Baseline and Early Predictors of Good Patient Candidates for Second-Line after Sorafenib Treatment in Unresectable Hepatocellular Carcinoma

Background: Recent advances in the development of tyrosine kinase inhibitors (TKIs) have enabled patients with unresectable hepatocellular carcinoma (HCC) to receive multiple TKIs in sequence. The aim of this study was to identify predictors of good candidates for second-line treatment after disease progression during sorafenib treatment. Methods: This is a retrospective cohort study of 190 consecutive HCC patients who were treated with sorafenib in our hospital. Three criteria of good candidates for second-line TKI at the time of disease progression during sorafenib treatment were defined as follows: criterion 1 was the same as the inclusion criteria of the regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE) study, criterion 2 was the inclusion criteria of the RESORCE study plus Child–Pugh score 5, and criterion 3 was the inclusion criteria of the RESORCE study plus albumin–bilirubin (ALBI) grade 1. Factors at baseline and at week 4 during sorafenib treatment were used to predict patients fulfilling each of these three criteria. Results: The distribution of patients was 29%, 13%, and 6% in criteria 1, 2, and 3, respectively. Significant factors for meeting criterion 1 was the combination of baseline albumin >3.7 g/dL (odds ratio (OR) 2.7) plus degree of decrease in albumin (Δalbumin) at week 4 <0.2 g/dL (OR 2.6), or the combination of baseline ALBI score <−2.33 (OR 2.5) and ΔALBI at week 4 <0.255 (OR 4.9). For criterion 2, the value of baseline albumin and ALBI score was identical to criterion 1; however, Δalbumin (<0.1 g/dL) and ΔALBI score (<0.19) became stricter. For criterion 3, the value of baseline albumin (>3.8 g/dL) and ALBI (<−2.55) became stricter, as did Δalbumin (<0.1 g/dL) and ΔALBI (<0.085). Furthermore, tumor burden (>11) was selected as an additional predictor (OR 5.4). Conclusion: Predictors to satisfy the RESORCE study inclusion criteria were as follows: preserved liver function at baseline, as reflected by albumin or ALBI score, and small deterioration of liver function early during sorafenib therapy, as reflected by Δalbumin or ΔALBI at week 4. Liver function at baseline and degree of change in liver function during sorafenib treatment need to be stricter for better outcomes of liver function with disease progression.

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How Much Time Should Be Waited and What Are the Main Findings to Evaluate the Hepatocellular Carcinoma Response to Regorafenib? A Real-Life Experience

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2021/6219896 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Gustavo Hideki Kawanami ◽

Leopoldo Katsuda ◽

Thiara Barcelos Rocha ◽

Fabio da Silva Yamashiro ◽

Leonardo Pelafsky ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Kinase Inhibitors ◽

Life Experience ◽

Real Life ◽

Treatment Modalities ◽

Screening Methods ◽

Second Line ◽

Imaging Findings ◽

Sorafenib Treatment

Background. Hepatocellular carcinoma is a relevant cause of mortality worldwide, mainly among patients who have a prior liver disease. In spite of clear recommendations regarding surveillance and screening methods, most patients are still diagnosed only when they are no longer candidates to curative treatment modalities, while others do not achieve the goals of such treatments, thus increasing the need of anticancer drugs. Moreover, when cirrhotic patients begin to receive these drugs, many types of adverse events are seen as a reason to withdrawal, even when there are findings suggesting a good response to the treatment. Case Summary. This case report is about a cirrhotic patient who received many types of treatment, from surgery and chemoembolization during early stages to first- and second-line systemic therapy when the disease turned to be advanced. Since he had no signs of liver dysfunction and suffered tumor progression during sorafenib treatment, regorafenib was initiated. The main findings that make this case important are the adverse events after taking this second-line agent, which would certainly be considered unacceptable and would lead to the drug withdrawal. The reasons why regorafenib was maintained are explained based on clinical and imaging findings, showing how this decision led to an excellent response. Conclusions. The knowledge of the main adverse events described in the pilot clinical trials can avoid unnecessary withdrawal of regorafenib. In addition, some clinical and imaging findings can be deemed as predictors of good response to tyrosine kinase inhibitors.

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Sorafenib for the treatment of patients with advanced hepatocellular carcinoma and alcoholic cirrhosis.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.352 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 352-352

Author(s):

P. Giovanis ◽

V. Vincenzi ◽

C. Manuppelli ◽

R. Berletti ◽

M. Marcante ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Function ◽

Disease Progression ◽

Median Time ◽

Alcoholic Cirrhosis ◽

Function Class ◽

Median Number ◽

Hcv Infection ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment

352 Background: Hepatocellular carcinoma (HCC) from alcoholic cirrhosis, associated or not with chronic hepatitis C virus (HCV) infection, is a particularly severe liver disease. Scanty and inconsistent data concerning the efficacy of sorafenib in patients (pts) with this disease are available. Methods: Since February 2009 we screened 26 Child-Pugh liver function class A pts bearing the above characteristics. Sixteen of them (61.5%), 15 males and 1 female with median age of 69 years (range 54-79), received 400 mg sorafenib b.i.d. Predominant cause of HCC was alcohol consumption in 13 pts (81.2%), associated with chronic HCV infection in 2 pts (12.5%), and hemosiderosis in 1 pt (6.2%). All pts suffered from multiple comorbidities, and 3 had been previously treated for Burkitt lymphoma, bladder and breast cancer. One pt with prostate cancer was on treatment with androgen blockade. Median number of concomitant medications was 4 (range 2-9). Four pts never received locoregional treatment, and none had received previous antineoplastic therapy. Results: Twelve pts (73%) discontinued sorafenib after a median time of 2 months (range 2-6). The reasons for treatment discontinuation were disease progression (4 pts), liver function deterioration (5 pts), and mild gastrointestinal adverse events (2 pts): 1 pt refused sorafenib treatment after 15 days. 2/4 patients still on treatment with sorafenib at 7, 8, 11, and 18 months showed partial response (RECIST criteria). Seven pts (40%) died because of disease progression at a median time of 5.5 months (range 2-9) and at a median overall survival time of 36 months from diagnosis (range 2-84). Conclusions: Treatment with sorafenib in pts affected by HCC and alcoholic cirrhosis seems effective and well tolerated with high-level compliance. The most common cause of discontinuation was progression of disease and liver function deterioration. No significant financial relationships to disclose.

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An investigation of the safety of continued treatment with sorafenib in patients with unresectable hepatocellular carcinoma after the first disease progression: Multicenter, open-label, phase II safety study.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.462 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 462-462

Author(s):

Noriyuki Akutsu ◽

Shigeru Sasaki ◽

Hideyasu Takagi ◽

Hiroyuki Kaneto ◽

Kazuhiko Yonezawa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Disease Progression ◽

Treatment Options ◽

Line Treatment ◽

First Line ◽

Open Label ◽

Sorafenib Treatment ◽

First Line Therapy ◽

Unresectable Hepatocellular Carcinoma

462 Background: Randomized studies showed that sorafenib significantly improved outcome in patients with unresectable hepatocellular carcinoma (HCC). However, there is no clear evidence to support the safety and benefit of continued treatment of sorafenib beyond disease progression (PD) in patients with HCC treated with sorafenib. We prospectively evaluated the safety and efficacy of sorafenib beyond PD in patients with HCC whose disease has progressed after first-line treatment with sorafenib. Methods: Unresectable HCC patients with evaluable lesion were treated with sorafenib until 1st PD, followed by soafenib until 2nd PD. The primary endpoint of the study was the safety after 1st PD until 2nd PD. Secondary endpoints of the study were response rate (RR), disease control rate (DCR), time to first PD (TTP1), time to second PD during continued treatment (TTP2), overall survival (OS), and safety throughout the treatment period. Adverse event was evaluated as per The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tumor response was evaluated as per Modified Response Evaluation in Solid Tumors (mRECIST) criteria. The Kaplan–Meier method was used to determine TTP and OS. Results: Of 30 patients enrolled from 6 sites in Japan, 29 patients received sorafenib treatment, and one patient refused chemotherapy. Twenty patients continued sorafenib beyond PD. Grade 3/4 adverse events occurred less frequently during TTP2 than during TTP1. No critical events related to sorafenib were reported during TTP2. In the first-line therapy, 29 patients treated with sorafenib showed RR of 10.3%, DCR of 60.7% and median TTP1 of 102 days. Twenty patients who received continued sorafenib beyond PD and showed RR of 0%, DCR of 45%, and median TTP2 of 77 days. Median survival time was 306 days. Conclusions: Sorafenib beyond PD had acceptable tolerability and considerable efficacy. In the present conditions without second line treatment, sorafenib beyond PD might be one of the treatment options. Clinical trial information: UMIN000005818.

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Efficacy and Safety of Lenvatinib Therapy for Unresectable Hepatocellular Carcinoma in a Real-World Practice in Korea

Liver Cancer ◽

10.1159/000512239 ◽

2021 ◽

pp. 1-11

Author(s):

Myung Ji Goh ◽

Joo Hyun Oh ◽

Yewan Park ◽

Jihye Kim ◽

Wonseok Kang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Disease Progression ◽

Real World ◽

Medical Center ◽

Objective Response ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Eligibility Criteria ◽

Unresectable Hepatocellular Carcinoma

Background: Lenvatinib has been recently approved as a first-line treatment option for patients with unresectable hepatocellular carcinoma (HCC) in Korea. We aimed to study the efficacy and safety of lenvatinib therapy in a real-world practice and to find prognostic factors related to survival and disease progression. Methods: A hospital-based retrospective study was conducted on 111 consecutive patients who had unresectable HCC and were treated with lenvatinib at Samsung Medical Center from October 2018 to March 2020. Efficacy was determined using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria in 111 patients who completed 1st tumor assessment. Safety was evaluated in 116 HCC patients including 5 patients who discontinued lenvatinib due to adverse events (AEs) before 1st tumor assessment using Common Terminology Criteria for AEs version 5.0. Results: A total of 111 patients with a median age of 59 years were analyzed during a median follow-up duration of 6.2 (4.4–9.0) months. The Kaplan-Meier estimate of overall survival was 10.5 months, and the median progression-free survival was 6.2 months. Based on mRECIST criteria, the objective response rate was 18.9% and disease control rate was 75.7%. AEs developed in 86/116 (74.1%) patients, and grade ≥3 AEs developed in 16/116 (13.8%) patients. Diarrhea, hand-foot skin rash, abdominal pain, hypertension, and anorexia were identified as the AEs with the highest frequencies of any grade. REFLECT eligibility criteria including tumor extent ≥50% liver occupation or inadequate bone marrow function and occurrence of anorexia were prognostic factors for survival, and occurrence of diarrhea was a favorable factor for disease progression. Conclusion: Lenvatinib therapy showed a favorable efficacy and safety in a real-world practice. The REFLECT eligibility criteria and specific AEs could be one of the prognostic markers.

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P-78 Post hoc analysis in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function in the phase 3 REFLECT study of lenvatinib vs sorafenib

Annals of Oncology ◽

10.1016/j.annonc.2021.05.133 ◽

2021 ◽

Vol 32 ◽

pp. S123-S124

Author(s):

J. Huynh ◽

M. Cho ◽

E. Kim ◽

M. Ren ◽

C. Amaya-Chanaga ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Function ◽

Phase 3 ◽

Post Hoc Analysis ◽

Unresectable Hepatocellular Carcinoma ◽

Post Hoc

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Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.324 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 324-324

Author(s):

Ciro Celsa ◽

Giuseppe Cabibbo ◽

Marco Enea ◽

Salvatore Battaglia ◽

Giacomo Emanuele Maria Rizzo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Data ◽

Survival Curve ◽

Second Line ◽

First Line ◽

Lifetime Horizon ◽

First Line Therapy ◽

Line Therapy ◽

Unresectable Hepatocellular Carcinoma ◽

Sequential Strategy

324 Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.

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Area between the hepatic and heart curves of99mTc-galactosyl-human serum albumin scintigraphy represents liver function and disease progression for preoperative evaluation in hepatocellular carcinoma patients

Journal of Hepato-Biliary-Pancreatic Sciences ◽

10.1007/s00534-011-0486-2 ◽

2011 ◽

Vol 19 (6) ◽

pp. 667-673 ◽

Cited By ~ 7

Author(s):

Kohei Harada ◽

Toru Mizuguchi ◽

Yoshimi Katagiri ◽

Masaki Kawamoto ◽

Yukio Nakamura ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Human Serum Albumin ◽

Liver Function ◽

Serum Albumin ◽

Human Serum ◽

Disease Progression ◽

Preoperative Evaluation ◽

Galactosyl Human Serum Albumin

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Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib

Oncology ◽

10.1159/000509387 ◽

2020 ◽

Vol 98 (11) ◽

pp. 787-797 ◽

Cited By ~ 2

Author(s):

Yuwa Ando ◽

Tomokazu Kawaoka ◽

Yosuke Suehiro ◽

Kenji Yamaoka ◽

Yumi Kosaka ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Multivariate Analysis ◽

Liver Function ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Class A ◽

Line Therapy ◽

Pugh Class ◽

Ecog Ps

Background: Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. Methods: Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. Results: One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465–18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (<400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099–0.886, p = 0.003), a relative tumor volume <50% at the time of progression (HR 0.204, 95% CI 0.07–0.592, p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12–0.746, p = 0.01) were significant prognostic factors. Conclusion: Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.

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