Abstract
The purpose was to determine the reproducibility of apparent diffusion coefficient (ADC) measurements in a two-centre phase I clinical trial; and to track ADC changes in response to the sequential administration of the vascular disrupting agent, combretastatin A4 phosphate (CA4P), and the anti-angiogenic drug, bevacizumab. Sixteen patients with solid tumours received CA4P and bevacizumab treatment. Echo-planar diffusion-weighted MRI was performed using six b values (b = 0–750 s/mm2) before (×2), and at 3 and 72 h after a first dose of CA4P. Bevacizumab was given 4 h after a second dose of CA4P, and imaging performed 3 h post CA4P and 72 h after bevacizumab treatment. The coefficient of repeatability (r) of ADC total (all b values), ADC high (b = 100–750) and ADC low (b = 0–100) was calculated by Bland–Altman analysis. The ADC total and ADC high showed good measurement reproducibility (r% = 13.3, 14.1). There was poor reproducibility of the perfusion-sensitive ADC low (r% = 62.5). Significant increases in the median ADC total and ADC high occurred at 3 h after the second dose of CA4P (p < 0.05). ADC measurements were highly reproducible in a two-centre clinical trial setting and appear promising for evaluating the effects of drugs that target tumour vasculature.
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This study was sponsored by Oxigene (Oxigene Inc, Waltham, MA, USA); and supported by Cancer Research UK Grant C1060/A5117 and NHS funding to the NIHR Biomedical Research Centre.
Appendix: details of Bland–Altman statistical analysis
Appendix: details of Bland–Altman statistical analysis
For each tumour, the distribution of the ADC pixel values was asymmetric, and the median values were thus used to summarise the distribution. However, the distribution of the median values of all tumours and the differences in the baseline median values of tumours conformed to a normal distribution (D’Angostino–Pearson test, p > 0.05), which allowed us to perform Bland–Altman analyses to determine measurement reproducibility of the ADC total, ADC high and ADC low. For each tumour, the difference between the two baseline median ADC measurements (d) was calculated. The mean squared difference was calculated by:
This was used to calculate the 95% confidence interval (CI) for changes in the study cohort of n individuals:
Thus, a change in the ADC value greater than this value in the patient cohort would be significant at the 5% level.
The within-patient coefficient of variance (wCV) was calculated by:
The coefficient of repeatability (r) was calculated by:
The value of the coefficient of repeatability indicates that the difference between the two baseline median ADC measurements for the same tumour will be less than this value for 95% of the pairs of observations. This value is usually expressed as an absolute value on the same scale as the ADC parameter, but may also be approximated as a percentage of the baseline values. For good measurement reproducibility on a per patient basis, both the within-patient coefficient of variance and the coefficient of repeatability should be low. Similarly, for good cohort measurement reproducibility, the group confidence interval should also be small.
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Koh, DM., Blackledge, M., Collins, D.J. et al. Reproducibility and changes in the apparent diffusion coefficients of solid tumours treated with combretastatin A4 phosphate and bevacizumab in a two-centre phase I clinical trial. Eur Radiol 19, 2728–2738 (2009). https://doi.org/10.1007/s00330-009-1469-4
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DOI: https://doi.org/10.1007/s00330-009-1469-4