PLoS One. 2016 Jan 8;11(1):e0146456.
The Efficacy of Continued Sorafenib Treatment after Radiologic Confirmation of Progressive Disease in Patients with Advanced Hepatocellular Carcinoma.
- 1Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
BACKGROUND: Whether radiologically detected progressive disease (PD) is an accurate metric for discontinuing sorafenib treatment in patients with hepatocellular carcinoma (HCC) is unclear. We investigated the efficacy of sorafenib treatment after radiologic confirmation of PD in patients with advanced HCC.
METHODS: We retrospectively analyzed HCC patients treated with sorafenib at Kyushu Medical Center. Six of the 92 patients with radiologically confirmed PD were excluded because they were classified as Child-Pugh C or had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3; 86 patients were ultimately enrolled.
RESULTS: Among the 86 patients, 47 continued sorafenib treatment after radiologic confirmation of PD (the continuous group), whereas 39 did not (the discontinuous group). The median survival time (MST) in the continuous group after confirmation was 12.9 months compared with 4.5 months in the discontinuous group (p <0.01). The time to progression in the continuous group after confirmation was 2.6 months compared with 1.4 months in the discontinuous group (p <0.01); it was 4.2 months and 2.1 months in patients who had received sorafenib ≥4 months and <4 months, respectively, before confirmation (p = 0.03). In these subgroups, the post-PD MST was 16.7 months and 9.6 months, respectively (p < 0.01). Independent predictors of overall survival after radiologic detection of PD were (hazard ratio, confidence interval): ECOG PS <2 (0.290, 0.107-0.880), Barcelona Clinical Liver Cancer stage B (0.146, 0.047-0.457), serum α-fetoprotein level ≥400 ng/mL (2.801, 1.355-5.691), and post-PD sorafenib administration (0.279, 0.150-0.510).
CONCLUSION: Continuing sorafenib treatment after radiologic confirmation of PD increased survival in patients with advanced HCC. Therefore, radiologically detected PD is not a metric for discontinuation of sorafenib treatment in such patients.
Sorafenib induces a response in 2.0–3.3% of patients with stable Hepatocellular carcinoma (HCC) and improves overall survival (OS) in patients with HCC in the absence of an objective response [1,2]. Its cytotoxicity may differ from that of cytotoxic anticancer agents that shrink tumors. In the SHARP and Asia-Pacific trials, sorafenib was administered until patients were diagnosed with symptomatic progressive disease (PD), and it significantly improved survival. However, whether the onset of radiologically detected PD (referred to as “radiologic PD”) is an accurate criterion for discontinuing sorafenib treatment is unclear. To address this issue, we evaluated the efficacy of continued sorafenib treatment after radiologic confirmation of PD in patients with HCC.
We reviewed data collected prospectively from 130 consecutive patients who received sorafenib for treatment of advanced HCC in the Department of Hepato-Biliary-Pancreatic Surgery at the National Hospital Organization Kyushu Medical Center between July 2009 and September 2013. Of the 116 patients whose radiologic responses were assessed in accordance with the modified Response Evaluation Criteria In Solid Tumors (RECIST) , 92 had radiologic PD. Six of the 92 patients were excluded from the study because their liver function reserve was classified as Child-Pugh C (n = 3) or because their Eastern Cooperative Oncology Group (ECOG) performance status (PS) was ≥3 (n = 3) at the time at which PD was detected. Ultimately, 86 patients were enrolled in our investigation of the efficacy of continuous sorafenib treatment.
Clinical features at the time of radiologic confirmation of PD were compared between two patient groups: the “continuous group” (n = 47) and the “discontinuous group” (n = 39). The continuous group continued to receive sorafenib after PD confirmation (i.e., sorafenib was the second-line treatment) at the same dose as before confirmation; no additional agents were administered along with sorafenib. The discontinuous group discontinued sorafenib treatment after PD confirmation and received the following second-line treatments: TACE (n = 11), hepatic arterial infusion chemotherapy (HAIC, n = 5), radiation (n = 3), systemic chemotherapy consisting of oral uracil and tegafur (n = 2), clinical trials (n = 4), or none (n = 14).
All patients in the continuous group received the same dose of sorafenib after radiologic confirmation of PD as before. In this group, 5, 4, 18, 3, and 17 patients received 800, 600, 400, 300, and 200 mg of sorafenib, respectively.
The median survival time after radiologic confirmation of PD was longer in the continuous group (12.9 months; 95% CI, 9.8–17.1) than in the discontinuous group (4.5 months, 95% CI, 2.5–7.6, p <0.01, log-rank test) (Fig 1). The OS rates were 56.8% (1-year) and 17.6% (2-year) in the continuous group, and 24.7% (1-year) and 12.4% (2-year) in the discontinuous group. These results suggest that radiologic PD may not be an accurate metric for discontinuing sorafenib treatment.
Twenty-three patients in the continuous group received sorafenib ≥4 months before radiologic confirmation of PD. As assessed according to the modified RECIST, their best radiologic responses to post-PD sorafenib were SD (n = 15, 65.2%) and PD (n = 8, 34.8%). Twenty-four patients in the continuous group received sorafenib <4 months before confirmation, and their best radiologic responses were SD (n = 5, 20.8%) and PD (n = 19, 79.2%). Interestingly, the TTP and median survival time (MST) in patients receiving sorafenib for ≥4 months before confirmation were 4.2 months (95% CI, 1.8–2.6) and 16.7 months (95% CI, 10.0–29.3), respectively. In contrast, the TTP and MST in patients receiving sorafenib for <4 months before confirmation were 2.1 months (95% CI, 1.8–2.6) (p <0.01, log-rank test) and 9.6 months (95% CI, 4.7–16.2) (p = 0.03, log-rank test), respectively (Fig 2).
A subgroup analysis showed that the survival benefits of continuous sorafenib treatment were associated with sex (male), the presence of extrahepatic spread, the presence or absence of macrovascular invasion, Barcelona Clinic Liver Cancer (BCLC) stage C, Child-Pugh status A or B, and the type of progression (extrahepatic growth or new extrahepatic lesion) (Fig 3).
Univariate analysis revealed a significant correlation between survival and the following parameters in patients with radiologic PD: age, PS, extrahepatic spread, macrovascular invasion, BCLC stage, post-PD sorafenib administration, serum AFP level, serum Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) level, serum DCP level, and type of progression (extrahepatic growth and new extrahepatic lesion). Furthermore, a multivariate analysis identified the following as independent predictors of OS in patients with radiologic PD (hazard ratio, 95% CI): ECOG PS <2 (0.290, 0.107–0.880), BCLC stage B (0.146, 0.047–0.457), serum AFP level ≥400 ng/mL (2.801, 1.355–5.691), and post-PD sorafenib administration (0.279, 0.150–0.510)
This study demonstrates the efficacy of continued sorafenib treatment after radiologic confirmation of PD in patients with advanced HCC. Therefore, radiologic PD is not a metric for discontinuation of sorafenib treatment in such patients.
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