The role of clinical imaging in oncological drug development.

Clinical imaging has the potential to provide key biomarkers to inform decision-making in drug development. There is considerable optimism that emerging functional imaging techniques will substantially add to the conventional morphological depiction of disease. The discovery, development and qualification of clinical imaging biomarkers remain a considerable undertaking. Once an imaging biomarker is developed, it must be implemented with a high degree of consistency to ensure the collection of robust clinical trial data. The aim of such a development and implementation process is to deliver sufficient confidence in an imaging biomarker to support "go/no-go" decisions made in a drug development programme. This article outlines the drug development process, with a focus on the current impact of clinical imaging on drug development and its probable future direction.

Pelvic malignancy: integrating form and function.

Despite the essential role morphological imaging plays in the management of patients with malignancy, anatomical techniques are limited in their ability to report on tumour biology and behaviour. It has therefore been necessary to develop imaging techniques that integrate form and function to probe the micro and molecular environments of cancers. The role of clinical functional and molecular magnetic resonance imaging is discussed with an emphasis on pelvic malignancy. It is argued that the radiological sciences need to take a lead in translating molecular and functional imaging techniques into man. Imaging in support of drug development is suggested as a focus for that development.

Investigation of microenvironmental factors influencing the longitudinal relaxation times of drugs and other compounds.

The aim of this study was to investigate the microenvironmental factors likely to influence the longitudinal relaxation time of MR visible drugs or compounds in vivo at 1.5 T. The relative influence that viscosity, albumin and paramagnetic contrast agent concentrations have on the observed longitudinal relaxation times of three 19F MR detectable drugs and compounds have been investigated. Our data show that for 5-fluorouracil, flucloxacillin and tetrafluorosuccinic acid-containing phantoms, the presence of albumin at normal physiological concentrations will have relaxation effects of the same order of magnitude as that of a commonly clinically administered contrast agent, gadolinium diethylenetriamine pentaacetic acid. The contribution of viscosity is shown, in the examples studied here, to be of minor importance, contributing less than 6.5% to the observed relaxation effects. It is also demonstrated that in the presence of competitive binding of other ligands for common binding sites on albumin, the 19F longitudinal relaxation time of 5-fluorouracil can increase by up to 340% from its value in the absence of the competing ligand. The relevance of the findings to in vivo studies is discussed.

Monitoring temozolomide treatment of low-grade glioma with proton magnetic resonance spectroscopy.

Assessment of low-grade glioma treatment response remains as much of a challenge as the treatment itself. Proton magnetic resonance spectroscopy ((1)H-MRS) and imaging were incorporated into a study of patients receiving temozolomide therapy for low-grade glioma in order to evaluate and monitor tumour metabolite and volume changes during treatment. Patients (n=12) received oral temozolomide (200 mg m(-2) day(-1)) over 5 days on a 28-day cycle for 12 cycles. Response assessment included baseline and three-monthly magnetic resonance imaging studies (pretreatment, 3, 6, 9 and 12 months) assessing the tumour size. Short (TE (echo time)=20 ms) and long (TE=135 ms) echo time single voxel spectroscopy was performed in parallel to determine metabolite profiles. The mean tumour volume change at the end of treatment was -33% (s.d.=20). The dominant metabolite in long echo time spectra was choline. At 12 months, a significant reduction in the mean choline signal was observed compared with the pretreatment (P=0.035) and 3-month scan (P=0.021). The reduction in the tumour choline/water signal paralleled tumour volume change and may reflect the therapeutic effect of temozolomide.

Molecular imaging in oncology.

Cancer is a genetic disease that manifests in loss of normal cellular homeostatic mechanisms. The biology and therapeutic modulation of neoplasia occurs at the molecular level. An understanding of these molecular processes is therefore required to develop novel prognostic and early biomarkers of response. In addition to clinical applications, increased impetus for the development of such technologies has been catalysed by pharmaceutical companies investing in the development of molecular therapies. The discipline of molecular imaging therefore aims to image these important molecular processes in vivo. Molecular processes, however, operate at short length scales and concentrations typically beyond the resolution of clinical imaging. Solving these issues will be a challenge to imaging research. The successful implementations of molecular imaging in man will only be realised by the close co-operation amongst molecular biologists, chemists and the imaging scientists.

Could assessment of glioma methylene lipid resonance by in vivo (1)H-MRS be of clinical value?

The potential clinical role of in vivo (1)H-MRS ((1)H-magnetic resonance spectroscopy) lipid methylene resonance measurements of human glioma has been assessed. 20 patients, 14 with low grade and 6 with high grade gliomas have been investigated using single voxel (1)H-MRS. Three of the low grade group had undergone transformation by clinical and imaging criteria. Short echo time (TE=20 ms, TR=2500 ms) single voxel Stimulated Echo Acquisition (STEAM) spectra with (acquisitions=64) and without (acquisitions=4) water suppression were acquired. Additionally, T(1) weighted (T(1)W) water spectra (TE=20 ms, TR=888 ms) were acquired pre- and post-injection of Gd-DTPA (0.2 mmol x kg(-1)). The T(1)W water spectra were used to determine the water proton enhancement occurring within the spectroscopic voxel. The enhancement expressed as a percentage was compared with the lipid methylene peak. All the high grade tumours had significantly higher levels of lipid than low grade tumours (p=0.002). Low grade tumours had significantly less water proton enhancement than transformers (p=0.04) and high grade tumours (p=0.001). The lipid methylene signal correlated strongly with the voxel water enhancement (r(2)=0.74, p<0.0001). The data support the view that the spectroscopically detected lipid methylene signal may be a useful criterion in grading glioma. The correlation of the lipid methylene signal with blood-brain barrier breakdown suggests that detection of a previously absent (1)H-MRS lipid methylene signal in low grade tumours might be an early indicator of transformation.

Non-invasive study of human gall bladder bile in vivo using (1)H-MR spectroscopy.

The sampling of gall bladder bile for analytical studies remains an invasive procedure. We demonstrate the application of the non-invasive methodology of (1)H-MR spectroscopy to the qualitative and quantitative assessment of human gall bladder bile in vivo. Spectral profiles in vivo are shown in relation to model and porcine gall bladder bile and the quantitation in man of the trimethylamine (choline) and lecithin concentrations were estimated to range from 25.9 mM to 48.4 mM (mean: 35.8 mM, standard deviation: 9.8). The composition of human gall bladder bile together with the quantitation of various constituents can be studied non-invasively in vivo.

Human rectal adenocarcinoma: demonstration of 1H-MR spectra in vivo at 1.5 T.

This study was designed to determine whether 1H-MR spectra of locally advanced human rectal adenocarcinoma could be acquired in vivo at 1.5 T. Despite the relatively large size of these neoplasms, only six out of 21 tumors accommodated a voxel size of 8 cm3. This was due to air pockets within the tumor mass, which limited voxel positioning. Localized proton spectra were acquired at short (20 ms) and long (135 ms) echo times (TEs) using a single-voxel technique. The most commonly detected metabolites were choline and lipid.

An algorithm for the optimum combination of data from arbitrary magnetic resonance phased array probes.

When summing the spectra acquired with phased array coils, signals with low signal-to-noise ratio or wrongly corrected phase may degrade the overall signal-to-noise ratio (SNR). Here we present a mathematical expression predicting the dependence of combined SNR on the signal-to-noise ratios and errors in phase correction of composite signals. Based on this equation, signals that do not lead to an overall increase in signal-to-noise ratio can be identified and excluded from the weighted sum of signals. This tool is particularly useful for the combination of large numbers of signals. Additionally, a simple and robust algorithm for calculating the complex weighting factors necessary for the signal-to-noise weighted combination of spectroscopic data is presented. Errors in the calculation and correction of relative phase differences between composite spectra are analysed. The errors have a negligible effect on the overall spectral SNR for typical clinical magnetic resonance spectroscopy (MRS). The signal combination routine developed here has been applied to the first in vivo MRS study of human rectal adenocarcinomas at 1.5 T (Dzik-Jurasz A S K, Murphy P S, George M, Prock T, Collins D J, Swift I and Leach M O 2001 Magn. Reson. Med. at press), showing improvements of combined spectral SNR of up to 34% over the maximum SNR from a single element.

Non-invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer.

BACKGROUND: Tumour neoangiogenesis can be assessed non-invasively by measuring angiogenic cytokine concentrations in peripheral circulation and by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The aim of this study was to assess whether these methods can predict and monitor response to treatment in patients with rectal cancer treated with preoperative chemoradiotherapy. METHODS: Serum and plasma vascular endothelial growth factor levels were measured in 31 patients with T3/T4 rectal cancers before quantitating tumour permeability (ln Ktrans) by DCE-MRI. Sixteen patients receiving preoperative chemoradiotherapy had serial vascular endothelial growth factor (VEGF) and DCE-MRI measurements. Response to treatment was assessed using World Health Organization criteria. RESULTS: Serum VEGF and ln Ktrans correlated before treatment (r = 0.48, P = 0.01). Responsive tumours (n = 8) had higher pretreatment permeability values than non-responsive tumours (n = 8) (mean ln Ktrans - 0.46 and - 0.72 respectively; P = 0.03). Compared with pretreatment values, responsive tumours showed a marked reduction in permeability at the end of treatment (mean ln Ktrans - 0.46 and - 0.86 respectively; P = 0.04). Pretreatment serum VEGF levels were not statistically different between the two groups. CONCLUSION: Rectal tumours with higher permeability at presentation appear to respond better to chemoradiotherapy than those of lower permeability. This may allow preselection of appropriate tumours for these regimens, with patients with low-permeability tumours being considered for alternative therapies.

The prevalence of avascular necrosis in patients treated with chemotherapy for testicular tumours.

To study the prevalence of avascular necrosis in patients receiving chemotherapy for testicular cancer we invited 103 consecutive patients treated by chemotherapy to attend for MRI scan of the hips. Four of 47 (9% (CI 2-20%)) patients scanned and 4/103 (3.8% (CI 1-10%)) of patients invited to participate in the study had evidence of avascular necrosis. As not all patients in the study had completed the at risk period this equates to a 3-year actuarial risk of 6.3% (95% confidence limits (CI) 2.4-16.1). These data suggest that avascular necrosis is an uncommon but significant complication of chemotherapy including steroids as anti-emetics.

The quantitative 19F-imaging of albumin at 1.5 T: a potential in-vivo tool.

19F-MR-imaging has been used to quantitate albumin concentration in a phantom at 1.5 T. The experimentally derived relationship between albumin concentration and the T1 relaxation time of a fluorinated marker, tetrafluorosuccinic acid (TFSA) was used to calculate the albumin concentration from a quantitative 19F T1 map acquired using a gradient echo sequence. There was close correlation between calculated and actual BSA concentrations (r = 0.99, SE = 0.15). The potentially interfering effect of paramagnetic species on T1 relaxation times was also investigated. Relaxivity data show that albumin concentration measurements should be performed prior to any contrast agent administration.

What is the prevalence of symptomatic or asymptomatic femoral head osteonecrosis in patients previously treated with chemoradiation? A magnetic resonance study of anal cancer patients.

It is generally assumed that femoral head osteonecrosis (FHO) is a serious but rare complication of pelvic radiotherapy. A review of the literature carried out by the authors indicates a prevalence of 4/763 (95% confidence interval 0.1%-1.3%). A recent publication has suggested that the prevalence of symptomatic FHO may be much greater than previously assumed as a result of sensitization of bone to radiation by concomitant treatment with chemotherapy. Magnetic resonance imaging (MRI) is currently the most sensitive modality for detecting and confirming symptomatic or asymptomatic FHO of any aetiology. The aim of this study therefore was to assess the prevalence of symptomatic and asymptomatic FHO in patients previously treated for anal cancer by chemoradiation (CRT). The hips of 34 currently disease-free individuals (11 men and 23 women; median age 67 years, range 32-86) were scanned using a coronal T1-weighted sequence. The images were assessed for evidence of FHO. The median time of scanning after the end of CRT was 35 months (range 6-107). No cases (0/34) of symptomatic or asymptomatic FHO were detected in these patients. Given the established sensitivity of MRI in the detection of FHO, it is concluded that changes indicative of osteonecrosis were uncommon after CRT in the current cohort of patients. Recent evidence from the literature suggests, however, that elderly females are at greatest risk of developing FHO after CRT.

Gallbladder localization of (19)F MRS catabolite signals in patients receiving bolus and protracted venous infusional 5-fluorouracil.

The hepatobiliary distribution of 5-fluorouracil (5FU) catabolites was investigated in nine patients. Using fluorine 3D-chemical shift imaging, four patients receiving protracted venous infusion of 5FU demonstrated catabolite localized to the gallbladder. No hepatobiliary fluorine signals were detected in three patients whose gallbladders were absent or abnormal. Signals from the gallbladder showed a 2.2-2.4 ppm high-frequency shift from alpha-fluoro-beta-alanine, suggesting the presence of alpha-fluoro-beta-alanine-bile-acid conjugates. 3D-chemical shift imaging of two patients receiving bolus 5FU revealed alpha-fluoro-beta-alanine to be localized to the liver within 1 hr of administration. In one patient examined 4 hr after bolus administration, catabolite signal was detected only in the gallbladder.

Spin-lattice relaxation of laser-polarized xenon in human blood.

The nuclear spin polarization of 129Xe can be enhanced by several orders of magnitude by using optical pumping techniques. The increased sensitivity of xenon NMR has allowed imaging of lungs as well as other in vivo applications. The most critical parameter for efficient delivery of laser-polarized xenon to blood and tissues is the spin-lattice relaxation time (T1) of xenon in blood. In this work, the relaxation of laser-polarized xenon in human blood is measured in vitro as a function of blood oxygenation. Interactions with dissolved oxygen and with deoxyhemoglobin are found to contribute to the spin-lattice relaxation time of 129Xe in blood, the latter interaction having greater effect. Consequently, relaxation times of 129Xe in deoxygenated blood are shorter than in oxygenated blood. In samples with oxygenation equivalent to arterial and venous blood, the 129Xe T1s at 37 degrees C and a magnetic field of 1.5 T were 6.4 s +/- 0.5 s and 4.0 s +/- 0.4 s, respectively. The 129Xe spin-lattice relaxation time in blood decreases at lower temperatures, but the ratio of T1 in oxygenated blood to that in deoxygenated blood is the same at 37 degrees C and 25 degrees C. A competing ligand has been used to show that xenon binding to albumin contributes to the 129Xe spin-lattice relaxation in blood plasma. This technique is promising for the study of xenon interactions with macromolecules.

Does 100 mm photofluorography always have a dose advantage over conventional film-screen radiography in barium meals?

It is generally held that 100 mm photofluorography has a significant dose saving advantage over conventional radiography. The dose area product (DAP) data for the two formats were available for study in consecutive patients undergoing barium meal examination. There was no significant difference in DAP readings between the two formats. Conventional radiographs expose a 40% greater area than the 100 mm format, probably accounting for the lower mean DAP value of photofluorography. The mean DAP for whole examinations was 26.1 Gy cm2 for photofluorography, and 30.5 Gy cm2 for conventional radiography. These are both above the third quartile of national reference dose levels. There is little apparent difference in the doses incurred by patients between the two formats in respect of the working practice of the department. Barium meals will therefore continue to be recorded on both formats.