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Functional imaging-guided radiotherapy dose escalation in rectal adenocarcinoma: a feasibility study

ABSTRACT: Interventions: This study will evaluate the feasibility of a diffusion-weighted magnetic resonance imaging (DW-MRI) guided radiotherapy boost for locally advanced rectal cancer. Patients will undergo pre-treatment MRI in the fortnight prior to commencing radiotherapy (+/- chemotherapy). Boost volume will be defined quantitatively according to intratumoural apparent diffusion coefficient (ADC) value. This volume will be targeted for a single-fraction 5-10Gy boost 3-5 days prior to commencing standard radiotherapy (50Gy delivered in 25 fractions). Treatment will be administered by the Radiation Oncology department at Sunshine Coast University Hospital (SCUH), Birtinya. Each treatment takes approximately 15 minutes per day. Patients will be reviewed once per week by radiation oncology medical staff as per normal practice. Patients will also be asked to complete a quality of life questionnaire at several timepoints prior to, during and following completion of the treatment course, which will take an additional 5-10 minutes on each occasion. Primary outcome(s): Rate of radiotherapy-related treatment toxicity as per Common Terminology Criteria for Adverse Events v5.0[Acute toxicity: throughout and up to 3 months after treatment Late toxicity: assessed at 3-12 monthly intervals after completion of treatment] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety/efficacy

DISEASE(S): Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Rectal Cancer

PROVIDER: 2470974 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:While hyperthermia has been shown to be an effective adjuvant anti-tumor treatment to radiotherapy, we still do not completely understand effects thermoradiotherapy on tumor phenotype or how these effects vary among different tumors. Here, we performed gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy. Diffusion weighted MRI (DWI) was done prior to the treatment course and at the end of therapy. Using supervised analysis, we identified significant correlation of DWI with several genes involved in VEGF signaling, telomerase, Wnt pathways and fatty acid synthesis. When the change of gene expression caused by treatment was examined, we found that thermoradiotherapy led to the induction of well known cycle regulators p21 and mdm2 and reduced cellular proliferation in most treated tumors. We also identified two tumor subtypes with dramatic differences in the gene expression response and treatment response at the end of therapy. In the subtype with strong expression and increase in DWI, the mRNA level of hsp70, POT1 and centrosomal proteins was significantly higher. In the other subtype with modest response to hyperthermia, levels of CD31, vWF and transferrin was noted to be significantly higher. It is also possible to build a predictive model based on the pre-treatment gene expression to predict the likely treatment response of the tumors. The differential expression between the two tumor subtypes was used to interrogate connectivity map and identify linkages to an HDAC inhibitor and geldanamycin, an HSP90 inhibitor. Both HDAC inhibitors and hsp90 inhibitor geldanamycin are shown to synergerize with thermoradiotherapy in reducing cell survival in clonogenic assays. Taken together, the gene expression studies of hyperthermia-treated spontaneous canine tumors shed mechanistic insights into the heterogeneity of thermoradiotherapy response and identified pathway-targeting compounds with synergistic potential to enhance its therapeutic benefits. To our knowledge, this is one of the first successful attempts to link genomic and functional imaging changes together. This is the first demonstration of using such associations to understand the connection between cellular and physiologic responses to treatment. gene expression analysis in 22 spontaneous canine sarcomas before and after the first hyperthermia treatment that was administered as an adjuvant to radiotherapy.

Project description:Interventions: Cohort: 10 patients with histologically proven squamous cell carcinoma (SCC) of the anus, presenting to Austin Health for chemo-radiotherapy from June 2015. Observation: for up to 3 years post-radiotherapy. Interventions additional to standard procedures for purpose of study are administered by qualified health professionals and include: Pre-radiotherapy imaging: During standard MRI imaging session – non-standard diffusion weighted MRI (dwMRI) and dynamic contrast enhanced (DCE) MRI scans within Radiology facility. During standard CT simulation session – additional CT scan in prone position within Austin Radiation Oncology. Post-Radiotherapy - 3-4 weeks post completion of radiotherapy - non-standard timepoint for these scans MRI session – including dwMRI and DCE MRI scans within Radiology facility. PET session - PET imaging within Austin Nuclear & Molecular Imaging department. A number of imaging scans are required to map disease for targeting of radiotherapy (RT), including CT, PET and MRI. Each provides slightly different information about the position, shape and composition of the disease that is used by a Radiation Oncologist to define where to target the radiation and how much radiation to deliver. We aim to add an extra, non-standard MRI imaging sequence called a diffusion weighted (dwMRI) scan, to understand the characteristics of the disease and how its use may change the size or shape of the target area so as to ensure complete treatment coverage and improved outcomes from treatment. Additionally, the use of contrast with MRI, dynamic contrast enhanced MRI (DCEMRI) has been shown in other cancer sites to help better identify and show the disease and to show response to treatment, and we wish to verify this in anal Primary outcome(s): Identify the differences in radiotherapy target volume definition on standard (CT, T1/T2 MRI and PET) versus non-standard imaging modalities (dwMRI & DCE-MRI).[2 years post-radiotherapy] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group

Project description:Background:To evaluate the association of multiparametric and multiregional MRI-features with key molecular characteristics in patients with newly-diagnosed glioblastoma. Methods:Retrospective data evaluation was approved by the local ethics committee of the University of Heidelberg (ethics approval number: S-320/2012) and informed consent was waived. Preoperative MRI-features were correlated with key molecular characteristics within a single-institutional cohort of 152 patients with newly-diagnosed glioblastoma. Preoperative MRI-features (n=31) included multiparametric (anatomical, diffusion-, perfusion-, and susceptibility-weighted images) and multiregional (contrast enhancing and non-enhancing FLAIR-hyperintense) information with (histogram) quantification of tumor volumes, volume ratios, apparent diffusion coefficients, cerebral blood flow / volume (CBF / CBV) and intratumoral susceptibility signals. Molecular characteristics determined with the Illumina Infinium HumanMethylation450 array included global DNA-methylation subgroups (e.g. mesenchymal (MES), RTK I “PGFRA”, RTK II “classic”), MGMT-promoter methylation status and hallmark copy-number-variations (EGFR-, PDGFRA-, MDM4- and CDK4-amplification; PTEN-, CDKN2A-, NF1- and RB1-loss). Univariate analyses (voxel-lesion-symptom-mapping for tumor location, Wilcoxon-test for all other MRI-features) as well as machine-learning models were applied to study the strength of association and discriminative value of MRI-features for predicting underlying molecular characteristics. Results: There was no tumor location predilection for any of the assessed molecular parameters (permutation-adjusted p>0.05 each). Univariate imaging parameter associations were noted for EGFR amplification and CDKN2A loss, both demonstrating increased nrCBV and nrCBF values (performance of these parameters, as assessed by the area under the ROC curve ranged from 63 to 69%, FDR-adjusted p<0.05, respectively). Subjecting all MRI-features to machine-learning-based classification allowed to predict EGFR amplification status and the RTK II “classic” GB subgroup with a moderate, yet significantly greater accuracy (63% for EGFR [p<0.01] and 61% for RTK II [p=0.01]) than the prediction by chance, whereas prediction accuracy for all other molecular parameters was non-significant (p>0.05, all models). Conclusions: In summary, we found univariate associations between established MRI-features and molecular characteristics, however not of sufficient strength to allow the generation of machine-learning classification models for reliable and clinically meaningful prediction of the assessed molecular characteristics in patients with newly-diagnosed glioblastoma.

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Functional imaging-guided radiotherapy dose escalation in rectal adenocarcinoma: a feasibility study

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