Diffusion-weighted and multiphase contrast-enhanced MRI as surrogate markers of response to neoadjuvant sunitinib in metastatic renal cell carcinoma

Abstract

Background: Current imaging criteria for categorising disease response in metastatic renal cell carcinoma (mRCC) correlate poorly with overall survival (OS) in patients on anti-angiogenic therapies. We prospectively assess diffusion-weighted and multiphase contrast-enhanced (MCE) MR imaging (MRI) as markers of outcome.

Methods: Treatment-naive mRCC patients on a phase II trial using sunitinib completed an MRI substudy. Whole-tumour apparent diffusion coefficient (ADC) maps and histograms were generated, and mean ADC and AUC(low) (proportion of the tumour with ADC values lying below the 25th percentile of the ADC histogram) recorded. On MCE-MRI, regions of interest were drawn around the most avidly enhancing components to analyse enhancement parameters. Baseline (n=26) and treatment-related changes in surviving patients (n=20) were correlated with OS. Imaged metastases were also analysed.

Results: Forty-seven per cent of the patients showed significant changes in whole-tumour mean ADC following therapy, but there was no correlation with outcome. Patients with a high baseline AUC(low) and greater-than-median AUC(low) increase had reduced OS (HR=3.67 (95% confidence interval (CI)=1.23-10.9), P=0.012 and HR=3.72 (95% CI=0.98-14.21), P=0.038, respectively). There was no correlation between MCE-MRI parameters and OS. Twenty-eight metastases were analysed and showed positive correlation with primary tumour mean ADC for individual patients (r=0.607; P<0.001).

Conclusion: Primary RCC ADC histogram analysis shows dynamic changes with sunitinib. Patients in whom the tumour ADC histogram demonstrated high baseline AUC(low) or a greater-than-median increase in AUC(low) with treatment had reduced OS.

Figure 1

Flow diagram illustrating the imaging performed in the MRI substudy cohort. *Four patients were excluded from the study because they did not complete post-treatment imaging for reasons other than progression. **In three patients, the initial DW-MRI study was performed using only two b-values. These patients have been excluded from the DW-MRI analysis but remain in the MCE-MRI analysis.

Figure 2

Magenetic resonance imaging substudy schema illustrating the relationship between neoadjuvant therapy, MR imaging and surgery in patients recruited to the MRI substudy. The second MRI study was performed in the second week off treatment following cycle 3 of sunitinib and before nephrectomy.

Figure 3

Region of interest placement. Axial section through a right-sided renal cell carcinoma (white arrow) showing the placement of a ROI within the low ADC tumour. Care is taken to sample only tumour tissue without contamination from adjacent normal tissues. Workstation-generated analysis gives a mean ADC value of 0.91 × 10⁻³ mm² s⁻¹ for the tumour at this level. This section also demonstrates involved retroperitoneal nodes (white stars), which return lower ADC values than the primary tumour. LK=left kidney.

Figure 4

ADC histogram analysis: derivation of AUC_low. Pre- and post-treatment ADC histograms were generated from pixel-by-pixel mean ADC measurements from the entire tumour volume. The highest and lowest 1% of ADC values (the tails of the bell-shaped curve) were discarded to remove artefact (blacked out regions). The 25th percentile point of the histogram range, the pixel ADC below which 25% of all tumour ADC values lie, was calculated for each curve and the proportion of the tumour with ADC values lying below this point was measured (AUC_low; outlined in green at baseline (A) and in purple following three treatment cycles (B)). (C) Pre- and post-treatment ADC histograms displayed on the same axis demonstrating the treatment-related changes in the histogram and AUC_low.

Figure 5

Box and whisker plots. Box and whisker plots showing (A) whole-tumour mean ADC and (B) mean AUC_low at baseline and following three cycles of sunitinib therapy. There was no statistical significance between the values (P=0.23 and P=0.27, respectively).

Figure 6

Overall survival correlated with AUC_low. (A) Baseline AUC_low: patients with a high (above median) AUC_low at baseline were compared with those who had a low baseline AUC_low (below median). Kaplan–Meier analysis shows a significant difference between the two groups (HR 3.67 (95% CI: 1.23–10.9), P=0.012). Those with higher baseline AUC_low values had reduced OS, that is, those patients with a larger proportion of the tumour with ADC values below the 25th percentile point of the ADC histogram at baseline had poorer OS. (B) Change in AUC_low between the pre- and post-treatment studies: patients with an above-median percentage change in AUC_low between the baseline scan and post three cycles of scan were compared with those who had a percentage change below the median. Kaplan–Meier analysis shows a significant difference between the two groups (HR=3.72 (95% CI=0.98–14.21), P=0.038). Those with a larger increase in AUC_low after three cycles had a reduced OS, that is, patients whose ADC histograms showed leftward shift (an increase in AUC_low and a move towards a more restricted picture) had a poorer OS (AUC_low=proportion of the tumour with ADC values lying below the 25th percentile of the ADC histogram).