[Show abstract][Hide abstract] ABSTRACT: The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1) H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1) H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling. This article is protected by copyright. All rights reserved.
International Journal of Cancer 11/2015; DOI:10.1002/ijc.29932 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the last few decades, significant improvements have been made in the radiotherapy (RT) treatment of head and neck malignancies. The progressive introduction of intensity-modulated RT and the use of multimodality imaging for target volume and organs at risk delineation, together with the use of altered fractionation regimens and concomitant administration of chemotherapy or targeted agents, have accompanied efficacy improvements in RT. Altogether, such improvements have translated into improvement in locoregional control and overall survival probability, with a decrease in the long-term adverse effects of RT and an improvement in quality of life. Further progress in the treatment of head and neck malignancies may come from a better integration of molecular imaging to identify tumor subvolumes that may require additional radiation doses (ie, dose painting) and from treatment adaptation tracing changes in patient anatomy during treatment. Proton therapy generates even more exquisite dose distribution in some patients, thus potentially further improving patient outcomes. However, the clinical benefit of these approaches, although promising, for patients with head and neck cancer need to be demonstrated in prospective randomized studies. In this context, our article will review some of these advances, with special emphasis on target volume and organ-at-risk delineation, use of molecular imaging for tumor delineation, dose painting for dose escalation, dose adaptation throughout treatment, and potential benefit of proton therapy.
[Show abstract][Hide abstract] ABSTRACT: AimsSlide digitalization has brought pathology to a new era, including powerful image analysis possibilities. However, while being a powerful prognostic tool, immunostaining automated analysis on digital images is still not worldwide implemented in routine clinical practice.Methods and ResultsDigitalized biopsy sections from two independent cohorts of patients, immunostained for membrane or nuclear markers, were quantified with two automated methods. The first one was based on stained cell counting through tissue segmentation while the second one relied on stained area proportion within tissue sections. Different steps of image preparation like automated tissue detection, folds exclusion, scanning magnification, were also assessed and validated. Quantification of either stained cells or stained area were found to be highly correlated for all tested markers. Both methods were also correlated to visual scoring performed by a pathologist. For an equivalent reliability, quantification of stained area is however faster and easier to fine-tune and is therefore more compatible with time constraints for prognosis.Conclusions
This work provides an incentive for the implementation of automated immunostaining analysis with a stained area method in routine laboratory practice.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: To develop a methodology for using FDG PET/CT in adaptive dose painting by numbers (DPBN) in head and neck squamous cell carcinoma (HNSCC) patients. Issues related to noise in PET and treatment robustness against geometric errors are addressed.
Five patients with locally advanced HNSCC scheduled for chemo-radiotherapy were imaged with FDG-PET/CT at baseline and 2-3 times during radiotherapy (RT). The GTVPET was segmented with a gradient-based method. A double median filter reduces the impact of noise in the PET uptake-to-dose conversion. Filtered FDG uptake values were linearly converted into a voxel-by-voxel prescription from 70 (median uptake) to 86 Gy (highest uptake). A PTVPET was obtained by applying a dilation of 2.5 mm to the entire prescription. Seven iso-uptake thresholds led to seven sub-levels compatible with the Tomotherapy HiArt(®) Treatment Planning System. Planning aimed to deliver a median dose of 56 Gy and 70 Gy in 35 fractions on the elective and therapeutic PTVs, respectively. Plan quality was assessed with quality volume histogram (QVH). At each time point, plans were generated with a total of 3-4 plans for each patient. Deformable image registration was used for automatic contour propagation and dose summation of the 3 or 4 treatment plans (MIMvista(®)).
GTVPET segmentations were performed successfully until week 2 of RT but failed in two patients at week 3. QVH analysis showed high conformity for all plans (mean VQ = 0.95 93%; mean VQ = 1.05 3.9%; mean QF 2.2%). Good OAR sparing was achieved while keeping high plan quality.
Our results show that adaptive FDG-PET-based escalated dose painting in patients with locally advanced HNSCC is feasible while respecting strict dose constraints to organs at risk. Clinical studies must be conducted to evaluate toxicities and tumor response of such a strategy.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To assess the predictive value of hypoxia imaging by (18)F-FAZA PET in identifying tumors that may benefit from radiotherapy combined with nimorazole, a hypoxic radiosensitizer.
Material and methods:
Rats of two tumor models (Rhabdomyosarcoma and 9L-glioma) were divided into two treated groups: radiotherapy (RT) alone or RT plus nimorazole. (18)F-FAZA PET images were obtained to evaluate tumor hypoxia before the treatment. Treatment outcome was assessed through the tumor growth time assay, defined as the time required for tumor to grow to 1.5 times its size before irradiation.
For rhabdomyosarcomas, the benefit of adding nimorazole to RT was not significant when considering all tumors. When stratifying into more and less hypoxic tumors according to the median (18)F-FAZA T/B ratio, we found that the combined treatment significantly improved the response of the "more hypoxic" subgroup, while there was no significant difference in the tumor growth time between the two treatment modalities for the "less hypoxic" subgroup. For 9L-gliomas, a clear benefit was demonstrated for the group receiving RT+nimorazole. However, the individual responses within the RT+nimorazole group were highly variable and independent of the (18)F-FAZA uptake.
(18)F-FAZA PET may be useful to guide hypoxia-directed RT using nimorazole as radiosensitizer. It identified a subgroup of more hypoxic tumors (displaying T/B ratio>2.72) that would benefit from this combined treatment. Nevertheless, the predictive power was limited to rhabdomyosarcomas and ineffective for 9L-gliomas.
Radiotherapy and Oncology 01/2015; 114(2). DOI:10.1016/j.radonc.2014.12.015 · 4.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In locally advanced head and neck squamous cell carcinoma (HNSCC), the role of imaging becomes more and more critical in the management process. In this framework, molecular imaging techniques such as PET allow noninvasive assessment of a range of tumour biomarkers such as metabolism, hypoxia and proliferation, which can serve different purposes. First, in a pretreatment setting they can influence therapy selection strategies and target delineation for radiation therapy. Second, their predictive and/or prognostic value could help enhance the therapeutic ratio in the management of HNSCC. Third, treatment modification can be performed through the generation of a molecular-based heterogeneous dose distribution with dose escalation to the most resistant parts of the tumour, a concept known as dose painting. Fourth, they are increasingly becoming a tool for monitoring response to therapy. In this review, PET imaging biomarkers used in the routine management of HNSCC or under investigation are discussed.
European journal of nuclear medicine and molecular imaging 01/2015; 42(4). DOI:10.1007/s00259-014-2972-7 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To evaluate from a planning point of view the dose distribution of adaptive radiation dose escalation in head and neck squamous cell carcinoma (HNSCC) using (18)F-Fluoroazomycin arabinoside (FAZA) positron emission tomography/computed tomography (PET-CT).
Twelve patients with locally advanced HNSCC underwent three FAZA PET-CT before treatment, after 7 fractions and after 17 fractions of a carboplatin-5FU chemo-radiotherapy regimen (70 Gy in 2 Gy per fraction over 7 weeks). The dose constraints were that every hypoxic voxel delineated before and during treatment (newborn hypoxic voxels) should receive a total dose of 86 Gy. A median dose of 2.47 Gy per fraction was prescribed on the hypoxic PTV defined on the pre-treatment FAZA PET-CT; a median dose of 2.57 Gy per fraction was prescribed on the newborn voxels identified on the first per-treatment FAZA PET-CT; a median dose of 2.89 Gy per fraction was prescribed on the newborn voxels identified on the second per-treatment FAZA PET-CT.
Ten of 12 patients had hypoxic volumes. Six of 10 patients completed all the FAZA PET-CT during radiotherapy. For the hypoxic PTVs, the average D50% matched the prescribed dose within 2% and the homogeneity indices reached 0.10 and 0.12 for the nodal PTV 86 Gy and the primary PTV 86 Gy, respectively. Compared to a homogeneous 70 Gy mean dose to the PTVs, the dose escalation up to 86 Gy to the hypoxic volumes did not typically modify the dose metrics on the surrounding normal tissues.
From a planning point of view, FAZA-PET-guided dose adaptive escalation is feasible without substantial dose increase to normal tissues above tolerance limits. Clinical prospective studies, however, need to be performed to validate hypoxia-guided adaptive radiation dose escalation in head and neck carcinoma.