations. In conclusion, patients with advanced HCC are likely to have deteriorating liver reserves and poor prognosis when first-line treatment fails. However, selected patients who have Child-Pugh class A liver function or who are potentially eligible for clinical trials may have substantially improved prognosis. Financial support This study was supported by grants from National Taiwan University Hospital, Taipei, Taiwan (NTUH.101-N1965) and National Science Council, Taiwan (NSC98-3112-B-002-038, NSC-1012314-B-002-141, NSC 102-2314-B-002-120, 100CAP1020-2). Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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. 08.027.
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Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy Yu-Yun Shao1,6, Chih-Horng Wu2,4, Li-Chun Lu5, Soa-Yu Chan1, Yu-Yi Ma7, Feng-Chu Yen7, Chih-Hung Hsu1,6,⇑, Ann-Lii Cheng1,3,6,⇑ 1
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 4Department of Medical Imaging, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan; 5Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan; 6Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; 7National Taiwan University Cancer Center Preparatory Office, National Taiwan University College of Medicine, Taipei, Taiwan See Editorial, pages 243–244
Background & Aims: No approved therapy is available for patients with advanced hepatocellular carcinoma (HCC) who fail first-line therapy. The prognosis of these patients, especially those eligible for clinical trials of second-line therapy, is unclear. Methods: All patients who participated in clinical trials of firstline systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included. Their clinicopathologic characteristics, when the firstline treatment failed, were analyzed and correlated with the overall survival (OS) from the date of first-line treatment failure. Results: A total of 192 patients were included. Before the start of the first-line therapy, all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program (CLIP) scores 64. After the failure of the first-line therapy, the median OS of the entire group was 4.0 months. Patients with Child-Pugh class A liver reserves, when the first-line treatment failed, had significantly better OS than patients with Child-Pugh class B or C liver reserves (median, A vs. B vs. C = 7.5 vs. 1.3 vs. 1.0 month, p <0.001). According to the key eligibility criteria of 3 published clinical trials for second-line therapy, 41%–56% of patients were
Keywords: Clinical trials; Hepatocellular carcinoma; Prognosis; Second-line therapy; Survival. Received 23 April 2013; received in revised form 15 August 2013; accepted 30 August 2013; available online 12 September 2013 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2013.10.031. ⇑ Corresponding authors. Addresses: Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan. Tel.: +886 2 23123456x67680; fax: +886 2 23711174 (C.-H. Hsu). Departments of Internal Medicine and Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan. Tel.: +886 2 23123456x67251; fax: +886 2 23711174 (A.-L. Cheng). E-mail addresses: [email protected] (C.-H. Hsu), [email protected] (A.-L. Cheng). Abbreviations: HCC, hepatocellular carcinoma; TTP, time to progression; NTUH, National Taiwan University Hospital; OS, overall survival; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG PS, Eastern Cooperative Oncology Group performance status.
potentially eligible. Compared to patients who were ineligible for clinical trials, potentially eligible patients had longer OS with a median of 7.8–8.6 months. Conclusions: Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials. Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Advanced hepatocellular carcinoma (HCC), which is defined as metastatic or locally advanced disease that is not amenable to loco-regional therapies, had no proven treatment until sorafenib was demonstrated to provide survival benefits in 2 phase III randomized clinical trials [1,2]. However, the efficacy of sorafenib is modest. The median time to progression (TTP) was 2.8– 5.5 months. Many novel compounds or combinations have been actively explored in phase II or even phase III studies [3–16]. However, none have proven to be more efficacious than sorafenib as first-line therapies. Currently, there is no proven second-line therapy for advanced HCC. Patients with advanced HCC, who fail first-line systemic therapy, are considered to have extremely poor prognosis. However, the exact course and prognosis of these patients are unclear because no report is available in literature. This information is critical for clinical trial design and practice. Because an increasing number of second-line clinical trials are being performed for advanced HCC, knowledge of the survival outcomes of potentially eligible patients is crucial for study designs and statistical considerations. In clinical practice, this information can help physicians to provide better risk stratification and cost-effective treatments to their patients. To address this issue, we used a large cohort of HCC patients, who had been enrolled in clinical trials of first-line systemic
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Research Article therapies for advanced diseases since 2005 at our center. We retrospectively reviewed their liver function reserves and laboratory findings at the time of first-line treatment failure, and analyzed them with the survival outcomes.
Patients and methods Study population and variables All patients who were enrolled in clinical trials involving first-line systemic therapy for advanced HCC from May 2005 to May 2011 at National Taiwan University Hospital (NTUH), Taipei, Taiwan were included in this study. All these clinical trials targeted HCC patients with metastatic or locally advanced disease that was not amenable to loco-regional therapies, including surgery, transcatheter (chemo-) embolization, and local ablation. The regimens used in these clinical trials included sorafenib and tegafur/uracil, thalidomide and tegafur/uracil, bevacizumab and capecitabine, bevacizumab and erlotinib, sorafenib vs. sunitinib, and sorafenib vs. brivanib [3–6,17]. The patient characteristics and laboratory examination results before the start of the first-line therapy were retrieved from the original study records. The dates of first-line treatment failure, either caused by disease progression or intolerable toxicities, were recorded according to the original clinical trial documents. We reviewed the medical records of all the enrolled patients and recorded the disease status and laboratory examination results when the firstline treatment failed. The laboratory results were acceptable for analysis if they were acquired within 1 week before or after the date of treatment failure. Overall survival (OS) was calculated from the date of the treatment failure to the date of death or the last follow-up. Statistical methods Statistical analyses were performed using SAS statistical software (version 9.1.3, SAS Institute Inc., Cary, NC, USA). In statistical testing, a two-sided p value 60.05 was considered statistically significant. For comparison of disease status and liver reserves before first-line treatment and upon treatment failure, the Wilcoxon signed-rank test was used. The Kaplan-Meier method was used to estimate OS, and the log-rank test was used to compare OS between various patient subgroups.
Results Patient characteristics before first-line therapy A total of 209 patients were enrolled in 6 clinical trials examining first-line systemic therapies, but 17 patients were excluded because no laboratory results were available when their treatment failed. Therefore, 192 patients were included in this study, with the median age of 56.9 years (Table 1). The hepatitis etiology was hepatitis B virus (HBV) in 138 (72%) patients and hepatitis C virus in 22 (11%) patients. The treatment regimens of first-line therapies included sorafenib (19%), sunitinib (10%), brivanib (10%), sorafenib with tegafur/uracil (28%), thalidomide with tegafur/uracil (17%), bevacizumab with capecitabine (10%), and bevacizumab with erlotinib (6%). Before the first-line therapy, all patients had good liver reserves that were classified as Child-Pugh class A. Extrahepatic spread (EHS) and macrovascular invasion (MVI) were found in 67% and 54% of patients, respectively (Table 2). Most (91%) of the patients had Barcelona Clinic Liver Cancer (BCLC) stage C disease. The patients had an even distribution of Cancer of the Liver Italian Program (CLIP) scores ranging from 0 to 4, and no patients had CLIP scores >4. In addition, 2 patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 2, although all other patients had ECOG PS of 0 or 1 (Table 2). 314
Patient characteristics when first-line therapy failed All 192 patients had first-line treatment failure, either due to disease progression (94%) or intolerable toxicities (6%). Compared to disease status and liver reserves prior to the first-line therapy, significantly more patients had EHS (p <0.001) and MVI (p <0.001) when first-line treatment failed (Table 2). Liver reserves significantly deteriorated when the first-line treatment failed (p <0.001). Although all patients had Child-Pugh A liver reserves before the first-line therapy, 69 (36%) patients had Child-Pugh class B (n = 66, 34%) or C (n = 3, 2%) liver reserves when the first-line therapy failed. Among patients with ChildPugh class B liver reserves, 37 patients had scores of 7, 19 patients had scores of 8, and 10 patients had scores of 9. In addition, CLIP scores significantly increased when first-line treatment failed (p <0.001). Before the first-line therapy, no patients had CLIP scores >4. When the first-line therapy failed, 31 (17%) patients had CLIP scores of 5 or 6. Furthermore, ECOG PS deteriorated (p <0.001) (Table 2). Survival after first-line therapy failed After first-line therapy failed, 77 (40%) of the patients received salvage systemic therapy, such as thalidomide (17%), 5-fluorouracil derivatives (11%), and tamoxifen (5%). Five patients were enrolled in clinical trials for second-line therapies. As of October 15, 2012, 175 (91%) patients had died. The median OS following first-line treatment failure was 4.0 months (95% confidence interval, 2.7–5.3 month) (Fig. 1A). Patients with Child-Pugh class A liver reserves had significantly longer OS than did patients with Child-Pugh class B or C liver reserves (median, 7.5 vs. 1.3 vs. 1.0 month, p <0.001; Fig. 1B). Among patients classified as Child-Pugh class A, patients with different Child-Pugh scores (i.e., 5 or 6) did not have significantly different OS (median 8.3 vs. 4.3 month, p = 0.321; Fig. 1C). Among patients classified as Child-Pugh class B, patients with different Child-Pugh scores (i.e., 7, 8, or 9) had similar OS (median, 1.3 vs. 1.6 vs. 0.7 month, p = 0.460; Fig. 1D). Patients with ChildPugh scores 7, compared to patients with Child-Pugh class A liver reserve, had significantly poorer OS (p <0.001) and were more likely to have MVI, AFP level >400 ng/ml, higher American Joint Committee on Cancer stages, higher CLIP scores, and poorer ECOG PS (Supplementary Table 1). In addition, patients with low CLIP scores or good ECOG PS had significantly better OS (p <0.001 and p <0.001, respectively; Fig. 1E and F). Patients with a-fetoprotein level >400 ng/ml upon tumor progression had poorer OS than patients with lower a-fetoprotein level (p = 0.003; Fig. 1G). TTP of first-line therapy also predicted OS (p <0.001; Fig. 1H). Shorter TTP of first-line therapy was associated with more MVI, poorer liver reserve, higher CLIP scores, and poorer performance status (Supplementary Table 2). Patients with MVI upon disease progression had poorer OS than patients with EHS only (Supplementary Fig. 1). Testing the eligibility for clinical trials following first-line treatment failure As of December 31, 2012, only 3 clinical trials of second-line therapy for advanced HCC published their results in full manuscripts. According to the key eligibility criteria of 3 clinical trials testing second-line therapies for advanced HCC, we analyzed how many
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JOURNAL OF HEPATOLOGY Table 1. Patient characteristics.
Total Age, yr. Median (range) Sex Female Male Hepatitis etiology Hepatitis B virus Hepatitis C virus Both above Alcoholism Unknown Diagnosis Histologic Clinical criteria First-line therapy Sorafenib Sunitinib Brivanib Sorafenib and tegafur/uracil Thalidomide and tegafur/uracil Bevacizumab and capecitabine Bevacizumab and erlotinib
Table 2. Patient characteristics, before first-line therapy and when first-line therapy failed.
N % 192 100 56.9 (23.6-83.1) 22 170
11 89
138 22 8 3 21
72 11 4 2 11
145 47
76 24
21 19 19 54 33 19 12
19 10 10 28 17 10 6
patients can be enrolled in clinical trials after first-line treatment failure. These 3 clinical trials comprised of the phase II study of brivanib [7], the phase III study comparing brivanib to a placebo (the phase III study of brivanib) [8], and the phase II study of tivantinib (the tivantinib study) [9]. The examined eligibility criteria are listed in Table 3. A total of 94 (49%) patients would have been ineligible for the phase II brivanib study. The most common reasons for the ineligibility included CLIP scores >3 (72%), hyperbilirubinemia (48%), and elevated levels of liver transaminases (46%). A total of 84 (44%) patients were ineligible for the phase III brivanib study. The most common reasons for the ineligibility included elevated levels of liver transaminases (51%), hyperbilirubinemia (43%), and inadequate Child-Pugh status (38%). A total of 109 (57%) patients were ineligible for the phase II tivantinib study. The most common reasons for the ineligibility included inadequate Child-Pugh status (61%), hyperbilirubinemia (50%), and elevated levels of liver transaminases (38%) (Table 3). None of the patients had elevated levels of liver transaminases due to HBV flare-ups. Among patients who were ineligible to second-line clinical trials, 25%–30% of patients actually received systemic therapy. The most common regimens included thalidomide, tamoxifen, oral fluorouracil derivatives, and hepatic arterial infusion of chemotherapy. Patients potentially eligible to the phase II brivanib study, compared to ineligible patients, had significantly longer OS (median, 8.3 vs. 1.7 month, p <0.001; Fig. 2A). Patients who were potentially eligible for the phase III brivanib study, compared to ineligible patients, had significantly longer OS (median, 7.8 vs. 1.7 month, p <0.001; Fig. 2B). Moreover, patients who were potentially eligible for the phase II tivantinib study, compared to ineligible patients, had significantly longer OS (median, 8.8 vs. 1.9 month, p <0.001; Fig. 2C).
Total Disease extent Extrahepatic spread Macrovascular invasion Either above AFP >400 ng/ml Child-Pugh score A B C AJCC stage II III IV BCLC stage B C D CLIP score 0 1 2 3 4 5 6 ECOG PS 0 1 2 3-4
N (%) Before first- Upon line treatment therapy failure 192 (100) 192 (100)
p value
128 (67) 103 (54) 176 (92) 110 (57)
144 (75) 119 (62) 181 (94) 116 (60)
<0.001 <0.001 0.059 0.201 <0.001
192 (100) 0 (0) 0 (0)
123 (64) 66 (34) 3 (2)
11 (6) 48 (25) 133 (69)
8 (4) 38 (20) 146 (76)
18 (9) 174 (91) 0 (0)
18 (9) 171 (89) 3 (2)
18 (9) 44 (23) 45 (23) 43 (22) 42 (22) 0 (0) 0 (0)
15 (8) 33 (17) 34 (18) 42 (22) 37 (19) 28 (15) 3 (2)
126 (66) 63 (33) 3 (2) 0 (0)
58 (30) 113 (59) 18 (9) 3 (2)
<0.001
0.083
<0.001
<0.001
AFP, a-fetoprotein; AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG PS, Eastern Cooperative Oncology Group performance status.
Discussion Our study specifically studied the disease course and prognosis of patients with advanced HCC who failed first-line therapy. The median OS of the patients after first-line treatment failure was 4 months. Intriguingly, in well-selected patients, the median OS was approximately 8 months, as we demonstrated in the patients with Child-Pugh class A liver reserves (7.5 month), and in the patients who were potentially eligible to clinical trials for second-line systemic therapies (7.8–8.6 month). We found that patients with low CLIP scores (0 or 1) or good ECOG PS (= 0) also had favorable prognosis. The majority (83%) of our patients had viral hepatitis as the hepatitis etiology, and 72% of them had HBV. We should be cautious to apply these results to other cohorts with more patients suffering from HCV or alcoholism because some reports have found that hepatitis etiology might be a prognostic factor in patients with advanced HCC [18,19].
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Research Article A
C
All patients
Child-Pugh A patients
B
D
Child-Pugh
Child-Pugh B patients
E
CLIP scores
F
ECOG PS
G
AFP >400 ng/ml
H
TTP of first-line therapy
Fig. 1. Kaplan-Meier analysis of OS. (A) All patients; (B) all patients grouped by Child-Pugh class; (C) Child-Pugh A patients grouped by different Child-Pugh scores; (D) Child-Pugh B patients grouped by different Child-Pugh scores; (E) all patients grouped by CLIP scores; (F) all patients grouped by ECOG PS; (G) all patients grouped by serum alpha-fetoprotein levels; and (H) all patients grouped by time to progression (TTP) of first-line therapy. The p values were obtained using the Log-rank test. The months shown in the figures are the median OS (MS). (This figure appears in color on the web.)
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JOURNAL OF HEPATOLOGY Table 3. Eligibility of study patients (n = 192) according to eligibility criteria of 3 clinical trials of second-line therapy for advanced HCC.
Variable Total ECOG PS CLIP score Child-Pugh Total bilirubin (mg/dl) AST/ALT (UNL*) Albumin (mg/dl) PT INR Creatinine (mg/dl) Neutrophil (/mm3) Hemoglobin (g/dl) Platelet (/μl)
Phase II: brivanib [7] Criteria Ineligible, N (%) 94 0-2 3 (3) ≤3 68 (72) ≤2.5 45 (48) <5x 43 (46) >2.8 6 (6) ≤1.8 2 (2) ≤2.0 3 (3) >60,000 4 (4)
Second-line study Phase III: brivanib vs. placebo [8] Criteria Ineligible, N (%) 84 0-2 3 (3) A or B7 32 (38) ≤3 36 (43) <5x 43 (51) ≥2.8 5 (6) ≤2.3 0 (0) ≤2.0 3 (4) ≥1500 13 (15) ≥8.5 8 (10) ≥60,000 4 (5)
Phase II: tivantinib [9] Criteria Ineligible, N (%) 109 0-1 21 (19) A 69 (61) ≤2 57 (50) <5x 43 (38) ≥2.8 5 (4) 0.8-1.4 11 (10) ≤1.5 9 (8) ≥1500 13 (12) ≥9.0 12 (11) ≥60,000 4 (4)
⁄
Equals to 155 IU/L at our hospital. ECOG PS, Eastern Cooperative Oncology Group performance status; CLIP, Cancer of the Liver Italian Program; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio.
A
B
C
Fig. 2. Kaplan-Meier analysis showing OS of the patients who met and did not meet the eligibility criteria of clinical trials. (A) the phase II clinical trial testing brivanib as a second-line therapy for advanced HCC; (B) the phase III clinical trial comparing brivanib vs. a placebo as a second-line therapy for advanced HCC; and (C) the phase II clinical trial testing tivantinib as a second-line therapy for advanced HCC. The p values were obtained using the Log-rank test. The months shown in the figures are the median OS. (This figure appears in color on the web.)
Patients had more severe and advanced disease, when they experienced disease progression with the first-line therapy. Patients were more likely to have EHS, MVI, and high CLIP scores when they failed first-line therapy for advanced HCC. Along with disease progression, many patients suffered from deteriorated liver reserves and performance status; 36% of the patients had their liver function reserves deteriorate from Child-Pugh class A to B or C, and 11% of the patients had ECOG PS P2. When the first-line therapy failed, approximately half of the patients were potentially eligible for clinical trials based on the key eligibility criteria of 3 published clinical trials [7–9]. The most common reasons for ineligibility included high CLIP scores, ChildPugh class B or C, hyperbilirubinemia and elevated liver transaminase levels. Deteriorated liver function is the most important reason for ineligibility. For patients with advanced HCC, who failed first-line therapies, the actual enrollment rates in second-line clinical trials should be even lower than we estimated. Patients may be unwilling to participate in further clinical trials, and may become ineligible during the ‘‘washout’’ period, that is a standard design for second-line studies. To avoid inevitably low enrollment rates, some studies have attempted to enroll patients with Child-Pugh
class B status (Child-Pugh scores 7–9) with scores of 7. In our analysis, we found that Child-Pugh B patients, including patients with scores of 7, had significantly poorer OS than did Child-A patients. For clinical trials exploring second-line therapy for advanced HCC, whether or not to enroll patients with Child-Pugh scores of 7 should be well considered. The prognosis of patients with advanced HCC can be substantially heterogeneous [20]. In the phase III study that compared sorafenib to a placebo in an East Asian population, the median OS from the start of first-line therapy was 6.5 months [1]. We showed that the median OS following first-line treatment failure can be approximately 8 months in selected patients with preserved liver function. For patients with CLIP scores 61, the median OS can be longer than 10 months. Regarding this information, we should be cautious when interpreting the results of singlearm clinical trials for advanced HCC because patient selection has a significant influence on prognosis. We found that TTP of first-line therapy had strong associations with many prognostic factors. Stratification using TTP of first-line therapy should be considered in randomized trials. The results of the first phase III clinical trial for second-line therapy for advanced HCC, which compared brivanib vs. placebo,
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Research Article were recently reported [8]. Patients who received brivanib had significantly better response rates, disease control rates, and TTP than did patients who received a placebo. The primary endpoint, OS, was not significantly different between the 2 groups (p = 0.3307) although numerically the median OS of the brivanib group was longer than that of the placebo group (9.4 vs. 8.2 month). In its study design, the median OS of the patients who failed first-line therapies and received placebo therapy for advanced HCC was supposed to be 4.0 months, which was the same as the median OS of our entire patient cohort who failed first-line therapies. However, the actual median OS of the placebo group in the phase III second-line brivanib study was twice as long as intended (8.2 month), which was similar to our results for the patients who were potentially eligible for clinical trials. When designing clinical trials for second-line systemic therapies for advanced HCC, investigators should consider the survival of potentially eligible patients, but not that of the general patient population, for sample size estimations. In conclusion, patients with advanced HCC are likely to have deteriorating liver reserves and poor prognosis when first-line treatment fails. However, selected patients who have Child-Pugh class A liver function or who are potentially eligible for clinical trials may have substantially improved prognosis. Financial support This study was supported by grants from National Taiwan University Hospital, Taipei, Taiwan (NTUH.101-N1965) and National Science Council, Taiwan (NSC98-3112-B-002-038, NSC-1012314-B-002-141, NSC 102-2314-B-002-120, 100CAP1020-2). Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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. 08.027.
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