Abstract
Purpose
This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC).
Methods
Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome.
Results
A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG40 %). Further analysis using TLG40 % showed significantly longer overall survival (OS) in patients with lower baseline TLG40 % (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG40 % after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in %ΔTLG40 % < −9.6 % and ≥ −9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in %ΔTLG40 % < −9.6 % and ≥ −9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049).
Conclusion
Measurement of TLG can predict treatment outcome of regorafenib in mCRC.
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References
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;45:228–47.
Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–12.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29–37.
Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–55.
Abou-Elkacem L, Arns S, Brix G, Gremse F, Zopf D, Kiessling F, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12:1322–31.
Schmieder R, Hoffmann J, Becker M, Bhargava A, Muller T, Kahmann N, et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer. 2014;135:1487–96.
Cyran CC, Kazmierczak PM, Hirner H, Moser M, Ingrisch M, Havla L, et al. Regorafenib effects on human colon carcinoma xenografts monitored by dynamic contrast-enhanced computed tomography with immunohistochemical validation. PLoS One. 2013;8, e76009.
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.
Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–29.
Lim Y, Han SW, Yoon JH, Lee JM, Lee JM, Paeng JC, et al. Clinical implication of anti-angiogenic effect of regorafenib in metastatic colorectal cancer. PLoS One. 2015;10, e0145004.
de Geus-Oei LF, van Laarhoven HW, Visser EP, Hermsen R, van Hoorn BA, Kamm YJ, et al. Chemotherapy response evaluation with FDG-PET in patients with colorectal cancer. Ann Oncol. 2008;19:348–52.
Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol. 1993;11:2101–11.
Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl J Med. 2006;354:496–507. doi:10.1056/NEJMra050276.
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S–50.
Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999;35:1773–82.
Van de Wiele C, Kruse V, Smeets P, Sathekge M, Maes A. Predictive and prognostic value of metabolic tumour volume and total lesion glycolysis in solid tumours. Eur J Nucl Med Mol Imaging. 2013;40:290–301.
Kim TM, Paeng JC, Chun IK, Keam B, Jeon YK, Lee SH, et al. Total lesion glycolysis in positron emission tomography is a better predictor of outcome than the International Prognostic Index for patients with diffuse large B cell lymphoma. Cancer. 2013;119:1195–202.
Keam B, Lee SJ, Kim TM, Paeng JC, Lee SH, Kim DW, et al. Total lesion glycolysis in positron emission tomography can predict gefitinib outcomes in non-small-cell lung cancer with activating EGFR mutation. J Thorac Oncol. 2015;10:1189–94.
Choi ES, Ha SG, Kim HS, Ha JH, Paeng JC, Han I. Total lesion glycolysis by 18F-FDG PET/CT is a reliable predictor of prognosis in soft-tissue sarcoma. Eur J Nucl Med Mol Imaging. 2013;40:1836–42.
Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One. 2012;7, e51862.
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.
De Bruyne S, Van Damme N, Smeets P, Ferdinande L, Ceelen W, Mertens J, et al. Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases. Br J Cancer. 2012;106:1926–33.
Lastoria S, Piccirillo MC, Caraco C, Nasti G, Aloj L, Arrichiello C, et al. Early PET/CT scan is more effective than RECIST in predicting outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab. J Nucl Med. 2013;54:2062–9.
Wong AL, Lim JS, Sinha A, Gopinathan A, Lim R, Tan CS, et al. Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib. J Transl Med. 2015;13:57.
Erdi YE, Mawlawi O, Larson SM, Imbriaco M, Yeung H, Finn R, et al. Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding. Cancer. 1997;80:2505–9.
Zasadny KR, Kison PV, Francis IR, Wahl RL. FDG-PET determination of metabolically active tumor volume and comparison with CT. Clin Positron Imaging. 1998;1:123–9.
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This research was supported by the Seoul National University Hospital Research Fund (grant number: 0320150440), the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1277), and by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Republic of Korea (grant number: 2009-0093820). Regorafenib was provided by Bayer Pharma AG.
Disclosure
Tae-You Kim has received research funds from Bayer Korea. The other authors declare no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee [IRB number: 1307-144-507] and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Yoojoo Lim and Ji-In Bang contributed equally as first authors.
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Lim, Y., Bang, JI., Han, SW. et al. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib. Eur J Nucl Med Mol Imaging 44, 757–764 (2017). https://doi.org/10.1007/s00259-016-3577-0
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DOI: https://doi.org/10.1007/s00259-016-3577-0