Abstract
Purpose
Hypoxia is associated with aggressive tumour behaviour and can influence response to systemic therapy and radiotherapy. The prevalence of hypoxia in metastatic colorectal cancer is poorly understood, and the relationship of hypoxia to patient outcomes has not been clearly established. The aims of the study were to evaluate hypoxia in metastatic colorectal cancer with [18F]Fluoromisonidazole ([18F]FMISO PET) and correlate these findings with glycolytic metabolism ([18F]FDG PET) and angiogenic blood biomarkers and patient outcomes.
Methods
Patients with metastatic colorectal cancer received routine staging investigations and both [18F] FMISO PET and [18F] FDG PET scans. Correlative blood specimens were also obtained at the time of the [18F] FMISO PET scan. Patient follow-up was performed to establish progression-free survival.
Results
A total of 40 patients were recruited into the trial. [18F]FMISO and [18F]FDG PET scans showed a significant correlation of SUVmax (p = 0.003). A significant correlation of progression-free survival and [18F] FMISO TNR (p = 0.02) and overall survival with [18F]FMISO TNR (p = 0.003) and [18F]FDG TGV (p = 0.02) was observed. Serum levels of osteopontin, but not VEGF, correlated with [18F] FMISO and [18F]FDG PET scan parameters.
Conclusion
[18F]FMISO PET uptake in metastatic colorectal cancer significantly correlates with glycolytic metabolism and is predictive of progression-free and overall survival. These findings have implications for the assessment and treatment of metastatic colorectal cancer patients with novel therapies which affect tumour angiogenesis and hypoxia.
Similar content being viewed by others
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
Nanji S, Cleary S, Ryan P, Guindi M, Selvarajah S, Al-Ali H, et al. Up-front hepatic resection for metastatic colorectal cancer results in favorable long-term survival. Ann Surg Oncol. 2013;20(1):295–304.
Pessaux P, Lermite E, Brehant O, Tuech JJ, Lorimier G, Arnaud JP. Repeat hepatectomy for recurrent colorectal liver metastases. J Surg Oncol. 2006;93(1):1–7.
Poston GJ, Adam R, Alberts S, Curley S, Figueras J, Haller D, et al. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol. 2005;23(28):7125–34.
Laurens ST, Oyen WJ. Impact of Fluorodeoxyglucose PET/computed tomography on the management of patients with colorectal cancer. PET Clin. 2015;10(3):345–60.
Scott AM, Gunawardana DH, Kelley B, Stuckey JG, Byrne AJ, Ramshaw JE, et al. PET changes management and improves prognostic stratification in patients with recurrent colorectal cancer: results of a multicenter prospective study. J Nucl Med. 2008;49(9):1451–7.
McIntyre A, Harris AL. Metabolic adaption to anti-angiogenic therapy. EMBO Mol Med. 2015;7(4):368–79.
Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–73.
Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, et al. Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxiareoxygenation. Cell Rep. 2014;9:349–65.
Ros S, Schulze A. Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab. 2013;1:8.
Cantelmo AR, Pircher A, Kalucka J, Carmeliet P. Vessel pruning or healing: endothelial metabolism as a novel target? Expert Opin Ther Targets. 2017;21(3):239.
Seeber A, Gunsilius E, Gastl G, Pircher A. Anti-Angiogenics: their value in colorectal cancer therapy. Oncol Res Treat. 2018;41(4):188–93.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.
Sturrock M, Miller IS, Kang G, Hannis Arba'ie N, O'Farrell AC, Barat A, et al. Anti-angiogenic drug scheduling optimisation with application to colorectal cancer. Sci Rep. 2018;8:11182.
Lee ST, Scott AM. Hypoxia positron emission tomography imaging with 18F-fluoromisonidazole. Semin Nucl Med. 2007;37(6):451–61.
Gagel B, Reinartz P, Dimartino E, Zimny M, Pinkawa M, Maneschi P, et al. pO(2) polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2′-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol. 2004;180(10):616–22.
Lawrentschuk N, Poon AM, Foo SS, Putra LG, Murone C, Davis ID, et al. Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography. BJU Int. 2005;96(4):540–6.
Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2015;112(2):238–50.
Zhao M, Liang F, Zhang B, Yan W, Zhang J. The impact of osteopontin on prognosis and clinicopathology of colorectal cancer patients: a systematic meta-analysis. Sci Rep. 2015;5:12713.
Nordsmark M, Bentzen SM, Overgaard J. Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity. Acta Oncol. 1994;33(4):383–9.
Wong RK, Fyles A, Milosevic M, Pintilie M, Hill RP. Heterogeneity of polarographic oxygen tension measurements in cervix cancer: an evaluation of within and between tumor variability, probe position, and track depth. Int J Radiat Oncol Biol Phys. 1997;39(2):405–12.
Cher LM, Murone C, Lawrentschuk N, Ramdave S, Papenfuss A, Hannah A, et al. Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using 18F-Fluoromisonidazole, 18F-FDG PET, and immunohistochemical studies. J Nucl Med. 2006;47(3):410–8.
Puri T, Greenhalgh TA, Wilson JM, Franklin J, Wang LM, Strauss V, et al. [18F]Fluoromisonidazole PET in rectal cancer. EJNMMI Res. 2017;7:78.
Cherk MH, Foo SS, Poon AM, Knight SR, Murone C, Papenfuss AT, et al. Lack of correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in non-small cell lung cancer assessed by 18F-Fluoromisonidazole and 18F-FDG PET. J Nucl Med. 2006;47(12):1921–6.
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.
Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS. C+Batchelor TT, Sorenson AG. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2010;6(6):327–38.
Ulivi P, Marisi G, Passardi A. Relationship between hypoxia and response to antiangiogenic therapy in metastatic colorectal cancer. Oncotarget. 2016;7(29):46667–91.
Funding
Funding from the Cancer Council Victoria and University of Melbourne for Sze Ting Lee, NHMRC grants (No. 1084178 and 1092788), and Operational Infrastructure Support Program provided by the Victorian Government is acknowledged.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical approval
Ethics approval from the Austin Hospital Human Research Ethics Committee for this study was obtained, and all subjects provided informed consent.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Oncology - Digestive tract
Rights and permissions
About this article
Cite this article
Lee, S., Muralidharan, V., Tebbutt, N. et al. Prevalence of hypoxia and correlation with glycolytic metabolism and angiogenic biomarkers in metastatic colorectal carcinoma. Eur J Nucl Med Mol Imaging 48, 1585–1592 (2021). https://doi.org/10.1007/s00259-020-05074-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-020-05074-5