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Well-preserved liver function enhances the clinical impact of curative-intent subsequent treatment during lenvatinib treatment for unresectable hepatocellular carcinoma

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A Correction to this article was published on 01 July 2023

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Abstract

Background

The aims of this study were to evaluate the clinical impact of curative-intent subsequent treatment on overall prognosis in lenvatinib-treated hepatocellular carcinoma (HCC) patients.

Methods

Eighty-three consecutive patients with intrahepatic target nodules who received lenvatinib were reviewed. The clinical impact of curative-intent subsequent treatments was investigated through analysis of overall survival (OS) according to pathological deterioration stratified by mALBI grade.

Results

In patients with mALBI grade 1 and 2a liver function, R0 resection and lenvatinib-transarterial chemoembolization (lenvatinib-TACE) sequential therapy resulted in significantly better OS compared with other, non-curative-intent subsequent therapy and lack of additional treatment (median OS, 37.6 vs 29.0 months and 17.1 vs 8.9 months, respectively; P < 0.001). Multivariate analysis confirmed that use of R0 resection and lenvatinib-TACE sequential therapy were associated with better OS (hazard ratio [HR], 0.021; P < 0.001 and 0.108; P < 0.001) compared with other, non–curative-intent subsequent treatment (HR 0.256; P = 0.010). In contrast, in patients with mALBI grade 2b liver function, multivariate analysis confirmed higher treatment efficacy for non–curative-intent subsequent treatment with respect to OS (HR 0.041; P < 0.001) compared with R0 resection and lenvatinib-TACE sequential therapy (HR 0.057; P = 0.027 and 0.063; P = 0.001).

Conclusion

Curative-intent subsequent treatment is more useful for HCC patients with better liver function (mALBI grade 1 and 2a) and intrahepatic target nodules who have received lenvatini b-based treatment.

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Data availability

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Change history

Abbreviations

AE:

Adverse event

AFP:

Alpha-fetoprotein

ALBI:

Albumin-bilirubin

BCLC:

Barcelona Clinic Liver Cancer

DCP:

Des-γ-carboxyprothrombin

HCC:

Hepatocellular carcinoma

mALBI:

Modified albumin-bilirubin

mRECIST:

Modified Response Evaluation Criteria in Solid Tumors

ORR:

Objective response rate

OS:

Overall survival

PFS:

Progression-free survival

PPS:

Post-progression survival RFA, radiofrequency ablation

TACE:

Transarterial chemoembolization

TKI:

Tyrosine kinase inhibitor

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Acknowledgements

This work was supported, in part, by grants from the Ministry of Health, Labour and Welfare in Japan and the Japan Agency for Medical Research and Development.

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Authors and Affiliations

  1. Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-Ku, Tokyo, 105-8470, Japan

    Yusuke Kawamura, Norio Akuta, Shunichiro Fujiyama, Tetsuya Hosaka, Satoshi Saitoh, Hitomi Sezaki, Fumitaka Suzuki, Yoshiyuki Suzuki, Kenji Ikeda, Yasuji Arase & Hiromitsu Kumada

  2. Department of Gastroenterological Surgery, Hepatobiliary-Pancreatic Surgery Division, Toranomon Hospital, Tokyo, Japan

    Junichi Shindoh, Masaru Matsumura, Satoshi Okubo & Masaji Hashimoto

  3. Radiation Oncology Division, Department of Radiology, Toranomon Hospital, Tokyo, Japan

    Licht Tominaga & Takuyo Kozuka

  4. Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan

    Yusuke Kawamura, Norio Akuta, Junichi Shindoh, Masaru Matsumura, Satoshi Okubo, Licht Tominaga, Shunichiro Fujiyama, Tetsuya Hosaka, Satoshi Saitoh, Hitomi Sezaki, Fumitaka Suzuki, Yoshiyuki Suzuki, Kenji Ikeda, Yasuji Arase, Masaji Hashimoto, Takuyo Kozuka & Hiromitsu Kumada

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  1. Yusuke Kawamura
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Contributions

YK, M.D., Ph.D.; study concept and design, acquisition of data, statistical analysis, and drafting of the manuscript. 2. NA, M.D., Ph.D.; acquisition of data. JS, M.D., Ph.D.; acquisition of data, statistical analysis, and critical revision of the manuscript. MM, M.D., Ph.D.; acquisition of data. SO, M.D., Ph.D.; acquisition of data. LT, M.D., Ph.D.; acquisition of data and statistical analysis. SF, M.D.; acquisition of data. TH, M.D.; acquisition of data. SS, M.D.; acquisition of data. HS, M.D.; acquisition of data. FS, M.D., Ph.D.; acquisition of data. YS, M.D., Ph.D.; acquisition of data. KI, M.D., Ph.D.; acquisition of data, statistical analysis, and study supervision. YA, M.D., Ph.D.; acquisition of data. MH, M.D., Ph.D.; acquisition of data. TK, M.D., Ph.D.; acquisition of data. HK, M.D., Ph.D.; acquisition of data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yusuke Kawamura.

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Conflict of interest

Yusuke Kawamura, M.D., Ph.D. reports honoraria from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., and TERUMO CORPORATION. Junichi Shindoh, M.D., Ph.D. reports honoraria from Eisai Co., Ltd., and Chugai Pharmaceutical Co., Ltd. Hiromitsu Kumada, M.D., Ph.D. reports honoraria from Eisai Co., Ltd. The other authors declare no conflicts of interest.

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Supplementary Information

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12328_2022_1723_MOESM1_ESM.tiff

Supplementary file1 Supplementary Figure 1: Original dynamic-CT study images showing each of the four enhancement patterns. (Reprinted with permission from John Wiley and Sons. [28]). The Type-1 pattern shows homogeneous enhancement with no increase in arterial blood flow, and the entire image appears uniform during the arterial and portal phases. The Type-2 pattern shows homogeneous enhancement with increased arterial blood flow, and the entire image appears uniform during the arterial and portal phases. The Type-3 pattern shows heterogeneous enhancement with septations, with heterogeneous enhancement and septations in the arterial phase and septations resembling near-uniform tumor tissue periphery in the portal phase. The Type-4 pattern shows heterogeneous enhancement with irregular ring-like structures; the arterial phase is marked by the presence of irregularly-shaped ring areas of enhancement and areas of little blood flow relative to the periphery of the tumor tissue, while the portal phase is characterized by areas of reduced blood flow. (TIFF 35874 KB)

12328_2022_1723_MOESM2_ESM.tiff

Supplementary file2 Supplementary Figure 2: Survival outcomes of all lenvatinib-treated HCC patients. (a) Progression-free survival rate, (b) post-progression survival rate, and (c) overall survival rate. (TIFF 107 KB)

12328_2022_1723_MOESM3_ESM.tiff

Supplementary file3 Supplementary Figure 3: Overall survival outcomes of lenvatinib-treated HCC patients with mALBI grade 1 and 2a liver function stratified by (a) tumor burden (estimated using Up-to-7 criteria), (b) presence of macrovascular invasion, (c) presence of extrahepatic spread, (d) pretreatment dynamic-CT enhancement patterns, and (e) use of subsequent treatment during treatment period. UT7, Up-to-7; MVI, microvascular invasion; EHS, extrahepatic spread; mALBI, modified albumin-bilirubin; LEN-TACE, lenvatinib-transarterial chemoembolization (TIFF 212 KB)

12328_2022_1723_MOESM4_ESM.tiff

Supplementary file4 Supplementary Figure 4: Overall survival outcomes of lenvatinib-treated HCC patients with mALBI grade 2b disease stratified by (a) tumor burden (estimated using Up-to-7 criteria), (b) presence of macrovascular invasion, (c) presence of extrahepatic spread, (d) pretreatment dynamic-CT enhancement patterns, and (e) use of subsequent treatment during treatment period. UT7, Up-to-7; MVI, microvascular invasion; EHS, extrahepatic spread; mALBI, modified albumin-bilirubin; LEN-TACE, lenvatinib-transarterial chemoembolization (TIFF 212 KB)

12328_2022_1723_MOESM5_ESM.tiff

Supplementary file5 Supplementary Figure 5: The ratio of each subsequent treatment during the treatment period according to residual liver function estimated by mALBI grade. mALBI, modified albumin-bilirubin; TACE, transarterial chemoembolization (TIFF 5182 KB)

12328_2022_1723_MOESM6_ESM.tiff

Supplementary file6 Supplementary Figure 6: Treatment strategy for subsequent treatment during lenvatinib treatment (TIFF 34023 KB)

Supplementary file7 Supplementary Table 1 (DOCX 29 KB)

Supplementary file8 Supplementary Table 2 (DOCX 32 KB)

Supplementary file9 Supplementary Table 3 (DOCX 33 KB)

Supplementary file10 Supplementary Table 4 (DOCX 33 KB)

Supplementary file11 Supplementary Table 5 (DOCX 30 KB)

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Kawamura, Y., Akuta, N., Shindoh, J. et al. Well-preserved liver function enhances the clinical impact of curative-intent subsequent treatment during lenvatinib treatment for unresectable hepatocellular carcinoma. Clin J Gastroenterol 16, 1–12 (2023). https://doi.org/10.1007/s12328-022-01723-4

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