Predicting neoadjuvant chemoradiotherapy response with functional imaging and liquid biomarkers in locally advanced rectal cancer.

INTRODUCTION: Noninvasive predictive quantitative biomarkers are required to guide treatment individualization in patients with locally advanced rectal cancer (LARC) in order to maximize therapeutic outcomes and minimize treatment toxicity. Magnetic resonance imaging (MRI), positron emission tomography (PET), and blood biomarkers have the potential to predict chemoradiotherapy (CRT) response in LARC. AREAS COVERED: This review examines the value of functional imaging (MRI and PET) and liquid biomarkers (circulating tumor cells (CTCs) and circulating tumor nucleic acid (ctNA)) in the prediction of CRT response in LARC. Selected imaging and liquid biomarker studies are presented and the current status of the most promising imaging (apparent diffusion coefficient (ADC), Ktrans, SUVmax, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and liquid biomarkers (CTCs, ctNA) is discussed. The potential applications of imaging and liquid biomarkers for treatment stratification and a pathway to clinical translation are presented. EXPERT OPINION: Functional imaging and liquid biomarkers provide novel ways of predicting CRT response. The clinical and technical validation of the most promising imaging and liquid biopsy biomarkers in multicenter studies with harmonized acquisition techniques is required. This will enable clinical trials to investigate treatment escalation or de-escalation pathways in rectal cancer.

Magnetic resonance imaging (MRI) guided proton therapy: A review of the clinical challenges, potential benefits and pathway to implementation.

Proton therapy and MRI-Linacs are two of the most exciting and fast growing technologies in radiation oncology. With over 100 MRI-Linacs and 100 proton therapy centres either in operation or under construction, an integrated approach that brings together the excellent soft tissue imaging of MRI with the superior dose conformity of proton therapy is compelling. The promise of MRI-guided proton therapy has prompted multiple research studies and the building of two pre-clinical experimental systems, taking us closer to realisation of this technology. Patients who would benefit most are those whose cancers have substantial tumour motion or anatomical variation, and those who are currently unable to receive safe dose-escalation due to nearby critical structures. MRI-guided proton therapy could allow more patients with pancreatic cancer, central lung cancer and oligo-metastatic cancers in the upper abdomen (e.g. liver and adrenal) to safely receive escalated curative doses. Head and neck, lung, brain and cervix cancers, where treatment accuracy is affected by inter-fraction tumour changes such as tumour regression or changing oedema, or normal anatomy variations, would also benefit from MRI-guidance. There will be new options to improve cure by functional MRI-guided biologically adapted proton therapy. This review focuses on the clinical aspects of MRI-guided proton therapy. We describe the clinical challenges in proton therapy and the clinical benefits from the addition of MRI-guidance. We provide updates on the design and beam modelling of in-line and perpendicular MRI-guided proton therapy systems, and a roadmap to clinical implementation.

Multi-parametric magnetic resonance imaging assessment of whole tumour heterogeneity for chemoradiotherapy response prediction in rectal cancer.

BACKGROUND AND PURPOSE: Prediction of chemoradiotherapy response (CRT) in locally advanced rectal cancer would enable stratification of management. The purpose was to prospectively evaluate multi-parametric magnetic resonance imaging (MRI) assessment of tumour heterogeneity combining diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI for the prediction of CRT response in locally advanced rectal cancer. MATERIALS AND METHODS: Patients with Stage II or III rectal adenocarcinoma undergoing neoadjuvant CRT and surgery underwent MRI (DWI and DCE) before, during (week 3), and after CRT (1 week before surgery). Patients with histopathology tumour regression grade (TRG) 0-1 were classified as responders, and TRG 2-3 were classified as non-responders. A whole tumour voxel-wise technique was used to produce apparent diffusion coefficient (ADC) and Ktrans (Tofts model) histograms derived from DWI and DCE-MRI, respectively. Logistic regression was used to predict response status for ADC and Ktrans quantiles. RESULTS: Thirty-three patients were included in this analysis; 16 responders, and 17 non-responders. On heterogeneity analysis, odds of being a responder were significantly higher after CRT (before surgery) for higher ADC 75th (p = 0.049) and ADC 90th (p = 0.034) percentile values. The Ktrans quantiles were lower in non-responders than responders before and during CRT, and higher after CRT although no significant association with response status was observed (p ≥ 0.10). CONCLUSIONS: DWI-MRI after CRT (before surgery) incorporating a histogram analysis of whole tumour heterogeneity was predictive of CRT response in patients with locally advanced rectal cancer. DCE-MRI did not add value in response prediction. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448.

Prognostic utility of serial 18F-FDG-PET/CT in patients with locally advanced rectal cancer who underwent tri-modality treatment.

OBJECTIVE: This study explored the value of serial 18-fludeoxyglucose-positron emission tomography (18F-FDG-PET/CT) in predicting disease-free survival (DFS) in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NCRT) and surgery. METHODS: We prospectively studied 46 patients with LARC who underwent NCRT and surgery. 18F-FDG-PET/CT scans were performed at three time-points before surgery (pre-NCRT-PET1, during NCRT-PET2 and following completion of NCRT-PET3). The following semi-quantitative PET parameters were analysed at each time point: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG). Absolute and percentage changes in these parameters were analysed between time points. Statistical analysis consisted of median tests, Cox regression and Kaplan-Meier analysis for DFS. RESULTS: The median follow-up time was 24 months. A reduction in PET parameters showed statistically significant differences for patients with recurrence compared to those without; percentage changes in MTV between PET1 and PET3 (cut-off: 87%, p = 0.023), percentage changes in TLG between PET1 and PET3 (cut-off: 94%, p = 0.02) and absolute change in MTV PET1 and PET2 (cut-off: 10.25, p = 0.001).An absolute reduction in MTV between PET1 and PET3 (p=0.013), a percentage reduction in TLG between PET1 and PET2 (p=0.021), SUVmax and SUVmean at PET2 (p = 0.01, p = 0.027 respectively)were also prognostic indicators of recurrence.MTV percentage change between PET1 and PET2 and SUVmean percentage change between PET1 and PET3 were also trending towards significance (p = 0.052, p = 0.053 respectively). CONCLUSION: Serial 18F-FDG-PET/CT is a potentially reliable non-invasive method to predict recurrence in patients with LARC. Volumetric parameters were the best predictors. This could allow risk-stratification in patients who may benefit from conservative management. ADVANCES IN KNOWLEDGE: This paper will add to the literature in risk-stratifying patients with LARC based on prognosis, using 18F-FDG-PET/CT. This may improve patient outcomes by selecting suitable candidates for conservative management.

Study protocol: multi-parametric magnetic resonance imaging for therapeutic response prediction in rectal cancer.

BACKGROUND: Response to neoadjuvant chemoradiotherapy (CRT) of rectal cancer is variable. Accurate imaging for prediction and early assessment of response would enable appropriate stratification of management to reduce treatment morbidity and improve therapeutic outcomes. Use of either diffusion weighted imaging (DWI) or dynamic contrast enhanced (DCE) imaging alone currently lacks sufficient sensitivity and specificity for clinical use to guide individualized treatment in rectal cancer. Multi-parametric MRI and analysis combining DWI and DCE may have potential to improve the accuracy of therapeutic response prediction and assessment. METHODS: This protocol describes a prospective non-interventional single-arm clinical study. Patients with locally advanced rectal cancer undergoing preoperative CRT will prospectively undergo multi-parametric MRI pre-CRT, week 3 CRT, and post-CRT. The protocol consists of DWI using a read-out segmented sequence (RESOLVE), and DCE with pre-contrast T1-weighted (VIBE) scans for T1 calculation, followed by 60 phases at high temporal resolution (TWIST) after gadoversetamide injection. A 3-dimensional voxel-by-voxel technique will be used to produce colour-coded ADC and Ktrans histograms, and data evaluated in combination using scatter plots. MRI parameters will be correlated with surgical histopathology. Histopathology analysis will be standardized, with chemoradiotherapy response defined according to AJCC 7th Edition Tumour Regression Grade (TRG) criteria. Good response will be defined as TRG 0-1, and poor response will be defined as TRG 2-3. DISCUSSION: The combination of DWI and DCE can provide information on physiological tumour factors such as cellularity and perfusion that may affect radiotherapy response. If validated, multi-parametric MRI combining DWI and DCE can be used to stratify management in rectal cancer patients. Accurate imaging prediction of patients with a complete response to CRT would enable a 'watch and wait' approach, avoiding surgical morbidity in these patients. Consistent and reliable quantitation from standardised protocols is essential in order to establish optimal thresholds of ADC and Ktrans and permit the role of multi-parametric MRI for early treatment prediction to be properly evaluated. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448 (retrospectively registered 8/12/2016).