Tumor Subvolumes Research Articles

The individualization in radiotherapy: Where are we now, and where are we going?

The synonym of the best treatment method is individualization of the treatment. Based on a description of the characteristics of the patient, his or her disease, treatment volume, etc., the best method of irradiation is proposed. The individualization could be considered in terms of the individual dose distribution and individual fractionation. However, the dose distribution and the fractionation are usually treated separately. Currently the individualization of dose distribution, thanks to development of technology, is very advanced. Several methods of Intensity Modulation Radiotherapy allowed to conform the dose distribution to the actual anatomy. Dose-painting becomes a common method of treatment. Nevertheless, due to inherent characteristic of radiation used in radiotherapy, the ideal dose distribution can’t be obtained. Proton therapy does offer improved dose conformity, compared to IMRT. Another limitation in individualisation of the dose distribution is the lack of precise (description) delineation of the tumour. Several new imaging methods (positron-emission tomography and magnetic resonance) are very promising. According to Bentzen, we are able not only to conform the dose distribution to the individual anatomy but also to deliver some additional dose to tumour subvolumes with a potential resistance. To describe this type of treatment he coined a term of dose-painting by numbers. Another area for individualization is a time pattern of the dose delivery. Several randomized trials proved the importance of overall treatment time shortening to avoid rapid tumour cell proliferation. Patient-specific fractionation schedule optimization can improve the therapeutic index at least for some patients. The new imaging and molecular data and more reliable models of tumour dynamics may help in making radiotherapy more personalized.

Radiomics in cancer diagnosis, cancer staging, and prediction of response to treatment

In the same way that genomics describes the characterization of tumor phenotype using a wide and diverse array of genetic alterations (copy number, gene expression, methylation etc.), the term ‘radiomics’ refers to the characterization of tumor phenotypes based on a diverse array of image-derived, quantitative measurements (shape, morphology, intensity histogram, texture etc.). The image analysis tools used in radiomics build on those developed over the past decades for tasks such as computer-aided diagnosis of lung nodules and breast lesions. In radiomics these tools are applied to very large patient datasets to extract a multitude of image features, and statistical approaches are then used to analyze the data. Aside from mining aspects about tumor shape and size, more recent radiomics approaches aim to characterize the distribution of gray level intensities in the tumor region in two or three dimensions, through histogram or ‘texture’ analysis. Radiomic studies can be used to understand relationships between imaging characteristics of tumors, such as heterogeneity, and their genetic characteristics, phenotype, or expected treatment outcome. As with genetic analysis providing a glimpse of the multiple clones of tumor cells that comprise a tumor, radiomic analysis of tumor subvolumes or habitats within the tumor volume serves as an imaging metric of the heterogeneity of tumors.

Nanoparticle-aided external beam radiotherapy leveraging the Čerenkov effect

This study investigates the feasibility of exploiting the Čerenkov radiation (CR) present during external beam radiotherapy (EBRT) for significant therapeutic gain, using titanium dioxide (titania) nanoparticles (NPs) delivered via newly designed radiotherapy biomaterials. Using Monte Carlo radiation transport simulations, we calculated the total CR yield inside a tumor volume during EBRT compared to that of the radionuclides. We also considered a novel approach for intratumoral titania delivery using radiotherapy biomaterials (e.g. fiducials) loaded with NPs. The intratumoral distribution/diffusion of titania released from the fiducials was calculated. To confirm the CR induced enhancement in EBRT experimentally, we used 6MV radiation to irradiate human lung cancer cells with or without titania NPs and performed clonogenic assays. For a radiotherapy biomaterial loaded with 20μg/g of 2-nm titania NPs, at least 1μg/g could be delivered throughout a tumor sub-volume of 2-cm diameter after 14days. This concentration level could inflict substantial damage to cancer cells during EBRT. The Monte Carlo results showed the CR yield by 6MV radiation was higher than by the radionuclides of interest and hence greater damage might be obtained during EBRT. In vitro study showed significant enhancement with 6MV radiation and titania NPs. These preliminary findings demonstrate a potential new approach that can be used to take advantage of the CR present during megavoltage EBRT to boost damage to cancer cells. The results provide significant impetus for further experimental studies towards the development of nanoparticle-aided EBRT powered by the Čerenkov effect.

Identification des sites de récidive sur la TEP/TDM initiale dans les cancers des VADS traités par radiochimiothérapie

ObjectiveHead and neck squamous cell carcinoma (HNSCC) treated by radio-chemotherapy have a significant local recurrence rate. It has been previously suggested that 18F-FDG PET could identify the high uptake areas that can be potential targets for dose boosting. The purpose of this study was to compare the location of the initial hypermetabolic lesions and with the location of the relapses after radio-chemotherapy in HNSCC. Materials and methodsFifty-four HNSCC patients treated with radio-chemotherapy were retrospectively included in this analysis. A rigid registration was performed on both baseline and follow-up 18F-FDG PET-CT. Seven metabolic tumor sub-volumes were obtained on the baseline scans using a fixed percentage threshold of SUVmax (I30, I40, I50, I60, I70, I80, and I90) and were subsequently compared with two post-treatment sub-volumes (R40, R90) in cases of local recurrence or residual disease. Overlap fraction, Dice and Jaccard indices, common volume/baseline volume and common volume/recurrent volume were used to estimate the overlap of the different estimated sub-volumes. ResultsThe initial tumor volume was significantly higher for 18 patients with proven local recurrence or residual disease (21.2 cc vs. 11.2 cc; P=0.0005). The overlap between baseline and follow-up sub-volumes were moderate with an overlap fraction range from 0.25 to 0.4 for R40 and I30 to I60. ConclusionIn our study the overlap between baseline and post-therapeutic metabolic tumor sub-volumes was moderate. These preliminary results need to be investigated in a larger cohort with a more standardized repositioning method.

In vivo spatial correlation between 18F-BPA and 18F-FDG uptakes in head and neck cancer

Background and purposeBorono-2-18F-fluoro-phenylalanine (18F-BPA) has been used to estimate the therapeutic effects of boron neutron capture therapy (BNCT), while 18F-fluorodeoxyglucose (18F-FDG) is the most commonly used positron emission tomography (PET) radiopharmaceutical in a routine clinical use. The aim of the present study was to evaluate spatial correlation between 18F-BPA and 18F-FDG uptakes using a deformable image registration-based technique. Material and methodsTen patients with head and neck cancer were recruited from January 2014 to December 2014. All patients underwent whole-body 18F-BPA PET/computed tomography (CT) and 18F-FDG PET/CT within a 2-week period. For each patient, 18F-BPA PET/CT and 18F-FDG PET/CT images were aligned based on a deformable image registration framework. The voxel-by-voxel spatial correlation of standardized uptake value (SUV) within the tumor was analyzed. ResultsOur image processing framework achieved accurate and validated registration results for each PET/CT image. In 9/10 patients, the spatial distribution of SUVs between 18F-BPA and 18F-FDG showed a significant, positive correlation in the tumor volume. ConclusionsDeformable image registration-based voxel-wise analysis demonstrated a spatial correlation between 18F-BPA and 18F-FDG uptakes in the head and neck cancer. A tumor sub-volume with a high 18F-FDG uptake may predict high accumulation of 18F-BPA.

Multiparametric [18F]Fluorodeoxyglucose/ [18F]Fluoromisonidazole Positron Emission Tomography/ Magnetic Resonance Imaging of Locally Advanced Cervical Cancer for the Non-Invasive Detection of Tumor Heterogeneity: A Pilot Study.

ObjectivesTo investigate fused multiparametric positron emission tomography/magnetic resonance imaging (MP PET/MRI) at 3T in patients with locally advanced cervical cancer, using high-resolution T2-weighted, contrast-enhanced MRI (CE-MRI), diffusion-weighted imaging (DWI), and the radiotracers [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoromisonidazol ([18F]FMISO) for the non-invasive detection of tumor heterogeneity for an improved planning of chemo-radiation therapy (CRT).Materials and MethodsSixteen patients with locally advanced cervix were enrolled in this IRB approved and were examined with fused MP [18F]FDG/ [18F]FMISO PET/MRI and in eleven patients complete data sets were acquired. MP PET/MRI was assessed for tumor volume, enhancement (EH)-kinetics, diffusivity, and [18F]FDG/ [18F]FMISO-avidity. Descriptive statistics and voxel-by-voxel analysis of MRI and PET parameters were performed. Correlations were assessed using multiple correlation analysis.ResultsAll tumors displayed imaging parameters concordant with cervix cancer, i.e. type II/III EH-kinetics, restricted diffusivity (median ADC 0.80x10-3mm2/sec), [18F]FDG- (median SUVmax16.2) and [18F]FMISO-avidity (median SUVmax3.1). In all patients, [18F]FMISO PET identified the hypoxic tumor subvolume, which was independent of tumor volume. A voxel-by-voxel analysis revealed only weak correlations between the MRI and PET parameters (0.05–0.22), indicating that each individual parameter yields independent information and the presence of tumor heterogeneity.ConclusionMP [18F]FDG/ [18F]FMISO PET/MRI in patients with cervical cancer facilitates the acquisition of independent predictive and prognostic imaging parameters. MP [18F]FDG/ [18F]FMISO PET/MRI enables insights into tumor biology on multiple levels and provides information on tumor heterogeneity, which has the potential to improve the planning of CRT.

FDG-PET-based differential uptake volume histograms: a possible approach towards definition of biological target volumes.

Integration of fluorine-18 fludeoxyglucose ((18)F-FDG)-positron emission tomography (PET) functional data into conventional anatomically based gross tumour volume delineation may lead to optimization of dose to biological target volumes (BTV) in radiotherapy. We describe a method for defining tumour subvolumes using (18)F-FDG-PET data, based on the decomposition of differential uptake volume histograms (dUVHs). For 27 patients with histopathologically proven non-small-cell lung carcinoma (NSCLC), background uptake values were sampled within the healthy lung contralateral to a tumour in those image slices containing tumour and then scaled by the ratio of mass densities between the healthy lung and tumour. Signal-to-background (S/B) uptake values within volumes of interest encompassing the tumour were used to reconstruct the dUVHs. These were subsequently decomposed into the minimum number of analytical functions (in the form of differential uptake values as a function of S/B) that yielded acceptable net fits, as assessed by χ(2) values. Six subvolumes consistently emerged from the fitted dUVHs over the sampled volume of interest on PET images. Based on the assumption that each function used to decompose the dUVH may correspond to a single subvolume, the intersection between the two adjacent functions could be interpreted as a threshold value that differentiates them. Assuming that the first two subvolumes spread over the tumour boundary, we concentrated on four subvolumes with the highest uptake values, and their S/B thresholds [mean ± standard deviation (SD)] were 2.88 ± 0.98, 4.05 ± 1.55, 5.48 ± 2.06 and 7.34 ± 2.89 for adenocarcinoma, 3.01 ± 0.71, 4.40 ± 0.91, 5.99 ± 1.31 and 8.17 ± 2.42 for large-cell carcinoma and 4.54 ± 2.11, 6.46 ± 2.43, 8.87 ± 5.37 and 12.11 ± 7.28 for squamous cell carcinoma, respectively. (18)F-FDG-based PET data may potentially be used to identify BTV within the tumour in patients with NSCLC. Using the one-way analysis of variance statistical tests, we found a significant difference among all threshold levels among adenocarcinomas, large-cell carcinoma and squamous cell carcinomas. On the other hand, the observed significant variability in threshold values throughout the patient cohort (expressed as large SDs) can be explained as a consequence of differences in the physiological status of the tumour volume for each patient at the time of the PET/CT scan. This further suggests that patient-specific threshold values for the definition of BTVs could be determined by creation and curve fitting of dUVHs on a patient-by-patient basis. The method of (18)F-FDG-PET-based dUVH decomposition described in this work may lead to BTV segmentation in tumours.

Personalized precision radiotherapy by integration of multi-parametric functional and biological imaging in prostate cancer: A feasibility study

BackgroundTo increase tumour control probability (TCP) in prostate cancer a method was developed integrating multi-parametric functional and biological information into a dose painting treatment plan aiming focal dose-escalation to tumour sub-volumes. A dose-escalation map was derived considering individual, multi-parametric estimated tumour aggressiveness. Methods and MaterialsMulti-parametric functional imaging (MRI, Choline-/PSMA-/FMISO-PET/CT) was acquired for a high risk prostate cancer patient with a high level of tumour load (cT3b cN0 cM0) indicated by subtotal involvement of prostate including the right seminal vesicle and by PSA-level >100. Probability of tumour presence was determined by a combination of multi-parametric functional image information resulting in a voxel-based map of tumour aggressiveness. This probability map was directly integrated into dose optimization in order to plan for inhomogeneous, biological imaging based dose painting.Histograms of the multi-parametric prescription function were generated in addition to a differential histogram of the planned inhomogeneous doses. Comparison of prescribed doses with planned doses on a voxel level was realized using an effective DVH, containing the ratio of prescribed vs. planned dose for each tumour voxel. ResultsMulti-parametric imaging data of PSMA, Choline and FMISO PET/CT as well as ADC maps derived from diffusion weighted MRI were combined to an individual probability map of tumour presence. Voxel-based prescription doses ranged from 75.3Gy up to 93.4Gy (median: 79.6Gy), whereas the planned dose painting doses varied only between 72.5 and 80.0Gy with a median dose of 75.7Gy. However, inhomogeneous voxel-based dose prescriptions can only be implemented into a treatment plan until a certain level. ConclusionMulti-parametric probability based dose painting in prostate cancer is technically and clinically feasible. However, detailed calibration functions to define the necessary probability functions need to be assessed in future clinical trials.

Highlights of This Issue

Immunotherapy with ipilimumab improves the survival of only around 20% of patients with metastatic melanoma. To explore reliable markers for the prediction of clinical outcome, Gebhardt and colleagues analyzed myeloid cells and related inflammatory factors in the peripheral blood of treated patients. Response to the therapy was associated with an early increase in eosinophil count, whereas nonresponders showed elevated amounts and function of circulating monocytic myeloid-derived suppressor cells as well as increased serum levels of S100A8/A9 and HMGB1. These novel complex predictive markers could help to identify metastatic melanoma patients who benefit from the ipilimumab therapy.The identification of biomarkers that early predicts the chemosensitivity of triple-negative breast cancers (TNBC) to standard neoadjuvant chemotherapy (NAC) is an important issue. Indeed, poorly responding women may be good candidates for emerging targeted therapy. Humbert and colleagues studied the predictive value of 18FDG-PET compared with clinicobiologic markers of TNBC. The authors demonstrated that combining positive EGFR status and a low 18FDG-PET tumor response after the first cycle of NAC can predict residual invasive carcinoma at the end of treatment. Multicenter trials using PET-guided treatment strategies are now necessary to evaluate the benefit of early therapeutic changes in poorly responding women.Clinical studies have demonstrated that tumor relapse after radiotherapy occurs preferentially in tumor areas with high 18F-fluorodeoxyglucose (FDG) uptake. To test the therapeutic gain from radiation dose escalation to the potentially radioresistant tumor subvolumes with high FDG, Trani and colleagues employed dose painting approaches in rat rhabdomyosarcoma: targeted dose escalation and dose redistribution. Although dose escalation to high FDG uptake was not superior to the same dose increase in low FDG uptake subvolumes, dose redistribution was even detrimental, consistent with the hypothesis that tumor response depends on the minimum intratumoral dose. These findings provide important information for the design of clinical trials.In HER2/ERBB2-amplified gastrointestinal tumors, concomitant HER2 targeting by trastuzumab antibody and the reversible inhibitor lapatinib is more effective than either agent alone. The mechanisms of this cooperation are unknown. Leto and colleagues found that trastuzumab and lapatinib complement each other to induce sustained neutralization of HER2 and its signaling partners HER3 and EGFR. This durable inhibition, which accounts for massive tumor shrinkage, is recapitulated by monotherapy with the HER2 irreversible inhibitor afatinib. These results provide functional evidence for the collaborative activity of trastuzumab and lapatinib and propose afatinib treatment as a means to diversify therapeutic opportunities in HER2-amplified gastrointestinal carcinomas.

Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake.

We tested therapeutic efficacy of two dose painting strategies of applying higher radiation dose to tumor subvolumes with high FDG uptake (biologic target volume, BTV): dose escalation and dose redistribution. We also investigated whether tumor response was determined by the highest dose in BTV or the lowest dose in gross tumor volume (GTV). FDG uptake was evaluated in rat rhabdomyosarcomas prior to irradiation. BTV was defined as 30% of GTV with the highest (BTVhot) or lowest (BTVcold) uptake. To test efficacy of dose escalation, tumor response (time to reach two times starting tumor volume, TGTV2) to Hot Boost irradiation (40% higher dose to BTVhot) was compared with Cold Boost (40% higher dose to BTVcold), while mean dose to GTV remained 12 Gy. To test efficacy of dose redistribution, TGTV2 after Hot Boost was compared with uniform irradiation with the same mean dose (8 or 12 Gy). TGTV2 after 12 Gy delivered heterogeneously (Hot and Cold Boost) or uniformly were not significantly different: 20.2, 19.5, and 20.6 days, respectively. Dose redistribution (Hot Boost) with 8 Gy resulted in faster tumor regrowth as compared with uniform irradiation (13.3 vs. 17.1 days; P = 0.026). Further increase in dose gradient to 60% led to a more pronounced decrease in TGTV2 (10.9 days; P < 0.0001). Dose escalation effect was independent of FDG uptake in target tumor volume, while dose redistribution was detrimental in this tumor model for dose levels applied here. Our data are consistent with the hypothesis that tumor response depends on the minimum intratumoral dose.

Advances in Radiotherapy for Head and Neck Cancer.

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.

Spatial distribution of FMISO in head and neck squamous cell carcinomas during radio-chemotherapy and its correlation to pattern of failure

ABSTRACTBackground. Tumour hypoxia can be measured by FMISO-PET and negatively impacts local tumour control in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The aim of this post hoc analysis of a prospective clinical trial was to investigate the spatial variability of FMISO hypoxic subvolumes during radio-chemotherapy and the co-localisation of these volumes with later recurrences as a basis for individualised dose prescription trials with dose escalation defined by FMISO-PET.Methods. Sequential FMISO scans of 12 (of 25) patients presenting residual hypoxia taken before (FMISOpre) and during (FMISOw1–FMISOw5) radio-chemotherapy were analysed regarding the stability of the FMISO subvolumes and, in case of local failure, their correlation to local relapse.Results. Consecutive FMISO-PET positive volumes could be classified as moderately stable with Dice conformity indices of 62% and 58% up to the second week of treatment. Substantial volumetric variation during treatment was observed, with more than 20% geographic miss in all patients and more than 40% in half of the patients. The localisation of the maximum standardised uptake value (SUVmax) differed with a mean distance of 7.0 mm and 13.5 mm between the pre-therapeutic and first or second FMISO-PET during treatment. A stable hypoxic consensual volume (i.e. overlap of pre-therapeutic FMISO and intra-treatment FMISO subvolumes up to week two, generated by different contouring methods) was determined for six patients with imaging information of local recurrence. Three of these six local recurrences were located within this consensual volume.Conclusions. Our data suggest that selective dose painting to hypoxic tumour subvolumes requires adaptation during treatment and sufficient margins. An alternative strategy is to escalate the dose to the gross tumour volume, accepting lesser escalation of dose outside hypoxic areas if indicated by constraints for organs at risk.

Predicting location of recurrence using FDG, FLT, and Cu-ATSM PET in canine sinonasal tumors treated with radiotherapy

Dose painting relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. This work assessed the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of residual FDG PET in canine tumors following radiotherapy. Nineteen canines with spontaneous sinonasal tumors underwent PET/CT imaging with radiotracers FDG, FLT, and Cu-ATSM prior to hypofractionated radiotherapy. Therapy consisted of 10 fractions of 4.2 Gy to the sinonasal cavity with or without an integrated boost of 0.8 Gy to the GTV. Patients had an additional FLT PET/CT scan after fraction 2, a Cu-ATSM PET/CT scan after fraction 3, and follow-up FDG PET/CT scans after radiotherapy. Following image registration, simple and multiple linear and logistic voxel regressions were performed to assess how well pre- and mid-treatment PET imaging predicted post-treatment FDG uptake. R2 and pseudo R2 were used to assess the goodness of fits. For simple linear regression models, regression coefficients for all pre- and mid-treatment PET images were significantly positive across the population (P < 0.05). However, there was large variability among patients in goodness of fits: R2 ranged from 0.00 to 0.85, with a median of 0.12. Results for logistic regression models were similar. Multiple linear regression models resulted in better fits (median R2 = 0.31), but there was still large variability between patients in R2. The R2 from regression models for different predictor variables were highly correlated across patients (R ≈ 0.8), indicating tumors that were poorly predicted with one tracer were also poorly predicted by other tracers. In conclusion, the high inter-patient variability in goodness of fits indicates that PET was able to predict locations of residual tumor in some patients, but not others. This suggests not all patients would be good candidates for dose painting based on a single biological target.

TH‐AB‐304‐03: Tumor Control Probability Applied to Lung Cancer: A Statistical Test of the Independence of Voxel Response

Purpose:Conventional radiotherapy planning uses simplified DVH‐derived metrics (e.g. D99, D95) as surrogates for tumor control probability when evaluating plan quality. While this has the advantage of providing an easily derived predictor variable, such metrics fail to consider critical aspects of the underlying radiobiology. Counter to observed radiobiological effects, there is a prevailing assumption of tumor subvolume independence. We tested this by introducing a parameter to capture departures from independence using a modified metric, termed the “generalized tumor dose” (gTD).Methods:For given dose distributions, cell survival was derived from a comprehensive biological model (Jeong, 2013 Phys. Med. Biol.). The gTD metric applied a generalized mean term, q, to subvolume survival values, with this term optimized according to its predictive power over the NSCLS cohort (N=316). Patients were treated 1.8–2.2 Gy/Fx in 28–39 Fxs (n=50), or 2.75 Gy/Fx in 24 fractions (n=266). Results were compared to other metrics according binary outcome and actuarial survival prediction.Results:Fitting model parameters to combined cohort data using log‐likelihood and actuarial methods, we derived an optimized generalized mean parameter q of −1.14 (95% confidence interval upper bound=0.08). Patient‐specific gTD values derived using this value showed superior performance to other clinical metrics. For gTD, normalized log‐likelihood=−0.471, AUC=0.634, and R^2=0.066, versus normalized log‐likelihood=−0.508/−0.504, AUC=0.473/0.462, and R^2=0.0011/0.0014 for D99/D95. Furthermore, when q wasn't incorporated into the model (q=1, implicitly), AUC decreased to 0.622, normalized log‐likelihood to −0.501 and R^2 to 0.0144.Conclusion:Negative q values suggest areas of highest dose play a greater role in determining outcome than expected based only on TCP.The biological origin of this effect could be of several potential causes, including bystander effects, genomic intra‐tumor heterogeneity, or tumor shrinkage. Accounting for these interactions, the gTD metric provides superior accuracy as a predictor of outcome.

SU‐E‐T‐750: Three Dimensional in Silico Study of Brachytherapy Application with In‐Situ Dose‐Painting Administered Via Gold‐Nanoparticle Eluters

Purpose:Brachytherapy Application with in‐situ Dose‐painting Administered via Gold‐Nanoparticle Eluters (BANDAGE) has been proposed as a new therapeutic strategy for radiation boosting of high‐risk prostate tumor subvolume while minimizing dose to neighboring organs‐at‐risk. In a previous study the one‐dimensional dose‐painting with gold nanoparticles (GNP) released from GNP‐loaded brachytherapy spacers was investigated. The current study investigates BANDAGE in three‐dimensions.Methods:To simulate GNPs transport in prostrate tumors, a three dimensional, cylindrically symmetric transport model was generated using a finite element method (FEM). A mathematical model of Gold nanoparticle (GNPs) transport provides a useful strategy to optimize potential treatment planning for BANDAGE. Here, treatment of tumors with a radius of 2.5 cm was simulated in 3‐D. This simulation phase considered one gold based cylindrical spacer (GBS of size 5mm × 0.8 mm) introduced at the center of the spherical tumor with initial concentration of 100 mg/g or 508 mol/m3 of GNP. Finite element mesh is used to stimulate the GNP transport. Gold concentrations within the tumor were obtained using a 3‐D FEM solution implemented by COMSOL.Results:The analysis shows the spread of the GNPs through‐out the tumor with the increase of concentration towards the periphery with time. The analysis also shows the concentration profiles and corresponding dose enhancement factors (dose boost factor) as a function of GNP size.Conclusion:This study demonstrates the use of computational modeling and optimal parameter estimation to predict local GNPs from central implant as a function of x, y and z axis . Such a study provides a useful reference for ongoing translational studies for the BANDAGE approach

PD-0144: Classification of tumor sub-volumes based on Dynamic Contrast Enhanced MRI model hierarchy for cervical cancer

PD-0144: Classification of tumor sub-volumes based on Dynamic Contrast Enhanced MRI model hierarchy for cervical cancer

High FDG uptake areas on pre-radiotherapy PET/CT identify preferential sites of local relapse after chemoradiotherapy for locally advanced oesophageal cancer.

The high failure rates in the radiotherapy (RT) target volume suggest that patients with locally advanced oesophageal cancer (LAOC) would benefit from increased total RT doses. High 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake (hotspot) on pre-RT FDG positron emission tomography (PET)/CT has been reported to identify intra-tumour sites at increased risk of relapse after RT in non-small cell lung cancer and in rectal cancer. Our aim was to confirm these observations in patients with LAOC and to determine the optimal maximum standardized uptake value (SUVmax) threshold to delineate smaller RT target volumes that would facilitate RT dose escalation without impaired tolerance. The study included 98 consecutive patients with LAOC treated by chemoradiotherapy (CRT). All patients underwent FDG PET/CT at initial staging and during systematic follow-up in a single institution. FDG PET/CT acquisitions were coregistered on the initial CT scan. Various subvolumes within the initial tumour (30, 40, 50, 60, 70, 80 and 90% SUVmax thresholds) and in the subsequent local recurrence (LR, 40 and 90% SUVmax thresholds) were pasted on the initial CT scan and compared[Dice, Jaccard, overlap fraction (OF), common volume/baseline volume, common volume/recurrent volume]. Thirty-five patients had LR. The initial metabolic tumour volume was significantly higher in LR tumours than in the locally controlled tumours (mean 25.4 vs 14.2 cc; p = 0.002). The subvolumes delineated on initial PET/CT with a 30-60% SUVmax threshold were in good agreement with the recurrent volume at 40% SUVmax (OF = 0.60-0.80). The subvolumes delineated on initial PET/CT with a 30-60% SUVmax threshold were in good to excellent agreement with the core volume (90% SUVmax) of the relapse (common volume/recurrent volume and OF indices 0.61-0.89). High FDG uptake on pretreatment PET/CT identifies tumour subvolumes that are at greater risk of recurrence after CRT in patients with LAOC. We propose a 60% SUVmax threshold to delineate high FDG uptake areas on initial PET/CT as reduced target volumes for RT dose escalation.

Areas of high 18F-FDG uptake on preradiotherapy PET/CT identify preferential sites of local relapse after chemoradiotherapy for non-small cell lung cancer.

The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non-small cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. Areas of high (18)F-FDG uptake on preradiotherapy (18)F-FDG PET/CT have been reported to identify intratumor subvolumes at high risk of relapse after radiotherapy. We wanted to confirm these observations on a cohort of patients included in 3 sequential prospective studies. Our aim was to assess an appropriate threshold (percentage of maximum standardized uptake value [SUVmax]) to delineate subvolumes on staging (18)F-FDG PET/CT scans assuming that a smaller target volume would facilitate isotoxic radiotherapy dose escalation. Thirty-nine patients with inoperable stage II or III NSCLC, treated with chemoradiation or with radiotherapy alone, were extracted from 3 prospective studies (ClinicalTrials.gov identifiers NCT01261585, NCT01261598, and RECF0645). All patients underwent (18)F-FDG PET/CT at initial staging, before radiotherapy, during radiotherapy, and during systematic follow-up in a single institution. All (18)F-FDG PET/CT acquisitions were coregistered on the initial scan. Various subvolumes in the initial acquisition (30%, 40%, 50%, 60%, 70%, 80%, and 90% SUVmax thresholds) and in the 3 subsequent acquisitions (40% and 90% SUVmax thresholds) were pasted on the initial scan and compared. Seventeen patients had a local relapse. The SUVmax measured during radiotherapy was significantly higher in locally relapsed tumors than in locally controlled tumors (mean, 6.8 vs. 4.6; P = 0.02). The subvolumes delineated on initial PET/CT scans with 70%-90% SUVmax thresholds were in good agreement with the recurrent volume at a 40% SUVmax threshold (common volume/baseline volume, 0.60-0.80). The subvolumes delineated on initial PET/CT scans with 30%-60% SUVmax thresholds were in good to excellent agreement with the core volume of the relapse (90% SUVmax threshold) (common volume/recurrent volume and overlap fraction indices, 0.60-0.93). The agreement was moderate (>0.51) when a 70% SUVmax threshold was used to delineate on initial PET/CT scans. High (18)F-FDG uptake areas on pretreatment PET/CT scans identify tumor subvolumes at greater risk of relapse in patients with NSCLC treated by concomitant chemoradiation. We propose a 70% SUVmax threshold to delineate areas of high (18)F-FDG uptake on initial PET/CT scans as the target volumes for potential radiotherapy dose escalation.

A Software App for Radiotherapy with In-situ Dose-painting using high Z nanoparticles.

The purpose of this work is to develop an user friendly and free-to-download application software that can be employed for modeling Radiotherapy with In-situ Dose-painting (RAID) using high-Z nanoparticles (HZNPs). The RAID APP is software program written in Matlab (Mathworks, Natick, MA, USA) based on deterministic code developed to simulate the space-time intra-tumor HZNPs biodistribution within the tumor, and the corresponding dose enhancement in response to low dose rate (LDR) brachytherapy of I-125, Pd-102, Cs-131 and kilovoltage x-rays such as 50 keV and 100 keV. Through the GUI of RAID APP, the user will be directed to different features to compute various parameters related to the dose enhancement and the biodistribution of NPs within high risk tumor sub-volumes. The software was developed as tool for research purposes with potential for subsequent development to guide dose-painting treatment planning using radiosensitizers such as gold (Au) and platinum (Pt).

Brachytherapy Application With In Situ Dose Painting Administered by Gold Nanoparticle Eluters

Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS). An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131). Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125. Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.