Skip to main content
Top
Published in: European Journal of Nuclear Medicine and Molecular Imaging 5/2017

01-05-2017 | Original Article

Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

Authors: Yoojoo Lim, Ji-In Bang, Sae-Won Han, Jin Chul Paeng, Kyung-Hun Lee, Jee Hyun Kim, Gyeong Hoon Kang, Seung-Yong Jeong, Kyu Joo Park, Tae-You Kim

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 5/2017

Login to get access

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.
Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
7.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
Metadata
Title
Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib
Authors
Yoojoo Lim
Ji-In Bang
Sae-Won Han
Jin Chul Paeng
Kyung-Hun Lee
Jee Hyun Kim
Gyeong Hoon Kang
Seung-Yong Jeong
Kyu Joo Park
Tae-You Kim
Publication date
01-05-2017
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 5/2017
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-016-3577-0

Other articles of this Issue 5/2017

European Journal of Nuclear Medicine and Molecular Imaging 5/2017 Go to the issue