The power of FDG-PET to detect treatment effects is increased by glucose correction using a Michaelis constant
We recently showed improved between-subject variability in our [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) experiments using a Michaelis-Menten transport model to calculate the metabolic tumor glucose uptake rate extrapolated to the hypothetical condition of glucose saturation: , where K i is the image-derived FDG uptake rate constant, K M is the half-saturation Michaelis constant, and [glc] is the blood glucose concentration. Compared to measurements of K i alone, or calculations of the scan-time metabolic glucose uptake rate (MRgluc = K i * [glc]) or the glucose-normalized uptake rate (MRgluc = K i*[glc]/(100 mg/dL), we suggested that could offer increased statistical power in treatment studies; here, we confirm this in theory and practice.
We compared K i, MRgluc (both with and without glucose normalization), and as FDG-PET measures of treatment-induced changes in tumor glucose uptake independent of any systemic changes in blood glucose caused either by natural variation or by side effects of drug action. Data from three xenograft models with independent evidence of altered tumor cell glucose uptake were studied and generalized with statistical simulations and mathematical derivations. To obtain representative simulation parameters, we studied the distributions of K i from FDG-PET scans and blood [glucose] values in 66 cohorts of mice (665 individual mice). Treatment effects were simulated by varying and back-calculating the mean K i under the Michaelis-Menten model with K M = 130 mg/dL. This was repeated to represent cases of low, average, and high variability in K i (at a given glucose level) observed among the 66 PET cohorts.
There was excellent agreement between derivations, simulations, and experiments. Even modestly different (20%) blood glucose levels caused K i and especially MRgluc to become unreliable through false positive results while remained unbiased. The greatest benefit occurred when K i measurements (at a given glucose level) had low variability. Even when the power benefit was negligible, the use of carried no statistical penalty. Congruent with theory and simulations, showed in our experiments an average 21% statistical power improvement with respect to MRgluc and 10% with respect to K i (approximately 20% savings in sample size). The results were robust in the face of imprecise blood glucose measurements and K M values.
When evaluating the direct effects of treatment on tumor tissue with FDG-PET, employing a Michaelis-Menten glucose correction factor gives the most statistically powerful results. The well-known alternative ‘correction’, multiplying K i by blood glucose (or normalized blood glucose), appears to be counter-productive in this setting and should be avoided.
- Wahl, RL, Henry, CA, Ethier, SP (1992) Serum glucose: effects on tumor and normal tissue accumulation of 2-[F-18]-fluoro-2-deoxy-d-glucose in rodents with mammary carcinoma. Radiology 183: pp. 643-647
- Lindholm, P, Minn, H, Leskinen-Kallio, S, Bergman, J, Ruotsalainen, U, Joensuu, H (1993) Influence of the blood glucose concentration on FDG uptake in cancer–a PET study. Journal of nuclear medicine: official publication. Soc Nucl Med 34: pp. 1-6
- Diederichs, CG, Staib, L, Glatting, G, Beger, HG, Reske, SN (1998) FDG-PET: elevated plasma glucose reduces both uptake and detection rate of pancreatic malignancies. J Nucl Med 39: pp. 1030-1033
- Torizuka, T, Zasadny, KR, Wahl, RL (1999) Diabetes decreases FDG accumulation in primary lung cancer. Clin Positron Imag Offic J Inst Clin PET 2: pp. 281-287 CrossRef
- Zhuang, HM, Cortes-Blanco, A, Pourdehnad, M, Adam, LE, Yamamoto, AJ, Martinez-Lazaro, R, Lee, JH, Loman, JC, Rossman, MD, Alavi, A (2001) Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders?. Nucl Med Commun 22: pp. 1123-1128 CrossRef
- Gorenberg, M, Hallett, WA, O'Doherty, MJ (2002) Does diabetes affect [(18)F]FDG standardised uptake values in lung cancer?. Eur J Nucl Med Mol Imaging 29: pp. 1324-1327 CrossRef
- Eary, JF, Mankoff, DA (1998) Tumor metabolic rates in sarcoma using FDG-PET. J Nucl Med Offic Publ, Soc Nucl Med 39: pp. 250-254
- Young, WG, Deutsch, JA (1980) Effects of blood glucose levels on [14 C]2-deoxyglucose uptake in rat brain tissue. Neurosci Lett 20: pp. 89-93 CrossRef
- Hallett, WA, Marsden, PK, Cronin, BF, O'Doherty, MJ (2001) Effect of corrections for blood glucose and body size on [18F]FDG-PET standardised uptake values in lung cancer. Eur J Nucl Med 28: pp. 919-922 CrossRef
- Hadi, M, Bacharach, SL, Whatley, M, Libutti, SK, Straus, SE, Rao, VK, Wesley, R, Carrasquillo, JA (2008) Glucose and insulin variations in patients during the time course of a FDG-PET study and implications for the "glucose-corrected" SUV. Nucl Med Biol 35: pp. 441-445 CrossRef
- Crouthamel, MC, Kahana, JA, Korenchuk, S, Zhang, SY, Sundaresan, G, Eberwein, DJ, Brown, KK, Kumar, R (2009) Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Can Res Offic J Am Assoc Canc Res 15: pp. 217-225 CrossRef
- Gallagher, EJ, Fierz, Y, Vijayakumar, A, Haddad, N, Yakar, S, Leroith, D (2011) Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia. Oncogene.
- Sokoloff, L, Reivich, M, Kennedy, C, Des Rosiers, MH, Patlak, CS, Pettigrew, KD, Sakurada, O, Shinohara, M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28: pp. 897-916 CrossRef
- Williams, SP, Flores-Mercado, JE, Port, RE, Bengtsson, T (2012) Quantitation of glucose uptake in tumors by dynamic FDG-PET has less glucose bias and lower variability when adjusted for partial saturation of glucose transport. EJNMMI Res 2: pp. 6 CrossRef
- Gottesman, I, Mandarino, L, Verdonk, C, Rizza, R, Gerich, J (1982) Insulin increases the maximum velocity for glucose uptake without altering the Michaelis constant in man. Evidence that insulin increases glucose uptake merely by providing additional transport sites. J Clin Investig 70: pp. 1310-1314 CrossRef
- Kuwabara, H, Evans, AC, Gjedde, A (1990) Michaelis-Menten constraints improved cerebral glucose metabolism and regional lumped constant measurements with [18F]fluorodeoxyglucose. J Cereb Blood Flow Metab 10: pp. 180-189 CrossRef
- Yki-Jarvinen, H, Young, AA, Lamkin, C, Foley, JE (1987) Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Investig 79: pp. 1713-1719 CrossRef
- Burrows, RC, Freeman, SD, Charlop, AW, Wiseman, RW, Adamsen, TC, Krohn, KA, Spence, AM (2004) [18F]-2-fluoro-2-deoxyglucose transport kinetics as a function of extracellular glucose concentration in malignant glioma, fibroblast and macrophage cells in vitro. Nucl Med Biol 31: pp. 1-9 CrossRef
- Rivenzon-Segal, D, Rushkin, E, Polak-Charcon, S, Degani, H (2000) Glucose transporters and transport kinetics in retinoic acid-differentiated T47D human breast cancer cells. Am J Physiol Endocrinol Metab 279: pp. E508-E519
- Kolch, W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351: pp. 289-305 CrossRef
- Thompson, N, Lyons, J (2005) Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. Curr Opin Pharmacol 5: pp. 350-356 CrossRef
- Williams SP, Fredrickson J, Mckenzie M, Jones C, Gates M, Hoeflich K, LoRusso P, Rosen L, Sikic B, Ma W, Chan I, de Crespigny AJ: Preclinical and clinical evidence for MEK pathway inhibition by GDC-0973 using FDG-PET. Presentation 1280/5. Proceedings of the American Association for Cancer Research 102nd Annual Meeting: April 2–6 2011; Orlando
- McArthur, GA, Puzanov, I, Ribas, A, Chapman, PB, Kim, KB, Sosman, JA (2010) Early FDG-PET responses to PLX4032 in BRAF-mutant advanced melanoma [abstract]. J Clin Oncol 28: pp. 15s
- Carlino, MS, Saunders, CA, Gebski, V, Menzies, AM, Ma, B, Lebowitz, PF (2011) Heterogeneity of FDG-PET response to GSK2118436, an inhibitor of oncogenic mutant BRAF-kinase in BRAF-mutant metastatic melanoma [abstract]. J Clin Oncol.
- Flores, JE, McFarland, LM, Vanderbilt, A, Ogasawara, AK, Williams, SP (2008) The effects of anesthetic agent and carrier gas on blood glucose and tissue uptake in mice undergoing dynamic FDG-PET imaging: sevoflurane and isoflurane compared in air and in oxygen. Mol Imag Biol 10: pp. 192-200 CrossRef
- Wan, PT, Garnett, MJ, Roe, SM, Lee, S, Niculescu-Duvaz, D, Good, VM, Jones, CM, Marshall, CJ, Springer, CJ, Barford, D, Marais, R (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116: pp. 855-867 CrossRef
- Zhang, BH, Guan, KL (2000) Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. EMBO J 19: pp. 5429-5439 CrossRef
- Hoeflich, KP, Herter, S, Tien, J, Wong, L, Berry, L, Chan, J, O'Brien, C, Modrusan, Z, Seshagiri, S, Lackner, M, Stern, H, Choo, E, Murray, L, Friedman, L, Belvin, M (2009) Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res 69: pp. 3042-3051 CrossRef
- Hoeflich, KP, O'Brien, C, Boyd, Z, Cavet, G, Guerrero, S, Jung, K, Januario, T, Savage, H, Punnoose, E, Truong, T, Zhou, W, Berry, L, Murray, L, Amler, L, Belvin, M, Friedman, L, Lackner, M (2009) In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 15: pp. 4649-4664 CrossRef
- R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna
- Rice, J (1995) Power. Mathematical Statistics and Data Analysis. Duxbury Press, Belmont
- Phelps, ME, Huang, SC, Hoffman, EJ, Selin, C, Sokoloff, L, Kuhl, DE (1979) Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-d-glucose: validation of method. Ann Neurol 6: pp. 371-388 CrossRef
- Boellaard, R, O'Doherty, MJ, Weber, WA, Mottaghy, FM, Lonsdale, MN, Stroobants, SG, Oyen, WJ, Kotzerke, J, Hoekstra, OS, Pruim, J, Marsden, PK, Tatsch, K, Hoekstra, CJ, Visser, EP, Arends, B, Verzijlbergen, FJ, Zijlstra, JM, Comans, EF, Lammertsma, AA, Paans, AM, Willemsen, AT, Beyer, T, Bockisch, A, Schaefer-Prokop, C, Delbeke, D, Baum, RP, Chiti, A, Krause, BJ (2010) FDG-PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging 37: pp. 181-200 CrossRef
- Arnold, SF (1990) Inferences in Multiple Regression. Mathematical Statistics. Prentice-Hall, NJ
- Christensen, R (1987) Plane Answers to Complex Questions: The Theory of Linear Models. Springer, New York
- The power of FDG-PET to detect treatment effects is increased by glucose correction using a Michaelis constant
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- Available under Open Access This content is freely available online to anyone, anywhere at any time.
- Online Date
- June 2012
- Online ISSN
- Additional Links
- Glucose correction
- Response to treatment
- Glucose bias
- Author Affiliations
- 1. Department of Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
- 2. Department of Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, CA, 94080, USA
- 3. Department of Biostatistics, Genentech, Inc., South San Francisco, CA, 94080, USA