Pretreatment Positron Emission Tomography with 18F-Fluorodeoxyglucose May Be a Useful New Predictor of Early Progressive Disease following Atezolizumab plus Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma

Abstract

Background and Aims: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of early progressive disease (e-PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). Methods: Twenty consecutive patients with measurable intrahepatic target nodules who received Atezo/Bev treatment were reviewed. The oncological aggressiveness of tumors estimated by 18F-FDG-PET/CT was analyzed using the rate of e-PD within 12 weeks and early progression-free survival (e-PFS) and overall survival (OS). Multivariate analysis was used to identify potential confounders for PD during Atezo/Bev therapy. Results: Using the Response Evaluation Criteria in Solid Tumors version 1.1, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with lower objective response rates compared with TLR values <2 (18% vs. 33%, respectively). Moreover, TLR values ≥2 were significantly associated with higher e-PD rates compared with TLR values <2 (64% vs. 11%, respectively) and worse e-PFS (p = 0.021). In multivariate analysis, TLR ≥2 showed marginal significance as a predictor of e-PD (p = 0.053), and utility as a predictor for worse e-PFS (hazard ratio, 7.153; 95% confidence interval, 1.258–40.689; p = 0.027). In contrast, no significant differences in OS with/without e-PD were observed during the treatment course. In this study, 8 patients experienced e-PD and almost 40% of patients experienced acceptable disease control following subsequent lenvatinib treatment. Conclusion: Pretreatment 18F-FDG-PET/CT may be a useful new predictor of e-PD and may enable early decision-making based on early treatment changes following Atezo/Bev treatment of HCC.

© 2022 The Author(s). Published by S. Karger AG, Basel

References Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378–90. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020 May 14;382(20):1894–905. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(3_Suppl l):267–7. Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:v874–5. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase iii trial. J Clin Oncol. 2020 Jan 20;38(3):193–202. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017 Apr 15;23(8):1920–8. Saada-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017 Jul 1;28(7):1605–11. Ferrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. 2018 Nov 1;4(11):1543–52. Kanjanapan Y, Day D, Wang L, Al-Sawaihey H, Abbas E, Namini A, et al. Hyperprogressive disease in early-phase immunotherapy trials: clinical predictors and association with immune-related toxicities. Cancer. 2019 Apr 15;125(8):1341–9. Kim CG, Kim KH, Pyo KH, Xin CF, Hong MH, Ahn BC, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol. 2019 Jul 1;30(7):1104–13. Wang X, Wang F, Zhong M, Yarden Y, Fu L. The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy. Mol Cancer. 2020 May 2;19(1):81. Scheiner B, Kirstein MM, Hucke F, Finkelmeier F, Schulze K, von Felden J, et al. Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther. 2019 May;49(10):1323–33. Kim CG, Kim C, Yoon SE, Kim KH, Choi SJ, Kang B, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol. 2021 Feb;74(2):350–9. Maesaka K, Sakamori R, Yamada R, Tahata Y, Imai Y, Ohkawa K, et al. Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy. Hepatol Res. 2021 Dec 16;52(3):298–307. Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Kasuya K, Sano T, et al. Pretreatment heterogeneous enhancement pattern of hepatocellular carcinoma may be a useful new predictor of early response to lenvatinib and overall prognosis. Liver Cancer. 2020;9:1–18. Kudo M, Han KH, Ye SL, Zhou J, Huang YH, Lin SM, et al. A changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: asia-pacific primary liver cancer expert consensus statements. Liver Cancer. 2020;9:1–16. Seo S, Hatano E, Higashi T, Hara T, Tada M, Tamaki N, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma. Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):427–33. Hatano E, Ikai I, Higashi T, Teramukai S, Torizuka T, Saga T, et al. Preoperative positron emission tomography with fluorine-18-fluorodeoxyglucose is predictive of prognosis in patients with hepatocellular carcinoma after resection. World J Surg. 2006 Sep;30(9):1736–41. Kitamura K, Hatano E, Higashi T, Seo S, Nakamoto Y, Yamanaka K, et al. Preoperative FDG-PET predicts recurrence patterns in hepatocellular carcinoma. Ann Surg Oncol. 2012 Jan;19(1):156–62. Song MJ, Bae SH, Lee SW, Song DS, Kim HY, Yoo IR, et al. 18F-fluorodeoxyglucose PET/CT predicts tumour progression after transarterial chemoembolization in hepatocellular carcinoma. Eur J Nucl Med Mol Imaging. 2013 Jun;40(6):865–73. Sung PS, Park HL, Yang K, Hwang S, Song MJ, Jang JW, et al. 18F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment. Eur J Nucl Med Mol Imaging. 2018 Mar;45(3):384–91. Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Kasuya K, Sano T, et al. 18F-fluorodeoxyglucose uptake in hepatocellular carcinoma as a useful predictor of an extremely rapid response to lenvatinib. Liver Cancer. 2019:1–9. Kudo M, Matsui O, Izumi N, Kadoya M, Okusaka T, Miyayama S, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology. 2014;87(Suppl 1):22–31. Kawamura Y, Ikeda K, Shindoh J, Kobayashi Y, Kasuya K, Fujiyama S, et al. No-touch ablation in hepatocellular carcinoma has the potential to prevent intrasubsegmental recurrence to the same degree as surgical resection. Hepatol Res. 2019;49(2):164–176. Hyun SH, Eo JS, Lee JW, Choi JY, Lee KH, Na SJ, et al. Prognostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with Barcelona clinic liver cancer stages 0 and a hepatocellular carcinomas: a multicenter retrospective cohort study. Eur J Nucl Med Mol Imaging. 2016 Aug;43(9):1638–45. National Cancer Institute. Division of cancer treatment and diagnosis. cancer therapy evaluation program. Adverse events/CTCAE. Available from: https://ctep.cancer.gov/protocol Development/electronic_applications/ctc.htm#ctc_40 (accessed January 21, 2021. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228–47. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646–9. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015 Feb 20;33(6):550–8. Hiraoka A, Kumada T, Tsuji K, Takaguchi K, Itobayashi E, Kariyama K, et al. Validation of modified ALBI grade for more detailed assessment of hepatic function in hepatocellular carcinoma patients: a multicenter analysis. Liver Cancer. 2019 Mar;8(2):121–9. Ito K, Schoder H, Teng R, Humm JL, Ni A, Wolchok JD, et al. Prognostic value of baseline metabolic tumor volume measured on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in melanoma patients treated with ipilimumab therapy. Eur J Nucl Med Mol Imaging. 2019 Apr;46(4):930–9. Castello A, Rossi S, Mazziotti E, Toschi L, Lopci E. Hyperprogressive disease in patients with non-small cell lung cancer treated with checkpoint inhibitors: the role of (18)F-FDG PET/CT. J Nucl Med. 2020 Jun;61(6):821–6. Chardin D, Paquet M, Schiappa R, Darcourt J, Bailleux C, Poudenx M, et al. Baseline metabolic tumor volume as a strong predictive and prognostic biomarker in patients with non-small cell lung cancer treated with PD1 inhibitors: a prospective study. J Immunother Cancer. 2020 Jul;8(2):e000645. Nakamoto R, Zaba LC, Rosenberg J, Reddy SA, Nobashi TW, Davidzon G, et al. Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy. Eur J Nucl Med Mol Imaging. 2020 Nov;47(12):2787–95. Seban RD, Moya-Plana A, Antonios L, Yeh R, Marabelle A, Deutsch E, et al. Prognostic 18F-FDG PET biomarkers in metastatic mucosal and cutaneous melanoma treated with immune checkpoint inhibitors targeting PD-1 and CTLA-4. Eur J Nucl Med Mol Imaging. 2020 Sep;47(10):2301–12. Wong A, Callahan J, Keyaerts M, Neyns B, Mangana J, Aberle S, et al. 18F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma. Cancer Imaging. 2020 May 14;20(1):36. Nakamoto R, C Zaba L, Rosenberg J, Arani Reddy S, W Nobashi T, Ferri V, et al. Imaging characteristics and diagnostic performance of 2-deoxy-2-[(18)F]fluoro-D-glucose PET/CT for melanoma patients who demonstrate hyperprogressive disease when treated with immunotherapy. Mol Imaging Biol. 2021 Feb;23(1):139–47. Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Okubo S, Muraishi N, et al. Pretreatment positron emission tomography with 18F-fluorodeoxyglucose may be a useful new predictor of overall prognosis following lenvatinib treatment. Oncology. 2021;99:1–11. Yamashige D, Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Okubo S, et al. Potential and clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography for evaluating liver cancer response to lenvatinib treatment. Oncology. 2020 Nov;18:1–8. Aoki T, Kudo M, Ueshima K, Morita M, Chishina H, Takita M, et al. Exploratory analysis of lenvatinib therapy in patients with unresectable hepatocellular carcinoma who have failed prior PD-1/PD-L1 checkpoint blockade. Cancers. 2020 Oct 20;12(10):3048. Kudo M. Sequential therapy for hepatocellular carcinoma after failure of atezolizumab plus bevacizumab combination therapy. Liver Cancer. 2021 Apr;10(2):85–93. Cheon J, Yoo C, Hong JY, Kim HS, Lee DW, Lee MA, et al. Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. Liver Int. 2022;42(3):674–81. Chuma M, Uojima H, Hattori N, Arase Y, Fukushima T, Hirose S, et al. Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: a multicenter analysis. Hepatol Res. 2022;52(3):269–80. Eso Y, Takeda H, Taura K, Takai A, Takahashi K, Seno H. Pretreatment neutrophil-to-lymphocyte ratio as a predictive marker of response to atezolizumab plus bevacizumab for hepatocellular carcinoma. Curr Oncol. 2021 Oct 14;28(5):4157–66. Article / Publication Details

First-Page Preview

Abstract of Clinical Study

Received: February 03, 2022
Accepted: February 22, 2022
Published online: March 01, 2022

Number of Print Pages: 11
Number of Figures: 5
Number of Tables: 5

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: https://www.karger.com/OCL

Figures Thumbnail Thumbnail Thumbnail Thumbnail Thumbnail Tables Thumbnail Thumbnail Thumbnail Thumbnail Thumbnail

Comments (0)

No login
gif