Evaluation of diffusion-weighted MRI and (18F) fluorothymidine-PET biomarkers for early response assessment in patients with operable non-small cell lung cancer treated with neoadjuvant chemotherapy

Abstract

Objective: To correlate changes in the apparent diffusion coefficient (ADC) from diffusion-weighted (DW)-MRI and standardised uptake value (SUV) from fluorothymidine (¹⁸FLT)-PET/CT with histopathological estimates of response in patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy and track longitudinal changes in these biomarkers in a multicentre, multivendor setting.

Methods: 14 patients with operable NSCLC recruited to a prospective, multicentre imaging trial (EORTC-1217) were treated with platinum-based neoadjuvant chemotherapy. 13 patients had DW-MRI and FLT-PET/CT at baseline (10 had both), 12 were re-imaged at Day 14 (eight dual-modality) and nine after completing chemotherapy, immediately before surgery (six dual-modality). Surgical specimens (haematoxylin-eosin and Ki67 stained) estimated the percentage of residual viable tumour/necrosis and proliferation index.

Results: Despite the small numbers,significant findings were possible. ADC_median increased (p < 0.001) and SUV_mean decreased (p < 0.001) significantly between baseline and Day 14; changes between Day 14 and surgery were less marked. All responding tumours (>30% reduction in unidimensional measurement pre-surgery), showed an increase at Day 14 in ADC75^th centile and reduction in total lesion proliferation (SUV_mean x proliferative volume) greater than established measurement variability. Change in imaging biomarkers did not correlate with histological response (residual viable tumour, necrosis).

Conclusion: Changes in ADC and FLT-SUV following neoadjuvant chemotherapy in NSCLC were measurable by Day 14 and preceded changes in unidimensional size but did not correlate with histopathological response. However, the magnitude of the changes and their utility in predicting (non-) response (tumour size/clinical outcome) remains to be established.

Advances in knowledge: During treatment, ADC increase precedes size reductions, but does not reflect histopathological necrosis.

Figure 1.

Design of this prospective, multicentre, single-arm imaging trial from registration to surgery.

Figure 2.

A 70-year-old patient with lung cancer treated with platinum based neoadjuvant chemotherapy: ADC map derived from DW-MRI prior to surgery (a), FLT-PET at the same time-point (b), show residual tumour with lateral consolidation (solid white arrows). Following resection, this was corroborated on the corresponding slice of the macroscopic surgical specimen (c, centre). Residual tumour was confirmed on H&E stained sections. Ki-67 stain shows the low level of proliferative activity (brown stain) within the centre of the tumour.

Figure 3.

Absolute values of (a) ADC_median, (b) ADC_25th and c) ADC_75th , (d) SUV_mean, (e) SUV_peak, and (f) SUV_max at each time-point (solid lines =responders, dashed lines=non-responders) show the increase in ADC values and decrease in FLT-SUV parameters with time on treatment.

Figure 4.

Comparison of change at Day 14 of treatment relative to baseline of a) DWI and b) FLT metrics for responders and non-responders with respect to measures of repeatability (dashed lines). Responders are shown with black filled markers and the y-axis for ∆ADC_early has been broken to include a patient with high ∆ADC_IQR. The increase in ADC₇₅ and ADC_IQR and decrease in FLT-TLP was outside the limits of measurement variability in responders.

Figure 5.

A comparison of changes at Day 14 (top row) and pre-surgery (bottom row) from baseline between tumour volumes derived from DWI and FLT (a, b), DWI and CT (c, d) and FLT and CT (e, f). Responders are represented by black filled markers (symbols: square=patient 11, triangle=patient 13, circle = patient 14).