Table 1 Summary of the main functional imaging techniques used in phase I clinical trials in which a significant change in imaging parameters following treatment has been observed

DCE (dynamic contrast enhanced)-MRI

Single organ; 12–14 slices (6–7 cm)

Changes in T1 signal intensity after administration of low molecular weight contrast agent

Tissue perfusion and vascularity

IAUGC (Integrated area under Gadolinium curve)

wCV=12–16% r=26–30% (Morgan et al, 2006)

Axitinib (AG013736)

VEGFR1, 2; PDGFR-β

2 and 28 days (Liu et al, 2005)

Cediranib (AZD2171)

VEGFR1,2,3; PDGFR-α, -β c-KIT

1 and 2 and 5 and 28 and 112 days (Batchelor et al, 2007; Drevs et al, 2007)

K^trans (transfer constant)

wCV=19–29% r=30–36% (Morgan et al, 2006)

Sorafenib (BAY 43–9006)

Raf-1; wtBRAF; VEGFR2,3; PDGFR-β; FLT-3; KIT; FGFR-1

12 weeks (Flaherty et al, 2008)

2.7–10.9 weeks (median 6.1) (Hahn et al, 2008)

wCV=24% (Galbraith et al, 2002a)

Intedanib (BIBF-1120)

VEGFR 1,2,3; FGFR 1, 2,3; PDGFR, Src, Lck, Lyn, FLT-3

3 and 30 days (Mross et al, 2010)

k_ep (rate constant)

wCV=9% (Galbraith et al, 2002a)

Brivanib (BMS-582664)

VEGFR2, VEGFR3, FGFR1 FGFR2

2 and 8 and 26 days (Jonker et al, 2011)

HuMV833

VEGF

48 h and 35 days (Jayson et al, 2002)

v_e (extracellular space)

Vatalanib (PTK787/ZK-222584)

VEGFR 2

2 and 28 and 30days (Morgan et al, 2003)

Sunitinib (SU11248)

VEGFR-1, -2; PDGFRβ; KIT; FLT-4; c-FMS

14 days (Zhu et al, 2009)

CA4P

Tubulin polymerization;

4–6 h and 24 h (Dowlati et al, 2002)

Vadimezan (DMXAA)

Established tumour blood vessels

24 h (Galbraith et al, 2002b)

ZD6126

Colchicin analogue (tubulin binding)

24 h (Evelhoch et al, 2004)

DCE-CT

Single organ 4–8 slices (2.5–5 mm)

Changes in CT density (HU) following administration of iodinated contrast agent

Tissue perfusion and vascularity

rBV (relative blood volume)

wCV 14–15% r=38% (Goh et al, 2006)

Bevacizumab

Humanized anti-VEGF monoclonal antibody

10–12 days (Jiang et al, 2012)

Sorafenib (BAY 43-9006)

Raf-1; wtBRAF; VEGFR-2, -3; PDGFR-β; FLT-3; KIT; FGFR-1

6 weeks (Fournier et al, 2010)

rBF (relative blood flow)

wCV=23% r=65% (Goh et al, 2006)

Sunitinib (SU11248)

VEGFR1,2,3; PDGFR-α, -β; KIT; FLT-3; CSFR-1; RET

6 weeks (Fournier et al, 2010)

MTT (mean transit time )

wCV=35% r=97% (Goh et al, 2006)

DCE-US

Single lesion single slice

Enhanced representation of the vasculature following administration of microbubbles

Tissue perfusion and vascularity

AUC (area under curve)

No data available in clinical studies

Bevacizumab

Humanized anti-VEGF monoclonal antibody

3 and 7 and 14 and 60 days (Lassau et al, 2011)

BF (blood flow)

Sorafenib (BAY 43-9006)

Raf 1; wtBRAF; VEGFR-2, -3; PDGFR-β; FLT-3; KIT; FGFR-1

3 and 6 weeks (Lamuraglia et al, 2006)

PI (peak intensity)

Sunitinib (SU11248)

VEGFR-1, -2,-3; PDGFR-α, β; KIT; FLT-3; CSFR-1; R

15 days (Lassau et al, 2010)

TPI (time to PI)

Diffusion Weighted Magnetic Resonance Imaging (DW-MRI)

Whole organ coverage routinely; whole body diffusion available

Measures water tissue diffusibility by applying two, balanced, opposing magnitude, gradient pulses to a conventional T2w, spin-echo MRI sequence

Indirect assessment of tissue cellularity and presence of necrosis

ADC) (apparent diffusion coefficient)

r%=13.3 (Koh et al, 2009) two centre trial

CA4P

Cediranib (AZD 2171)

Tubulin polymerization

VEGFR1,2,3; PDGFR-α, -β c-KIT

3 h after 2nd dose (Koh et al, 2009)

1 and 28 and 56 days (Batchelor et al, 2007)

¹⁸F-FDG (glucose analogue) PET

Whole body

¹⁸F-FDG enters the cell via glucose transporters, phosphorylated by hexokinase and then trapped within cells.

Glucose utilization in tumour cells.

SUV max (standardized unit value)

wCV=10.7–15.9% r=−(34–27)% to +(37–52)% multicenter data

Sorafenib (BAY 43-9006)

Raf-1; wtBRAF; VEGFR-2, -3; PDGFR-β; FLT-3; KIT; FGFR-1

3 weeks (Siemerink et al, 2008)

r=6–10–42%

Sunitinib (SU11248)

VEGFR-1, -2,-3; PDGFR-α, -β; KIT; FLT-3; CSFR-1; RET

10–14 day (Van den Abbeele et al, 2008)

Single centre data acquisition (Nahmias and Wahl, 2008; Velasquez et al, 2009)

rh-Endo recombinant human endostatin

Proliferation and migration of capillary endothelial cells

28 and 56 days (Herbst et al, 2002)

SUV mean

1–7% (Nahmias and Wahl, 2008)

Gefitinib

EGFR

2 days and 4 weeks (Sunaga et al, 2008)

¹⁸F-FLT (flurothymidine) PET

Whole body

Enter cells via nucleoside transporter proteins, phosphorylated by thymidine kinase, trapped intracellularly, but not incorporated into DNA

Tissue proliferation rate

SUV 41%

ICC=0.98 (95% CI 0.95–0.99) r=15%

Sunitinib

VEGFR-1, -2,-3; PDGFR-α, -β; KIT; FLT-3; CSFR-1; RET

4 weeks (Liu et al, 2011)

SUV max

ICC=0.93 (95% CI 0.85–0.97) r=20–25% (de Langen et al, 2009)

H2¹⁵O- (labeled H₂O) PET

Whole body

Inhaled C¹⁵O₂ or intravenous H₂¹⁵O. reach an equilibrium in which the diffusion rate into the tissue from the arterial blood is balanced by the diffusion rate out of the tissue into venous blood and the rate of radioactive decay of the ¹⁵O:

Tissue blood flow and oxygen utilization

Tumour perfusion

r=15.8–40% (depending on VOI selection method) (van der Veldt et al, 2010)

rh-Endo recombinant human endostatin

Proliferation and migration of capillary endothelial cells

28 and 56 days (Herbst et al, 2002)

CA4P

Tubulin polymerization

24 h (Anderson et al, 2003)

Regional flow

wCV 11% (van der Veldt et al, 2010)

Volume of distribution (VT or V_d)

r=32% (van der Veldt et al, 2010)

r=36–47% (de Langen et al, 2008)