Skip to main content

Advertisement

Log in

Imaging pharmacodynamics in oncology: the potential significance of “flares”

  • Review Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

The clinical use of 18F-fluorodeoxyglucose (FDG) positron emission tomography in monitoring anticancer treatment is expanding. At the same time a number of radiotracers aiming to image different aspects of tumour biology such as proliferation and apoptosis are being developed. However, the factors determining changes of radiotracer uptake parameters in response to treatment are not well understood. In many cases, cellularity may be the primary determinant of changes of FDG uptake and may confound the interpretation of metabolic changes. Early imaging assessments have in some cases showed transient increases of uptake parameters, commonly termed “flares”, which are likely to be unaffected by cellularity and directly reflect pharmacodynamics at a cellular level. In this review a number of settings where molecular imaging “flares” have been described are discussed. Such changes may often be clinically informative and warrant careful study as potential predictive biomarkers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–14.

    Article  CAS  PubMed  Google Scholar 

  2. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.

    Article  CAS  PubMed  Google Scholar 

  3. Gayed I, Vu T, Iyer R, Johnson M, Macapinlac H, Swanston N, et al. The role of 18F-FDG PET in staging and early prediction of response to therapy of recurrent gastrointestinal stromal tumors. J Nucl Med. 2004;45:17–21.

    CAS  PubMed  Google Scholar 

  4. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–7.

    Article  CAS  PubMed  Google Scholar 

  5. Jaffe CC. Response assessment in clinical trials: implications for sarcoma clinical trial design. Oncologist. 2008;13(suppl 2):14–8.

    Article  PubMed  Google Scholar 

  6. Ahn SH, Garewal HS, Dragovich T. Discrepancy in the assessment of tumor response in patients with pancreatic cancer: WHO versus RECIST criteria. J BUON. 2008;13:359–62.

    CAS  PubMed  Google Scholar 

  7. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J Clin Oncol. 2009;27:1999–2006.

    Article  CAS  Google Scholar 

  8. Weber WA. Assessing tumor response to therapy. J Nucl Med. 2009;50:1S–10S.

    Article  CAS  PubMed  Google Scholar 

  9. Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL. Intratumoral distribution of tritiated-FDG in breast carcinoma: correlation between Glut-1 expression and FDG uptake. J Nucl Med. 1996;37:1042–7.

    CAS  PubMed  Google Scholar 

  10. Higashi T, Tamaki N, Torizuka T, Nakamoto Y, Sakahara H, Kimura T, et al. FDG uptake, GLUT-1 glucose transporter and cellularity in human pancreatic tumors. J Nucl Med. 1998;39:1727–35.

    CAS  PubMed  Google Scholar 

  11. Kato H, Takita J, Miyazaki T, Nakajima M, Fukai Y, Masuda N, et al. Correlation of 18-F-fluorodeoxyglucose (FDG) accumulation with glucose transporter (Glut-1) expression in esophageal squamous cell carcinoma. Anticancer Res. 2003;23:3263–72.

    CAS  PubMed  Google Scholar 

  12. Koga H, Matsuo Y, Sasaki M, Nakagawa M, Kaneko K, Hayashi K, et al. Differential FDG accumulation associated with GLUT-1 expression in a patient with lymphoma. Ann Nucl Med. 2003;17:327–31.

    Article  PubMed  Google Scholar 

  13. Mamede M, Higashi T, Kitaichi M, Ishizu K, Ishimori T, Nakamoto Y, et al. [18F]FDG uptake and PCNA, Glut-1, and Hexokinase-II expressions in cancers and inflammatory lesions of the lung. Neoplasia. 2005;7:369–79.

    Article  CAS  PubMed  Google Scholar 

  14. Marom EM, Aloia TA, Moore MB, Hara M, Herndon JE 2nd, Harpole DH Jr, et al. Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer. Lung Cancer. 2001;33:99–107.

    Article  CAS  PubMed  Google Scholar 

  15. Ong LC, Jin Y, Song IC, Yu S, Zhang K, Chow PK. 2-[18F]-2-deoxy-d-glucose (FDG) uptake in human tumor cells is related to the expression of GLUT-1 and hexokinase II. Acta Radiol. 2008;49:1145–53.

    Article  PubMed  Google Scholar 

  16. Tian M, Zhang H, Nakasone Y, Mogi K, Endo K. Expression of Glut-1 and Glut-3 in untreated oral squamous cell carcinoma compared with FDG accumulation in a PET study. Eur J Nucl Med Mol Imaging. 2004;31:5–12.

    Article  CAS  PubMed  Google Scholar 

  17. Hamada K, Tomita Y, Qiu Y, Zhang B, Ueda T, Myoui A, et al. 18F-FDG-PET of musculoskeletal tumors: a correlation with the expression of glucose transporter 1 and hexokinase II. Ann Nucl Med. 2008;22:699–705.

    Article  PubMed  Google Scholar 

  18. Higashi T, Saga T, Nakamoto Y, Ishimori T, Mamede MH, Wada M, et al. Relationship between retention index in dual-phase (18)F-FDG PET, and hexokinase-II and glucose transporter-1 expression in pancreatic cancer. J Nucl Med. 2002;43:173–80.

    CAS  PubMed  Google Scholar 

  19. Paudyal B, Oriuchi N, Paudyal P, Tsushima Y, Higuchi T, Miyakubo M, et al. Clinicopathological presentation of varying 18F-FDG uptake and expression of glucose transporter 1 and hexokinase II in cases of hepatocellular carcinoma and cholangiocellular carcinoma. Ann Nucl Med. 2008;22:83–6.

    Article  PubMed  Google Scholar 

  20. Shim HK, Lee WW, Park SY, Kim H, Kim SE. Relationship between FDG uptake and expressions of glucose transporter type 1, type 3, and hexokinase-II in Reed-Sternberg cells of Hodgkin lymphoma. Oncol Res. 2009;17:331–7.

    Article  PubMed  Google Scholar 

  21. Tian M, Zhang H, Higuchi T, Oriuchi N, Nakasone Y, Takata K, et al. Hexokinase-II expression in untreated oral squamous cell carcinoma: comparison with FDG PET imaging. Ann Nucl Med. 2005;19:335–8.

    Article  CAS  PubMed  Google Scholar 

  22. Azuma A, Tozaki M, Ito K, Fukuma E, Tanaka T, O’Uchi T. Ductal carcinoma in situ: correlation between FDG-PET/CT and histopathology. Radiat Med. 2008;26:488–93.

    Article  PubMed  Google Scholar 

  23. Cho SM, Park YG, Lee JM, Byun JY, Lee JM, Lee KY, et al. 18F-fluorodeoxyglucose positron emission tomography in patients with recurrent ovarian cancer: in comparison with vascularity, Ki-67, p53, and histologic grade. Eur Radiol. 2007;17:409–17.

    Article  PubMed  Google Scholar 

  24. Tateishi U, Nishihara H, Tsukamoto E, Morikawa T, Tamaki N, Miyasaka K. Lung tumors evaluated with FDG-PET and dynamic CT: the relationship between vascular density and glucose metabolism. J Comput Assist Tomogr. 2002;26:185–90.

    Article  PubMed  Google Scholar 

  25. Guo J, Higashi K, Ueda Y, Oguchi M, Takegami T, Toga H, et al. Microvessel density: correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas. J Nucl Med. 2006;47:419–25.

    CAS  PubMed  Google Scholar 

  26. Charnley N, Airley R, Du Plessis D, West C, Brock C, Barnett C, et al. No relationship between 18F-fluorodeoxyglucose positron emission tomography and expression of Glut-1 and -3 and hexokinase I and II in high-grade glioma. Oncol Rep. 2008;20:537–42.

    CAS  PubMed  Google Scholar 

  27. Shim HK, Lee WW, Park SY, Kim H, So Y, Kim SE. Expressions of glucose transporter types 1 and 3 and hexokinase-II in diffuse large B-cell lymphoma and other B-cell non-Hodgkin’s lymphomas. Nucl Med Biol. 2009;36:191–7.

    Article  CAS  PubMed  Google Scholar 

  28. Dierckx RA, Van de Wiele C. FDG uptake, a surrogate of tumour hypoxia? Eur J Nucl Med Mol Imaging. 2008;35:1544–9.

    Article  CAS  PubMed  Google Scholar 

  29. Zhao S, Kuge Y, Mochizuki T, Takahashi T, Nakada K, Sato M, et al. Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor. J Nucl Med. 2005;46:675–82.

    CAS  PubMed  Google Scholar 

  30. Buck AC, Schirrmeister HH, Guhlmann CA, Diederichs CG, Shen C, Buchmann I, et al. Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity? J Nucl Med. 2001;42:721–5.

    CAS  PubMed  Google Scholar 

  31. Mu DB, Wang SP, Yang WF, Fu Z, Chen XX, Sun XR, et al. Correlation between FDG PET/CT and the expression of glutl and ki-67 antigen in esophageal cancer. Zhonghua Zhong Liu Za Zhi. 2007;29:30–3.

    CAS  PubMed  Google Scholar 

  32. Nguyen XC, Lee WW, Chung JH, Park SY, Sung SW, Kim YK, et al. FDG uptake, glucose transporter type 1, and Ki-67 expressions in non-small-cell lung cancer: correlations and prognostic values. Eur J Radiol. 2007;62:214–9.

    Article  PubMed  Google Scholar 

  33. Tsuyuguchi N. Kinetic analysis of glucose metabolism by FDG-PET versus proliferation index of Ki-67 in meningiomas–comparison with gliomas. Osaka City Med J. 1997;43:209–23.

    CAS  PubMed  Google Scholar 

  34. Vesselle H, Salskov A, Turcotte E, Wiens L, Schmidt R, Jordan CD, et al. Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology, and Ki-67 proliferation index. J Thorac Oncol. 2008;3:971–8.

    Article  PubMed  Google Scholar 

  35. Yamamoto Y, Nishiyama Y, Ishikawa S, Nakano J, Chang SS, Bandoh S, et al. Correlation of 18F-FLT and 18F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2007;34:1610–6.

    Article  CAS  PubMed  Google Scholar 

  36. Taylor MD, Smith PW, Brix WK, Wick MR, Theodosakis N, Swenson BR, et al. Correlations between selected tumor markers and fluorodeoxyglucose maximal standardized uptake values in esophageal cancer. Eur J Cardiothorac Surg. 2009;35:699–705.

    Article  PubMed  Google Scholar 

  37. Spaepen K, Stroobants S, Dupont P, Bormans G, Balzarini J, Verhoef G, et al. [(18)F]FDG PET monitoring of tumour response to chemotherapy: does [(18)F]FDG uptake correlate with the viable tumour cell fraction? Eur J Nucl Med Mol Imaging. 2003;30:682–8.

    CAS  PubMed  Google Scholar 

  38. van Waarde A, Been LB, Ishiwata K, Dierckx RA, Elsinga PH. Early response of sigma-receptor ligands and metabolic PET tracers to 3 forms of chemotherapy: an in vitro study in glioma cells. J Nucl Med. 2006;47:1538–45.

    PubMed  Google Scholar 

  39. Higashi K, Clavo AC, Wahl RL. Does FDG uptake measure proliferative activity of human cancer cells? In vitro comparison with DNA flow cytometry and tritiated thymidine uptake. J Nucl Med. 1993;34:414–9.

    CAS  PubMed  Google Scholar 

  40. Kenny L, Coombes RC, Vigushin DM, Al-Nahhas A, Shousha S, Aboagye EO. Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3’-deoxy-3′-[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging. 2007;34:1339–47.

    Article  PubMed  Google Scholar 

  41. Pio BS, Park CK, Pietras R, Hsueh WA, Satyamurthy N, Pegram MD, et al. Usefulness of 3′-[F-18]fluoro-3′-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy. Mol Imaging Biol. 2006;8:36–42.

    Article  PubMed  Google Scholar 

  42. Pressacco J, Mitrovski B, Erlichman C, Hedley DW. Effects of thymidylate synthase inhibition on thymidine kinase activity and nucleoside transporter expression. Cancer Res. 1995;55:1505–8.

    CAS  PubMed  Google Scholar 

  43. Charles-Edwards EM, deSouza NM. Diffusion-weighted magnetic resonance imaging and its application to cancer. Cancer Imaging. 2006;6:135–43.

    Article  PubMed  Google Scholar 

  44. Patterson DM, Padhani AR, Collins DJ. Technology insight: water diffusion MRI—a potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol. 2008;5:220–33.

    Article  PubMed  Google Scholar 

  45. Su H, Forbes A, Gambhir SS, Braun J. Quantitation of cell number by a positron emission tomography reporter gene strategy. Mol Imaging Biol. 2004;6:139–48.

    Article  PubMed  Google Scholar 

  46. Minn H, Paul R, Ahonen A. Evaluation of treatment response to radiotherapy in head and neck cancer with fluorine-18 fluorodeoxyglucose. J Nucl Med. 1988;29:1521–5.

    CAS  PubMed  Google Scholar 

  47. Ichiya Y, Kuwabara Y, Otsuka M, Tahara T, Yoshikai T, Fukumura T, et al. Assessment of response to cancer therapy using fluorine-18-fluorodeoxyglucose and positron emission tomography. J Nucl Med. 1991;32:1655–60.

    CAS  PubMed  Google Scholar 

  48. Kubota K, Ishiwata K, Kubota R, Yamada S, Tada M, Sato T, et al. Tracer feasibility for monitoring tumor radiotherapy: a quadruple tracer study with fluorine-18-fluorodeoxyglucose or fluorine-18-fluorodeoxyuridine, l-[methyl-14C]methionine, [6-3H]thymidine, and gallium-67. J Nucl Med. 1991;32:2118–23.

    CAS  PubMed  Google Scholar 

  49. Kong FM, Frey KA, Quint LE, Ten Haken RK, Hayman JA, Kessler M, et al. A pilot study of [18F]fluorodeoxyglucose positron emission tomography scans during and after radiation-based therapy in patients with non small-cell lung cancer. J Clin Oncol. 2007;25:3116–23.

    Article  PubMed  Google Scholar 

  50. Mac Manus MP, Hicks RJ, Matthews JP, McKenzie A, Rischin D, Salminen EK, et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol. 2003;21:1285–92.

    Article  PubMed  Google Scholar 

  51. Higashi K, Clavo AC, Wahl RL. In vitro assessment of 2-fluoro-2-deoxy-d-glucose, l-methionine and thymidine as agents to monitor the early response of a human adenocarcinoma cell line to radiotherapy. J Nucl Med. 1993;34:773–9.

    CAS  PubMed  Google Scholar 

  52. Furuta M, Hasegawa M, Hayakawa K, Yamakawa M, Ishikawa H, Nonaka T, et al. Rapid rise in FDG uptake in an irradiated human tumour xenograft. Eur J Nucl Med. 1997;24:435–8.

    CAS  PubMed  Google Scholar 

  53. Fujibayashi Y, Waki A, Sakahara H, Konishi J, Yonekura Y, Ishii Y, et al. Transient increase in glycolytic metabolism in cultured tumor cells immediately after exposure to ionizing radiation: from gene expression to deoxyglucose uptake. Radiat Res. 1997;147:729–34.

    Article  CAS  PubMed  Google Scholar 

  54. Higashi T, Fisher SJ, Brown RS, Nakada K, Walter GL, Wahl RL. Evaluation of the early effect of local irradiation on normal rodent bone marrow metabolism using FDG: preclinical PET studies. J Nucl Med. 2000;41:2026–35.

    CAS  PubMed  Google Scholar 

  55. Yao WJ, Hoh CK, Hawkins RA, Glaspy JA, Weil JA, Lee SJ, et al. Quantitative PET imaging of bone marrow glucose metabolic response to hematopoietic cytokines. J Nucl Med. 1995;36:794–9.

    CAS  PubMed  Google Scholar 

  56. Jacene HA, Ishimori T, Engles JM, Leboulleux S, Stearns V, Wahl RL. Effects of pegfilgrastim on normal biodistribution of 18F-FDG: preclinical and clinical studies. J Nucl Med. 2006;47:950–6.

    CAS  PubMed  Google Scholar 

  57. Sugawara Y, Fisher SJ, Zasadny KR, Kison PV, Baker LH, Wahl RL. Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol. 1998;16:173–80.

    CAS  PubMed  Google Scholar 

  58. Hautzel H, Muller-Gartner HW. Early changes in fluorine-18-FDG uptake during radiotherapy. J Nucl Med. 1997;38:1384–6.

    CAS  PubMed  Google Scholar 

  59. Erdi YE, Macapinlac H, Rosenzweig KE, Humm JL, Larson SM, Erdi AK, et al. Use of PET to monitor the response of lung cancer to radiation treatment. Eur J Nucl Med. 2000;27:861–6.

    Article  CAS  PubMed  Google Scholar 

  60. van Baardwijk A, Bosmans G, Dekker A, van Kroonenburgh M, Boersma L, Wanders S, et al. Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients. Radiother Oncol. 2007;82:145–52.

    Article  PubMed  Google Scholar 

  61. De Ruysscher D, Houben A, Aerts HJ, Dehing C, Wanders R, Ollers M, et al. Increased (18)F-deoxyglucose uptake in the lung during the first weeks of radiotherapy is correlated with subsequent radiation-induced lung toxicity (RILT): a prospective pilot study. Radiother Oncol. 2009;91:415–20.

    Article  PubMed  CAS  Google Scholar 

  62. Kubota R, Kubota K, Yamada S, Tada M, Ido T, Tamahashi N. Active and passive mechanisms of [fluorine-18] fluorodeoxyglucose uptake by proliferating and prenecrotic cancer cells in vivo: a microautoradiographic study. J Nucl Med. 1994;35:1067–75.

    CAS  PubMed  Google Scholar 

  63. Maruyama I, Sadato N, Waki A, Tsuchida T, Yoshida M, Fujibayashi Y, et al. Hyperacute changes in glucose metabolism of brain tumors after stereotactic radiosurgery: a PET study. J Nucl Med. 1999;40:1085–90.

    CAS  PubMed  Google Scholar 

  64. Spence AM, Muzi M, Graham MM, O’Sullivan F, Link JM, Lewellen TK, et al. 2-[(18)F]Fluoro-2-deoxyglucose and glucose uptake in malignant gliomas before and after radiotherapy: correlation with outcome. Clin Cancer Res. 2002;8:971–9.

    PubMed  Google Scholar 

  65. Buzdar AU, Hortobagyi G. Update on endocrine therapy for breast cancer. Clin Cancer Res. 1998;4:527–34.

    CAS  PubMed  Google Scholar 

  66. Vogel CL, Schoenfelder J, Shemano I, Hayes DF, Gams RA. Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol. 1995;13:1123–8.

    CAS  PubMed  Google Scholar 

  67. Mortimer JE, Dehdashti F, Siegel BA, Trinkaus K, Katzenellenbogen JA, Welch MJ. Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol. 2001;19:2797–803.

    CAS  PubMed  Google Scholar 

  68. Noguchi S, Motomura K, Inaji H, Imaoka S, Koyama H. Up-regulation of estrogen receptor by tamoxifen in human breast cancer. Cancer. 1993;71:1266–72.

    Article  CAS  PubMed  Google Scholar 

  69. Reddel RR, Sutherland RL. Tamoxifen stimulation of human breast cancer cell proliferation in vitro: a possible model for tamoxifen tumour flare. Eur J Cancer Clin Oncol. 1984;20:1419–24.

    Article  CAS  PubMed  Google Scholar 

  70. Chen JQ, Brown TR, Russo J. Regulation of energy metabolism pathways by estrogens and estrogenic chemicals and potential implications in obesity associated with increased exposure to endocrine disruptors. Biochim Biophys Acta. 2009;1793(7):1128–43.

    Article  CAS  PubMed  Google Scholar 

  71. Dehdashti F, Mortimer JE, Trinkaus K, Naughton MJ, Ellis M, Katzenellenbogen JA, et al. PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat. 2009;113:509–17.

    Article  CAS  PubMed  Google Scholar 

  72. Bading JR, Shields AF. Imaging of cell proliferation: status and prospects. J Nucl Med. 2008;49(Suppl 2):64S–80S.

    Article  CAS  PubMed  Google Scholar 

  73. Dittmann H, Dohmen BM, Kehlbach R, Bartusek G, Pritzkow M, Sarbia M, et al. Early changes in [18F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging. 2002;29:1462–9.

    Article  CAS  PubMed  Google Scholar 

  74. Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, et al. 3′-Deoxy-3′-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res. 2003;63:3791–8.

    CAS  PubMed  Google Scholar 

  75. Direcks WG, Berndsen SC, Proost N, Peters GJ, Balzarini J, Spreeuwenberg MD, et al. [18F]FDG and [18F]FLT uptake in human breast cancer cells in relation to the effects of chemotherapy: an in vitro study. Br J Cancer. 2008;99:481–7.

    Article  CAS  PubMed  Google Scholar 

  76. Perumal M, Pillai RG, Barthel H, Leyton J, Latigo JR, Forster M, et al. Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography. Cancer Res. 2006;66:8558–64.

    Article  CAS  PubMed  Google Scholar 

  77. Pillai RG, Forster M, Perumal M, Mitchell F, Leyton J, Aibgirhio FI, et al. Imaging pharmacodynamics of the alpha-folate receptor-targeted thymidylate synthase inhibitor BGC 945. Cancer Res. 2008;68:3827–34.

    Article  CAS  PubMed  Google Scholar 

  78. Wells P, Aboagye E, Gunn RN, Osman S, Boddy AV, Taylor GA, et al. 2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337. J Natl Cancer Inst. 2003;95:675–82.

    Article  CAS  PubMed  Google Scholar 

  79. Rustum YM. Thymidylate synthase: a critical target in cancer therapy? Front Biosci. 2004;9:2467–73.

    Article  CAS  PubMed  Google Scholar 

  80. Kenny LM, Contractor KB, Stebbing J, Al-Nahhas A, Palmieri C, Shousha S, et al. Altered tissue 3′-deoxy-3′-[18F]fluorothymidine pharmacokinetics in human breast cancer following capecitabine treatment detected by positron emission tomography. Clin Cancer Res. 2009;15:6649–57.

    Article  CAS  PubMed  Google Scholar 

  81. McArthur GA, Hicks RM, Shalinsky DR, Binns D, O’Kane C, Hogg A, et al. Positron-emission tomography reveals early flare in uptake of FLT in tumors following chemotherapy with gemcitabine. J Clin Oncol (Meeting Abstracts). 2007;25:2537.

    Google Scholar 

  82. Haberkorn U, Morr I, Oberdorfer F, Bellemann ME, Blatter J, Altmann A, et al. Fluorodeoxyglucose uptake in vitro: aspects of method and effects of treatment with gemcitabine. J Nucl Med. 1994;35:1842–50.

    CAS  PubMed  Google Scholar 

  83. Haberkorn U, Oberdorfer F, Klenner T, Strauss LG, Stohr M, Wallich R, et al. Metabolic and transcriptional changes in osteosarcoma cells treated with chemotherapeutic drugs. Nucl Med Biol. 1994;21:835–45.

    Article  CAS  PubMed  Google Scholar 

  84. Haberkorn U, Reinhardt M, Strauss LG, Oberdorfer F, Berger MR, Altmann A, et al. Metabolic design of combination therapy: use of enhanced fluorodeoxyglucose uptake caused by chemotherapy. J Nucl Med. 1992;33:1981–7.

    CAS  PubMed  Google Scholar 

  85. Haberkorn U, Bellemann ME, Altmann A, Gerlach L, Morr I, Oberdorfer F, et al. PET 2-fluoro-2-deoxyglucose uptake in rat prostate adenocarcinoma during chemotherapy with gemcitabine. J Nucl Med. 1997;38:1215–21.

    CAS  PubMed  Google Scholar 

  86. Smith TA, Maisey NR, Titley JC, Jackson LE, Leach MO, Ronen SM. Treatment of SW620 cells with Tomudex and oxaliplatin induces changes in 2-deoxy-d-glucose incorporation associated with modifications in glucose transport. J Nucl Med. 2000;41:1753–9.

    CAS  PubMed  Google Scholar 

  87. Aide N, Poulain L, Briand M, Dutoit S, Allouche S, Labiche A, et al. Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease. Eur J Nucl Med Mol Imaging. 2009;36:396–405.

    Article  CAS  PubMed  Google Scholar 

  88. Rozental JM, Levine RL, Nickles RJ, Dobkin JA. Glucose uptake by gliomas after treatment. A positron emission tomographic study. Arch Neurol. 1989;46:1302–7.

    CAS  PubMed  Google Scholar 

  89. De Witte O, Hildebrand J, Luxen A, Goldman S. Acute effect of carmustine on glucose metabolism in brain and glioblastoma. Cancer. 1994;74:2836–42.

    Article  PubMed  Google Scholar 

  90. Findlay M, Young H, Cunningham D, Iveson A, Cronin B, Hickish T, et al. Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil. J Clin Oncol. 1996;14:700–8.

    CAS  PubMed  Google Scholar 

  91. Blankenberg FG. In vivo detection of apoptosis. J Nucl Med. 2008;49(suppl 2):81S–95S.

    Article  CAS  PubMed  Google Scholar 

  92. Smith G, Nguyen QD, Aboagye EO. Translational imaging of apoptosis. Anticancer Agents Med Chem. 2009.

  93. Belhocine T, Steinmetz N, Hustinx R, Bartsch P, Jerusalem G, Seidel L, et al. Increased uptake of the apoptosis-imaging agent (99m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res. 2002;8:2766–74.

    CAS  PubMed  Google Scholar 

  94. Haas RL, de Jong D, Valdes Olmos RA, Hoefnagel CA, van den Heuvel I, Zerp SF, et al. In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients. Int J Radiat Oncol Biol Phys. 2004;59:782–7.

    PubMed  Google Scholar 

  95. Kartachova M, Haas RL, Olmos RA, Hoebers FJ, van Zandwijk N, Verheij M. In vivo imaging of apoptosis by 99mTc-Annexin V scintigraphy: visual analysis in relation to treatment response. Radiother Oncol. 2004;72:333–9.

    Article  CAS  PubMed  Google Scholar 

  96. Rottey S, Loose D, Vakaet L, Lahorte C, Vermeersch H, Van Belle S, et al. 99mTc-HYNIC Annexin-V imaging of tumors and its relationship to response to radiotherapy and/or chemotherapy. Q J Nucl Med Mol Imaging. 2007;51:182–8.

    CAS  PubMed  Google Scholar 

  97. Kartachova M, van Zandwijk N, Burgers S, van Tinteren H, Verheij M, Valdes Olmos RA. Prognostic significance of 99mTc Hynic-rh-annexin V scintigraphy during platinum-based chemotherapy in advanced lung cancer. J Clin Oncol. 2007;25:2534–9.

    Article  CAS  PubMed  Google Scholar 

  98. Blankenberg F. To scan or not to scan, it is a question of timing: technetium-99m-annexin V radionuclide imaging assessment of treatment efficacy after one course of chemotherapy. Clin Cancer Res. 2002;8:2757–8.

    PubMed  Google Scholar 

  99. Blankenberg FG. Imaging the molecular signatures of apoptosis and injury with radiolabeled annexin V. Proc Am Thorac Soc. 2009;6:469–76.

    Article  CAS  PubMed  Google Scholar 

  100. Contractor KB, Aboagye EO. Monitoring predominantly cytostatic treatment response with 18F-FDG PET. J Nucl Med. 2009;50(suppl 1):97S–105S.

    Article  CAS  PubMed  Google Scholar 

  101. Solit DB, Santos E, Pratilas CA, Lobo J, Moroz M, Cai S, et al. 3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition. Cancer Res. 2007;67:11463–9.

    Article  CAS  PubMed  Google Scholar 

  102. Tarn C, Skorobogatko YV, Taguchi T, Eisenberg B, von Mehren M, Godwin AK. Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. Cancer Res. 2006;66:5477–86.

    Article  CAS  PubMed  Google Scholar 

  103. Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, et al. 18FDG-positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003;39:2012–20.

    Article  CAS  PubMed  Google Scholar 

  104. Van den Abbeele AD, Badawi RD, Manola J, Morgan JA, Desai J, Kazanovicz A, et al. Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning. J Clin Oncol (Meeting Abstracts). 2004;22:3012.

    Google Scholar 

  105. Van den Abbeele A, Melenevsky Y, de Vries D. Imaging kinase target inhibition with SU11248 by FDG-PET in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (I-R GIST). J Clin Oncol. 2005. In: ASCO annual meeting proceedings. vol. 23, no. 16S, Part I of II June 1 Supplement; 2005. p. 9006.

  106. Van den Abbeele AD. The lessons of GIST—PET and PET/CT: a new paradigm for imaging. Oncologist. 2008;13(suppl 2):8–13.

    Article  PubMed  Google Scholar 

  107. Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in metastatic breast cancer. J Clin Oncol. 2004;22:2942–53.

    Article  PubMed  Google Scholar 

  108. Even-Sapir E, Metser U, Flusser G, Zuriel L, Kollender Y, Lerman H, et al. Assessment of malignant skeletal disease: initial experience with 18F-fluoride PET/CT and comparison between 18F-fluoride PET and 18F-fluoride PET/CT. J Nucl Med. 2004;45:272–8.

    PubMed  Google Scholar 

  109. Wade AA, Scott JA, Kuter I, Fischman AJ. Flare response in 18F-fluoride ion PET bone scanning. AJR Am J Roentgenol. 2006;186:1783–6.

    Article  PubMed  Google Scholar 

  110. Krupitskaya Y, Eslamy HK, Nguyen DD, Kumar A, Wakelee HA. Osteoblastic bone flare on F18-FDG PET in non-small cell lung cancer (NSCLC) patients receiving bevacizumab in addition to standard chemotherapy. J Thorac Oncol. 2009;4:429–31.

    Article  PubMed  Google Scholar 

  111. Jager PL, Gietema JA, van der Graaf WT. Imatinib mesylate for the treatment of gastrointestinal stromal tumours: best monitored with FDG PET. Nucl Med Commun. 2004;25:433–8.

    Article  CAS  PubMed  Google Scholar 

  112. Wells P, West C, Jones T, Harris A, Price P. Measuring tumor pharmacodynamic response using PET proliferation probes: the case for 2-[(11)C]-thymidine. Biochim Biophys Acta. 2004;1705:91–102.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the support of the Oglesby Charitable Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ioannis Trigonis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trigonis, I., Jackson, A. Imaging pharmacodynamics in oncology: the potential significance of “flares”. Ann Nucl Med 24, 137–147 (2010). https://doi.org/10.1007/s12149-009-0332-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-009-0332-7

Keywords

Navigation