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  • Wiley  (11)
  • Toyoda, Hidenori  (11)
  • 1
    In: International Journal of Cancer, Wiley, Vol. 154, No. 6 ( 2024-03-15), p. 1043-1056
    Abstract: Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first‐line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real‐world AB‐treated HCC patients were analyzed in uni‐ and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α‐FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni‐ and multivariate analyses for OS of a comparable lenvatinib‐treated HCC population. Finally, comparison between treatments was performed in patients with low and high α‐FAtE scores and predictivity estimated by interaction analysis. Time‐to‐progression (TTP) was a secondary endpoint. OS of AB‐treated HCC patients was statistically longer in those with α‐fetoprotein 〈 400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) 〈 125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α‐FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p 〈 .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p 〈 .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α‐FAtE score resulted as negative predictive factor of response to AB ( p = .0004). In conclusion, α‐FAtE is a novel prognostic and predictive score of response to first‐line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 2
    In: Hepatology Research, Wiley, Vol. 52, No. 9 ( 2022-09), p. 773-783
    Abstract: Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u‐HCC) patients classified as Child‐Pugh A (CP‐A). This study aimed to elucidate the prognosis of patients treated with Atez/Bev, especially CP‐A and ‐B cases. Materials/methods From September 2020 to March 2022, 457 u‐HCC patients treated with Atez/Bev were enrolled (median age 74 years, male:female = 368:89, CP‐A:CP‐B = 427:30, Child‐Pugh score [CPS] 5:6:7:8:9 = 271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated. Results There were no significant differences between CP‐A and ‐B patients in regard to best response (CR:PR:SD:PD = 16:91:194:81 vs. 0:7:13:8, p  = 0.739; objective response rate/disease control rate = 28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value  〈  0.10 for comparisons between patients with CP‐A and ‐B showed that the progression‐free survival (PFS) rate for CP‐A cases was better (6‐/12‐/18‐month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non‐estimable [NE], p   〈  0.001), as was overall survival (OS) rate (6‐/12‐/18‐month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p   〈  0.001). Median PFS (mPFS) and median OS (mOS) for the CPS‐5 were 9.5 months/NE, and 5.1/14.0 months for the CPS‐6 (both p   〈  0.001). Furthermore, for modified albumin‐bilirubin grade (mALBI)‐1/2a/2b, mPFS was 9.4/8.5/5.3 months ( p   〈  0.001) and mOS was NE/17.8/13.4 months ( p   〈  0.001). Conclusion Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u‐HCC patients, whereas for CP‐B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.
    Type of Medium: Online Resource
    ISSN: 1386-6346 , 1872-034X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2006439-1
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  • 3
    In: Hepatology Research, Wiley, Vol. 52, No. 3 ( 2022-03), p. 308-316
    Abstract: Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u‐HCC) classified as beyond the up‐to‐7 criteria (UT‐7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u‐HCC patients classified as UT‐7 out/multiple. Material/Methods From September 2020 to September 2021, 95 u‐HCC Japanese patients classified as UT‐7 out/multiple/Child‐Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child‐Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Results Atez/Bev was given as first‐line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child‐Pugh A/modified Albumin‐bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any‐grade, 〉 10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Conclusion Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.
    Type of Medium: Online Resource
    ISSN: 1386-6346 , 1872-034X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2006439-1
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  • 4
    In: Cancer Medicine, Wiley, Vol. 12, No. 1 ( 2023-01), p. 325-334
    Abstract: A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first‐line therapy for unresectable hepatocellular carcinoma (u‐HCC) in regard to progression‐free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u‐HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. Materials/Methods From 2020 to January 2022, 251 u‐HCC (Child–Pugh A, ECOG PS 0/1, BCLC‐B/C) treated were enrolled (Atez/Bev‐group, n  = 194; lenvatinib‐group, n  = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). Results There was a greater number of patients with macro‐vascular invasion in Atez/Bev‐group (22.7% vs. 8.8%, p  = 0.022). In lenvatinib‐group, the frequencies of appetite loss (38.6% vs. 19.6%, p  = 0.002), hypothyroidism (21.1% vs. 6.7%, p  = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p   〈  0.001), and diarrhea (10.5% vs. 4.6%, p  = 0.012) were greater, while that of general fatigue was lower (22.8% vs. 26.3%, p  = 0.008). Comparisons of therapeutic best response using modified response evaluation criteria in solid tumors (mRECIST) did not show significant differences between the present groups (Atez/Bev vs. lenvatinib: CR/PR/SD/PD = 6.1%/39.1%/39.1%/15.6% vs. 0%/48.0%/38.0%/14.0%, p  = 0.285). In patients of discontinuation of treatments, 48.2% switched to lenvatinib, 10.6% continued beyond PD, 8.2% received another systemic treatment, 5.9% underwent transcatheter arterial chemoembolization (TACE), 3.5% received hepatic arterial infusion chemotherapy (HAIC), and 1.2% underwent surgical resection in Atez/Bev‐group, while 42.2% switched to Atez/Bev, 4.4% continued beyond PD, 4.4% received another systemic treatment, 2.2% nivolumab, 6.7% received TACE, and 2.2% received HAIC in lenvatinib‐group. Following adjustment with inverse probability weighting (IPW), Atez/Bev‐group showed better PFS (0.5−/1−/1.5‐years: 56.6%/31.6%/non‐estimable vs. 48.6%/20.4%/11.2%, p   〈  0.0001) and OS rates (0.5−/1−/1.5‐years: 89.6%/67.2%/58.1% vs. 77.8%/66.2%/52.7%, p  = 0.002). Conclusion The present study showed that u‐HCC patients who received Atez/Bev as a first‐line treatment may have a better prognosis than those who received lenvatinib.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 5
    In: Liver International, Wiley
    Abstract: The study goal was to compare the outcomes of patients with intermediate‐stage (Barcelona Clinic Liver Cancer [BCLC]‐B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first‐line systemic therapy. Methods A total of 358 patients with BCLC‐B HCC treated with Atezo/Bev ( n  = 177) or LEN ( n  = 181) as first‐line systemic therapy were included. Results The median progression‐free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8–12.6) and 7.3 months (95% CI, 6.3–8.5), respectively ( p  = .019). In the propensity score‐matched cohort, the median PFS times in the Atezo/Bev ( n  = 151) and LEN ( n  = 151) groups were 10.2 months (95% CI, 7.0–12.3) and 6.9 months (95% CI, 5.9–8.1), respectively ( p  = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months ( p  = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up‐to‐seven criteria, the median PFS times in the Atezo/Bev ( n  = 134) and LEN ( n  = 117) groups were 10.5 months (95% CI, 7.0–11.8) and 6.3 months (95% CI, 5.5–7.3), respectively ( p  = .044). Conclusions The use of Atezo/Bev as first‐line systemic therapy in patients with BCLC‐B HCC is expected to result in good PFS.
    Type of Medium: Online Resource
    ISSN: 1478-3223 , 1478-3231
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2124684-1
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  • 6
    In: Cancer Reports, Wiley, Vol. 5, No. 2 ( 2022-02)
    Abstract: Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u‐HCC), changes in hepatic function during therapy have yet to be reported. Aim This retrospective clinical study aimed to elucidate early responses to Atez/Bev. Methods From September 2020 to April 2021, 171 u‐HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin‐bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively. Results In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR‐6W/DCR‐6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR‐6W/DCR‐6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post‐progression treatment following lenvatinib (ORR‐6W/DCR‐6W = 7.7%/79.5%), for which no known effective post‐progression treatment has been established. In 111 patients who underwent a 6‐week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (−2.525 ± 0.419 vs −2.323 ± 0.445, p   〈  .001), but then recovered at 6‐weeks (−2.403 ± 0.452) as compared to 3‐weeks ( p  = .001). During the observation period, the most common adverse events were appetite loss (all grades) (12.3%), general fatigue/hypertension (all grades) (11.1%, respectively), and urine protein (all grades) (10.5%). Conclusion Atez/Bev might have therapeutic potential not only as first but also later‐line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.
    Type of Medium: Online Resource
    ISSN: 2573-8348 , 2573-8348
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2920367-3
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  • 7
    In: Hepatology Research, Wiley, Vol. 51, No. 8 ( 2021-08), p. 880-889
    Abstract: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure. Methods From June 2017 to October 2020, 63 patients with Child–Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R‐L group, n  = 47) and those who did not receive lenvatinib after regorafenib (non‐R‐L group, n  = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting. Results Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R‐L and non‐R‐L groups, whereas the albumin‐bilirubin score, Child–Pugh class, and tumor burden were not. Progression‐free survival was also not significantly different (median 4.1 vs. 3.8 months, p  = 0.586). As for overall survival, the R‐L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p   〈  0.001 and p  = 0.022, respectively). Modified albumin‐bilirubin grade 2b (score 〉 −2.27) at the start of regorafenib (HR 2.074, p  = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p  = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment. Conclusion These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.
    Type of Medium: Online Resource
    ISSN: 1386-6346 , 1872-034X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2006439-1
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  • 8
    In: Hepatology Research, Wiley, Vol. 52, No. 12 ( 2022-12), p. 1050-1059
    Abstract: The identification of new prognostic factors able to stratify hepatocellular carcinoma patients candidate to first‐line therapy is urgent. In the present work we validated the prognostic value of the lenvatinib prognostic index. Methods Data of Eastern and Western patients treated with lenvatinib as first‐line for Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma were recollected. The lenvatinib prognostic index was composed by three classes of risk according with our previous study. The “low risk” group includes patients with prognostic nutritional index (PNI) 〉 43.3 and with previous transarterial chemoembolization. The “medium risk” group includes patients with PNI 〉 43.3, but without previous transarterial chemoembolization and patients with PNI 〈 43.3, albumin‐bilirubin grade 1 and Barcelona Clinic Liver Cancer stage B. The “high risk” group includes patients with PNI 〈 43.3, albumin‐bilirubin grade 2, and patients with PNI 〈 43.3, albumin‐bilirubin grade 1 and Barcelona Clinic Liver Cancer stage C. Results A total of 717 patients were included. The median overall survival was 20.7 months (95% CI 16.1–51.6) in patients with low risk ( n  = 223), 16.7 months (95% CI 13.3–47.0) in patients with medium risk ( n  = 264), and 10.7 months (95% CI 9.3–12.2) in patients with high risk ( n  = 230; HR 1, 1.29, and 1.92, respectively; p   〈  0.0001). Median progression‐free survival was 7.3 months (95% CI 6.3–46.5) in patients with low risk, 6.4 months (95% CI 5.3–8.0) in patients with medium risk ,and 4.9 months (95% CI 4.3–5.5) in patients with high risk (HR 1, 1.07, 1.47 respectively; p  = 0.0009). Conclusion The lenvatinib prognostic index confirms its prognostic value on an external cohort of hepatocellular carcinoma patients treated with Lenvatinib.
    Type of Medium: Online Resource
    ISSN: 1386-6346 , 1872-034X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2006439-1
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  • 9
    In: Journal of Gastroenterology and Hepatology, Wiley, Vol. 36, No. 7 ( 2021-07), p. 1812-1819
    Abstract: This study aimed to elucidate the clinical importance of muscle volume loss (pre‐sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u‐HCC). Methods Of 437 u‐HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre‐sarcopenia was diagnosed based on a previously reported cut‐off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm 2 )/height (m) 2 ]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre‐sarcopenia. Results Cox hazard multivariate analysis showed alpha‐fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P   〈  0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P  = 0.018), and positive for pre‐sarcopenia (HR 1.652, P  = 0.042) to be significant prognostic factors. OS rates for the pre‐sarcopenia group ( n  = 41) were worse than those for the non‐pre‐sarcopenia group ( n  = 110) (0.5‐, 1‐, and 1.5‐year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P   〈  0.001), as was progression‐free survival ( P  = 0.025). Time to stopping lenvatinib or disease progression was better in the non‐pre‐sarcopenia group (0.5‐, 1‐, and 1.5‐year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P   〈  0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre‐sarcopenia group (43.9% vs 18.2%, P  = 0.003). Conclusion Pre‐sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u‐HCC.
    Type of Medium: Online Resource
    ISSN: 0815-9319 , 1440-1746
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2006782-3
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  • 10
    In: Cancer Medicine, Wiley, Vol. 8, No. 8 ( 2019-07), p. 3719-3728
    Abstract: We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u‐HCC) by investigating real‐world clinical features of patients. Materials/methods One hundred fifty two u‐HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child‐Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin‐bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively. Results Overall‐response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine‐kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649‐13.02, P  = 0.004) in Cox‐hazard multivariate analysis. In patients with Child‐Pugh A, c‐index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without ( P  = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m 2 , P   〈  0.001), while patients with a hand‐foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without ( P  = 0.007). Conclusion Good hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2659751-2
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