Skip to main content

Advertisement

SpringerLink
Log in

The use of perfusion CT for the evaluation of therapy combining AZD2171 with gefitinib in cancer patients

  • Oncology
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

The purpose of this study was to determine the feasibility of dynamic contrast–enhanced perfusion CT (CTP) in evaluating the hemodynamic response of tumors in the chest and abdomen treated with a combination of AZD2171 and gefitinib. Thirteen patients were examined just before and every 4-6 weeks after starting therapy. Following intravenous injection of a contrast agent, dynamic image acquisition was obtained at the level of a selected tumor location. To calculate perfusion, the maximum-slope method was used. Pre-treatment average perfusion for extra-hepatic masses was 84 ml/min/100 g, for liver masses arterial perfusion was 25 ml/min/100 g, and a portal perfusion of 30 ml/min/100 g was found. After the administration of AZD2171 and gefitinib, in extra-hepatic masses an initial decrease in perfusion of 18% was followed by a plateau and in liver masses an initial decrease of 39% within the lesions and of 36% within a rim region surrounding the lesions was followed by a tendency to recovery of hepatic artery flow. In conclusion, CTP is feasible in showing changes of perfusion induced by anti-angiogenic therapy.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  PubMed  CAS  Google Scholar 

  2. World Health Organisation (1979) WHO Handbook for reporting results of cancer treatment. World Health Organisation, Geneva, Switzerland, p 48

    Google Scholar 

  3. Hawthorn J (1994) A practical guide to EORTC studies. European Organisation for the Research and Treatment of Cancer (EORTC), Brussels

    Google Scholar 

  4. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer 92:205–216

    Article  CAS  Google Scholar 

  5. Miles KA, Hayball M, Dixon AK (1991) Colour perfusion imaging: a new application of computed tomography. Lancet 337:643–645

    Article  PubMed  CAS  Google Scholar 

  6. Miles KA (1991) Measurement of tissue perfusion by dynamic computed tomography. Br J Radiol 64:409–412

    Article  PubMed  CAS  Google Scholar 

  7. Swensen SJ, Viggiano RW, Midthun DE, Muller NL, Sherrick A, Yamashita K, Naidich DP, Patz EF, Hartman TE, Muhm JR, Weaver AL (2000) Lung nodule enhancement at CT: multicenter study. Radiology 214:73–80

    PubMed  CAS  Google Scholar 

  8. Zhang M, Kono M (1997) Solitary pulmonary nodules: evaluation of blood flow patterns with dynamic CT. Radiology 205:471–478

    PubMed  CAS  Google Scholar 

  9. Leggett DA, Kelley BB, Bunce IH, Miles KA (1997) Colorectal cancer: diagnostic potential of CT measurements of hepatic perfusion and implications for contrast enhancement protocols. Radiology 205:716–720

    PubMed  CAS  Google Scholar 

  10. Dugdale PE, Miles KA, Bunce I, Kelley BB, Leggett DA (1999) CT measurements of perfusion and permeability within lymphoma masses and its ability to assess grade, activity and chemotherapeutic response. J Compu Assist Tomogr 23:540–547

    Article  CAS  Google Scholar 

  11. Miles KA, Leggett DAC, Kelley BB, Hayball MP, Sinnatamby R, Bunce I (1998) In vivo assessment of neovascularization of liver metastases using perfusion CT. Br J Radiol 71:276–281

    PubMed  CAS  Google Scholar 

  12. Hermans R, Meijerink M, Van den Bogaert W, Rijnders A, Weltens C, Lambin P (2003) Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy. Int J Radiat Oncol Biol Phys 57:1351–1356

    Article  PubMed  Google Scholar 

  13. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    Article  PubMed  CAS  Google Scholar 

  14. Xiong HQ, Herbst R, Faria SC, Scholz C, Davis D, Jackson EF, Madden T, McConkey D, Hicks M, Hess K, Charnsangavej C, Abbruzzese JL (2004) A phase I surrogate endpoint study of SU6668 in patients with solid tumors. Invest New Drugs 22:459–466

    Article  PubMed  CAS  Google Scholar 

  15. Thomas JP, Arzoomanian RZ, Alberti D, Marnocha R, Lee F, Friedl A, Tutsch K, Dresen A, Geiger P, Pluda J, Fogler W, Schiller JH, Wilding G (2003) Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 21:223–231

    Article  PubMed  CAS  Google Scholar 

  16. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jurgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  PubMed  CAS  Google Scholar 

  17. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237–2246

    Article  PubMed  CAS  Google Scholar 

  18. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158

    Article  PubMed  CAS  Google Scholar 

  19. Wedge SR, Kendrew J, Hennequin LF (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  PubMed  CAS  Google Scholar 

  20. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655

    PubMed  CAS  Google Scholar 

  21. Tsushima Y, Funabasama S, Aoki J, Sanada S, Endo K (2004) Quantitative perfusion map of malignant liver tumors, created from dynamic computed tomography data. Acad Radiol 11:215–223

    Article  PubMed  Google Scholar 

  22. Tsushima Y, Funabasama S, Sanada S, Aoki J, Endo K (2002) Development of perfusion CT software for personal computers. Acad Radiol 9:922–926

    Article  PubMed  Google Scholar 

  23. Miles KA, Hayball MP, Dixon AK (1993) Functional images of hepatic perfusion obtained with dynamic CT. Radiology 188:405–411

    PubMed  CAS  Google Scholar 

  24. Tsushima Y, Blomley MJ, Kusano S, Endo K (2002) Measuring portal venous perfusion with contrast-enhanced CT: comparison of direct and indirect methods. Acad Radiol 9:276–282

    Article  PubMed  Google Scholar 

  25. Mullani N, Herbst R, Abbruzzese J, Charnsangavej C, Kim E, Tran H, Barron B, Lamki L, Gould K (2000) Antiangiogenic treatment with endostatin results in uncoupling of blood flow and glucose metabolism in human tumors. Clin Positron Imaging 3:151

    Article  PubMed  Google Scholar 

  26. Maxwell RJ, Wilson J, Prise VE, Vojnovic B, Rustin GJ, Lodge MA, Tozer GM (2002) Evaluation of the anti-vascular effects of combretastatin in rodent tumours by dynamic contrast enhanced MRI. NMR Biomed 15:89–98

    Article  PubMed  CAS  Google Scholar 

  27. Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L, Masson E, Puccio-Pick M, Laurent D, Steward WP (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23:4162–4171

    Article  PubMed  CAS  Google Scholar 

  28. Miller KD, Miller M, Mehrotra S, Agarwal B, Mock BH, Zheng QH, Badve S, Hutchins GD, Sledge GW Jr (2006) A physiologic imaging pilot study of breast cancer treated with AZD2171. Clin Cancer Res 12:281–288

    Article  PubMed  CAS  Google Scholar 

  29. Tsushima Y, Blomley MJ, Yokoyama H, Kusano S, Endo K (2001) Does the presence of distant and local malignancy alter parenchymal perfusion in apparently disease-free areas of the liver? Dig Dis Sci 46:2113–2119

    Article  PubMed  CAS  Google Scholar 

  30. van Cruijsen H, Voest EE, van Herpen CM, Hoekman K, Witteveen PO, Punt CJ, Puchalski TA, Fernandes N, Koehler M, Giaccone G (2005) Phase I evaluation of AZD2171 in combination with gefinitib (Iressa) in patients with advanced tumours. Proc Am Soc Clin Oncol Abstract 3030

  31. Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, Jayson GC, Judson IR, Knopp MV, Maxwell RJ, McIntyre D, Padhani AR, Price P, Rathbone R, Rustin GJ, Tofts PS, Tozer GM, Vennart W, Waterton JC, Williams SR, Workman P; Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee, Drug Development Office, Cancer Research UK (2005) The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 92:1599–1610

    Article  PubMed  CAS  Google Scholar 

  32. Ridge JA, Bading JR, Gelbard AS, Benua RS, Daly JM (1987) Perfusion of colorectal hepatic metastases. Relative distribution of flow from the hepatic artery and portal vein. Cancer 59:1547–1553

    Article  PubMed  CAS  Google Scholar 

  33. Kruskal JB, Thomas P, Kane RA, Goldberg SN (2004) Hepatic perfusion changes in mice livers with developing colorectal cancer metastases. Radiology 231:482–490

    Article  PubMed  Google Scholar 

  34. Miles KA, Leggett DA, Kelley BB, Hayball MP, Sinnatamby R, Bunce I (1998) In vivo assessment of neovascularization of liver metastases using perfusion CT. Br J Radiol 71:276–281

    PubMed  CAS  Google Scholar 

  35. Irie T, Tsushima Y, Terahata S, Hatsuse K, Kusano S, Itai Y (1997) Rim enhancement in colorectal metastases at CT during infusion hepatic arteriography. Does it represent liver parenchyma or live tumor cell zone? Acta Radiol 38:416–421

    PubMed  CAS  Google Scholar 

  36. Blomley MJ, Coulden R, Dawson P, Kormano M, Donlan P, Bufkin C, Lipton MJ (1995) Liver perfusion studied with ultrafast CT. J Comput Assist Tomogr 19:424–433

    Article  PubMed  CAS  Google Scholar 

  37. Tsushima Y, Blomley MJ, Kusano S, Endo K (1999) The portal component of hepatic perfusion measured by dynamic CT: an indicator of hepatic parenchymal damage. Dig Dis Sci 44:1632–1638

    Article  PubMed  CAS  Google Scholar 

  38. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

  39. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563

    PubMed  CAS  Google Scholar 

  40. Brix G, Bahner ML, Hoffmann U, Horvath A, Schreiber W (1999) Regional blood flow, capillary permeability, and compartmental volumes: measurement with dynamic CT-initial experience. Radiology 210:269–276

    PubMed  CAS  Google Scholar 

  41. Pandharipande PV, Krinsky GA, Rusinek H, Lee VS (2005) Perfusion imaging of the liver: current challenges and future goals. Radiology 234:661–673

    Article  PubMed  Google Scholar 

  42. Leveson SH, Wiggins PA, Nasiru TA, Giles GR, Robinson PJ, Parkin A (1983) Improving the detection of hepatic metastases by the use of dynamic flow scintigraphy. Br J Cancer 47:719–721

    PubMed  CAS  Google Scholar 

  43. Krix M, Plathow C, Kiessling F, Herth F, Karcher A, Essig M, Schmitteckert H, Kauczor HU, Delorme S (2004) Quantification of perfusion of liver tissue and metastases using a multivessel model for replenishment kinetics of ultrasound contrast agents. Ultrasound Med Biol 30:1355–1363

    Article  PubMed  Google Scholar 

  44. Harpen MD, Lecklitner ML (1984) Derivation of gamma variate indicator dilution function from simple convective dispersion model of blood flow. Med Phys 11:690–692

    Article  PubMed  CAS  Google Scholar 

  45. Materne R, Smith AM, Peeters F, Dehoux JP, Keyeux A, Horsmans Y, Van Beers BE (2002) Assessment of hepatic perfusion parameters with dynamic MRI. Magn Reson Med 47:135–142

    Article  PubMed  CAS  Google Scholar 

  46. Jackson A, Haroon H, Zhu XP, Li KL, Thacker NA, Jayson G (2002) Breath-hold perfusion and permeability mapping of hepatic malignancies using magnetic resonance imaging and a first-pass leakage profile model. NMR Biomed 15:164–173

    Article  PubMed  CAS  Google Scholar 

  47. Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp MV, Larsson HB, Lee TY, Mayr NA, Parker GJ, Port RE, Taylor J, Weisskoff RM (1999) Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging 10:223–232

    Article  PubMed  CAS  Google Scholar 

  48. Padhani AR, Hayes C, Landau S, Leach MO (2002) Reproducibility of quantitative dynamic MRI of normal human tissues. NMR Biomed 15:143–153

    Article  PubMed  Google Scholar 

  49. Van Beers BE, Leconte I, Materne R, Smith AM, Jamart J, Horsmans Y (2001) Hepatic perfusion parameters in chronic liver disease: dynamic CT measurements correlated with disease severity. Am J Roentgenol 176:667–673

    Google Scholar 

  50. Turetschek K, Floyd E, Helbich T, Roberts TP, Shames DM, Wendland MF, Carter WO, Brasch RC (2001) MRI assessment of microvascular characteristics in experimental breast tumors using a new blood pool contrast agent (MS-325) with correlations to histopathology. J Magn Reson Imaging 14:237–242

    Article  PubMed  CAS  Google Scholar 

  51. Fournier LS, Cuenod CA, de Bazelaire C, Siauve N, Rosty C, Tran PL, Frija G, Clement O (2004) Early modifications of hepatic perfusion measured by functional CT in a rat model of hepatocellular carcinoma using a blood pool contrast agent. Eur Radiol 14:2125–2133

    Article  PubMed  Google Scholar 

  52. Kety SS (1951) The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev 3:1–41

    PubMed  CAS  Google Scholar 

  53. Kety SS (1960) Theory of blood-tissue exchange and its application to measurement of blood flow. Methods Med Res 8:228–236

    Google Scholar 

  54. Wells P, Jones T, Price P (2003) Assessment of inter- and intra-patient variability in C15O2 positron emission tomography measurements of blood flow in patients with intra-abdominal cancers. Clin Cancer Res 9:6350–6356

    PubMed  Google Scholar 

  55. Flower MA, Zweit J, Hall AD, Burke D, Davies MM, Dworkin MJ, Young HE, Mundy J, Ott RJ, McCready VR, Carnochan P, Allen-Mersh TG (2001) 62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases. Eur J Nucl Med 28:99–103

    Article  PubMed  CAS  Google Scholar 

  56. Miller JC, Pien HH, Sahani D, Sorensen AG, Thrall JH (2005) Imaging angiogenesis: applications and potential for drug development. J Natl Cancer Inst 97:172–187

    Article  PubMed  CAS  Google Scholar 

  57. Materne R, Van Beers BE, Smith AM, Leconte I, Jamart J, Dehoux JP, Keyeux A, Horsmans Y (2000) Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model. Clin Sci (Lond) 99:517–525

    Article  CAS  Google Scholar 

  58. Axel L (1980) Cerebral blood flow determination by rapid-sequence computed tomography: theoretical analysis. Radiology 137:679–686

    PubMed  CAS  Google Scholar 

  59. Gobbel GT, Cann CE, Fike JR (1991) Measurement of regional cerebral blood flow using ultrafast computed tomography. Theoretical aspects. Stroke 22:768–771

    PubMed  CAS  Google Scholar 

  60. Nabavi DG, Cenic A, Craen RA, Gelb AW, Bennett JD, Kozak R, Lee TY (1999) CT assessment of cerebral perfusion: experimental validation and initial clinical experience. Radiology 213:141–149

    PubMed  CAS  Google Scholar 

  61. Cenic A, Nabavi DG, Craen RA, Gelb AW, Lee TY (2000) A CT method to measure hemodynamics in brain tumors: validation and application of cerebral blood flow maps. Am J Neuroradiol 21:462–470

    PubMed  CAS  Google Scholar 

  62. Kiessling F, Boese J, Corvinus C, Ederle JR, Zuna I, Schoenberg SO, Brix G, Schmahl A, Tuengerthal S, Herth F, Kauczor HU, Essig M (2004) Perfusion CT in patients with advanced bronchial carcinomas: a novel chance for characterization and treatment monitoring? Eur Radiol 14:1226–1233

    PubMed  CAS  Google Scholar 

  63. Mullani NA, Gould KL (1983) First-pass measurements of regional blood flow with external detectors. J Nucl Med 24:577–581

    PubMed  CAS  Google Scholar 

  64. Gillard JH, Antoun NM, Burnet NG, Pickard JD (2001) Reproducibility of quantitative CT perfusion imaging. Br J Radiol 74:552–555

    PubMed  CAS  Google Scholar 

  65. Blomley MJ, Kormano M, Coulden R, Lim-Dunham J, Dawson P, Lipton MJ (1997) Splenic blood flow: evaluation with computed tomography. Acad Radiol 4:13–20

    Article  PubMed  CAS  Google Scholar 

  66. ICRP Publication 60 (1991) 1990 Recommendations of the International Commission on Radiological Protection. Ann ICRP 31:1–3

    Google Scholar 

Download references

Acknowledgment

The authors thank Dr. Richard Golding for reviewing the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiology, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, Amsterdam, The Netherlands

    Martijn R. Meijerink, Matthijs Kater, Cors van Schaik, Jan Hein T. M. van Waesberghe & Radu A. Manoliu

  2. Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, Amsterdam, The Netherlands

    Hester van Cruijsen, Klaas Hoekman & Giuseppe Giaccone

Authors
  1. Martijn R. Meijerink
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hester van Cruijsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaas Hoekman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthijs Kater
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cors van Schaik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Hein T. M. van Waesberghe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giuseppe Giaccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Radu A. Manoliu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martijn R. Meijerink.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meijerink, M.R., van Cruijsen, H., Hoekman, K. et al. The use of perfusion CT for the evaluation of therapy combining AZD2171 with gefitinib in cancer patients. Eur Radiol 17, 1700–1713 (2007). https://doi.org/10.1007/s00330-006-0425-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00330-006-0425-9

Keywords

Search

Navigation