Stephen R. Bowen

Intensity-modulated x-ray (IMXT) versus proton (IMPT) therapy for theragnostic hypoxia-based dose painting

In this work the abilities of intensity-modulated x-ray therapy (IMXT) and intensity-modulated proton therapy (IMPT) to deliver boosts based on theragnostic imaging were assessed. Theragnostic imaging is the use of functional or molecular imaging data for prescribing radiation dose distributions. Distal gradient tracking, an IMPT method designed for the delivery of non-uniform dose distributions, was assessed. Dose prescriptions for a hypoxic region in a head and neck squamous cell carcinoma patient were designed to either uniformly boost the region or redistribute the dose based on positron emission tomography (PET) images of the (61)Cu(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) ((61)Cu-ATSM) hypoxia surrogate. Treatment plans for the prescriptions were created for four different delivery methods: IMXT delivered with step-and-shoot and with helical tomotherapy, and IMPT delivered with spot scanning and distal gradient tracking. IMXT and IMPT delivered comparable dose distributions within the boost region for both uniform and redistributed theragnostic boosts. Normal tissue integral dose was lower by a factor of up to 3 for IMPT relative to the IMXT. For all delivery methods, the mean dose to the nearby organs at risk changed by less than 2 Gy for redistributed versus uniform boosts. The distal gradient tracking method resulted in comparable plans to the spot scanning method while reducing the number of proton beam spots by a factor of over 3.

On the sensitivity of IMRT dose optimization to the mathematical form of a biological imaging-based prescription function

Voxel-based prescriptions of deliberately non-uniform dose distributions based on molecular imaging, so-called dose painting or theragnostic radiation therapy, require specification of a transformation that maps the image data intensities to prescribed doses. However, the functional form of this transformation is currently unknown. An investigation into the sensitivity of optimized dose distributions resulting from several possible prescription functions was conducted. Transformations between the radiotracer activity concentrations from Cu-ATSM PET images, as a surrogate of tumour hypoxia, and dose prescriptions were implemented to yield weighted distributions of prescribed dose boosts in high uptake regions. Dose escalation was constrained to reflect clinically realistic whole tumour doses and constant normal tissue doses. Optimized heterogeneous dose distributions were found by minimizing a voxel-by-voxel quadratic objective function in which all tumour voxels were given equal weight. Prescriptions based on a polynomial mapping function were found to be least constraining on their optimized plans, while prescriptions based on a sigmoid mapping function were the most demanding to deliver. A prescription formalism that fixed integral dose was less sensitive to errors in the choice of the mapping function than one that boosted integral dose. Integral doses to normal tissue and critical structures were insensitive to the shape of the prescription function. Planned target dose conformity improved with smaller beamlet dimensions until the inherent spatial resolution of the functional image was matched. Clinical implementation of dose painting depends on advances in absolute quantification of functional images and improvements in delivery techniques over smaller spatial scales.

Quantitative radiomics: impact of stochastic effects on textural feature analysis implies the need for standards

Abstract. Image heterogeneity metrics such as textural features are an active area of research for evaluating clinical outcomes with positron emission tomography (PET) imaging and other modalities. However, the effects of stochastic image acquisition noise on these metrics are poorly understood. We performed a simulation study by generating 50 statistically independent PET images of the NEMA IQ phantom with realistic noise and resolution properties. Heterogeneity metrics based on gray-level intensity histograms, co-occurrence matrices, neighborhood difference matrices, and zone size matrices were evaluated within regions of interest surrounding the lesions. The impact of stochastic variability was evaluated with percent difference from the mean of the 50 realizations, coefficient of variation and estimated sample size for clinical trials. Additionally, sensitivity studies were performed to simulate the effects of patient size and image reconstruction method on the quantitative performance of these metrics. Complex trends in variability were revealed as a function of textural feature, lesion size, patient size, and reconstruction parameters. In conclusion, the sensitivity of PET textural features to normal stochastic image variation and imaging parameters can be large and is feature-dependent. Standards are needed to ensure that prospective studies that incorporate textural features are properly designed to measure true effects that may impact clinical outcomes.

Characterization of positron emission tomography hypoxia tracer uptake and tissue oxygenation via electrochemical modeling

PURPOSE Unique uptake and retention mechanisms of positron emission tomography (PET) hypoxia tracers make in vivo comparison between them challenging. Differences in imaged uptake of two common hypoxia radiotracers, [(61)Cu]Cu-ATSM and [(18)F]FMISO, were characterized via computational modeling to address these challenges. MATERIALS AND METHODS An electrochemical formalism describing bioreductive retention mechanisms of these tracers under steady-state conditions was adopted to relate time-averaged activity concentration to tissue partial oxygen tension (PO(2)), a common metric of hypoxia. Chemical equilibrium constants of product concentration to reactant concentration ratios were determined from free energy changes and reduction potentials of pertinent reactions reported in the literature. Resulting transformation functions between tracer uptake and PO(2) were compared against measured values in preclinical models. Additionally, calculated PO(2) distributions from imaged Cu-ATSM tracer activity concentrations of 12 head and neck squamous cell carcinoma (HNSCC) patients were validated against microelectrode PO(2) measurements in 69 HNSCC patients. RESULTS Both Cu-ASTM- and FMISO-modeled PO(2) transformation functions were in agreement with preclinical measured values within single-deviation confidence intervals. High correlation (r(2)=0.94, P<.05) was achieved between modeled PO(2) distributions and measured distributions in the patient populations. On average, microelectrode hypoxia thresholds (2.5 and 5.0 mmHg) corresponded to higher Cu-ATSM uptake [2.5 and 2.0 standardized uptake value (SUV)] and lower FMISO uptake (2.0 and 1.4 SUV). Uncertainties in the models were dominated by variations in the estimated specific activity and intracellular acidity. CONCLUSIONS Results indicated that the high dynamic range of Cu-ATSM uptake was representative of a narrow range of low oxygen tension whose values were dependent on microenvironment acidity, while FMISO uptake was representative of a wide range of PO(2) values that were independent of acidity. The models shed light on possible causes of these discrepancies, particularly as it pertains to image contrast, and may prove to be a useful methodology in quantifying relationships between other hypoxia tracers. Comprehensive and robust assessment of tumor hypoxia prior to as well as in response to therapy may be best provided by imaging of multiple hypoxia markers that provide complementary rather than interchangeable information.

Feasibility and sensitivity study of helical tomotherapy for dose painting plans

Abstract Important limitations for dose painting are due to treatment planning and delivery constraints. The purpose of this study was to develop a methodology for creating voxel-based dose painting plans that are deliverable using the clinical TomoTherapy Hi-Art II treatment planning system (TPS). Material and methods. Uptake data from a head and neck patient who underwent a [61Cu]Cu-ATSM (hypoxia surrogate) PET/CT scan was retrospectively extracted for planning. Non-uniform voxel-based prescriptions were converted to structured-based prescriptions for compatibility with the Hi-Art II TPS. Optimized plans were generated by varying parameters such as dose level, structure importance, prescription point normalization, DVH volume, min/max dose, and dose penalty. Delivery parameters such as pitch, jaw width and modulation factor were also varied. Isodose distributions, quality volume histograms and planning target volume percentage receiving planned dose within 5% of the prescription (Q0.95–1.05) were used to evaluate plan conformity. Results. In general, the conformity of treatment plans to dose prescriptions was found to be adequate for delivery of dose painting plans. The conformity was better as the dose levels increased from three to nine levels (Q0.95–1.05: 69% to 93%), jaw decreased in width from 5.0cm to 1.05cm (Q0.95–1.05: 81% to 93%), and modulation factor increased up to 2.0 (Q0.95–1.05: 36% to 92%). The conformity was invariant to changes in pitch. Plan conformity decreased as the prescription DVH constraint (Q0.95–1.05: 93% vs. 89%) or the normalization point (Q0.95–1.05: 93% vs. 90%) deviated from the means. Conclusion. This investigation demonstrated the ability of the Hi-Art II TPS to create voxel-based dose painting plans. Results indicated that agreement in prescription dose and planned dose distributions for all plans were sensitive to physical delivery parameter changes in jaw width and modulation factors, but insensitive to changes in pitch. Tight constraints on target structures also resulted in decreased plan conformity while under a relaxed set of optimization parameters, plan conformity was increased.

Challenges and opportunities in patient-specific, motion-managed and PET/CT-guided radiation therapy of lung cancer: review and perspective

The increasing interest in combined positron emission tomography (PET) and computed tomography (CT) to guide lung cancer radiation therapy planning has been well documented. Motion management strategies during treatment simulation PET/CT imaging and treatment delivery have been proposed to improve the precision and accuracy of radiotherapy. In light of these research advances, why has translation of motion-managed PET/CT to clinical radiotherapy been slow and infrequent? Solutions to this problem are as complex as they are numerous, driven by large inter-patient variability in tumor motion trajectories across a highly heterogeneous population. Such variation dictates a comprehensive and patient-specific incorporation of motion management strategies into PET/CT-guided radiotherapy rather than a one-size-fits-all tactic. This review summarizes challenges and opportunities for clinical translation of advances in PET/CT-guided radiotherapy, as well as in respiratory motion-managed radiotherapy of lung cancer. These two concepts are then integrated into proposed patient-specific workflows that span classification schemes, PET/CT image formation, treatment planning, and adaptive image-guided radiotherapy delivery techniques.

Heterogeneity in Intratumor Correlations of 18F-FDG, 18F-FLT, and 61Cu-ATSM PET in Canine Sinonasal Tumors

Intratumor heterogeneity in biologic properties and in relationships between various phenotypes may present a challenge for biologically targeted therapies. Understanding the relationships between different phenotypes in individual tumor types could help inform treatment selection. The goal of this study was to characterize spatial correlations of glucose metabolism, proliferation, and hypoxia in 2 histologic types of tumors. Methods: Twenty canine veterinary patients with spontaneously occurring sinonasal tumors (13 carcinomas and 7 sarcomas) were imaged with 18F-FDG, 18F-labeled 3′-deoxy-3′-fluorothymidine (18F-FLT), and 61Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) (61Cu-ATSM) PET/CT on 3 consecutive days. Precise positioning and immobilization techniques coupled with anesthesia enabled motionless scans with repeatable positioning. Standardized uptake values (SUVs) of gross sarcoma and carcinoma volumes were compared by use of Mann–Whitney U tests. Patient images were rigidly registered together, and intratumor tracer uptake distributions were compared. Voxel-based Spearman correlation coefficients were used to quantify intertracer correlations, and the correlation coefficients of sarcomas and carcinomas were compared. The relative overlap of the highest uptake volumes of the 3 tracers was quantified, and the values were compared for sarcomas and carcinomas. Results: Large degrees of heterogeneity in SUV measures and phenotype correlations were observed. Carcinoma and sarcoma tumors differed significantly in SUV measures, with carcinoma tumors having significantly higher 18F-FDG maximum SUVs than sarcoma tumors (11.1 vs. 5.0; P = 0.01) as well as higher 61Cu-ATSM mean SUVs (2.6 vs. 1.2; P = 0.02). Carcinomas had significantly higher population-averaged Spearman correlation coefficients than sarcomas in comparisons of 18F-FDG and 18F-FLT (0.80 vs. 0.61; P = 0.02), 18F-FLT and 61Cu-ATSM (0.83 vs. 0.38; P < 0.0001), and 18F-FDG and 61Cu-ATSM (0.82 vs. 0.69; P = 0.04). Additionally, the highest uptake volumes of the 3 tracers had significantly greater overlap in carcinomas than in sarcomas. Conclusion: The relationships of glucose metabolism, proliferation, and hypoxia were heterogeneous across different tumors, with carcinomas tending to have high correlations and sarcomas having low correlations. Consequently, canine carcinoma tumors are robust targets for therapies that target a single biologic property, whereas sarcoma tumors may not be well suited for such therapies. Histology-specific PET correlations have far-reaching implications for the robustness of biologic target definition.

Spatially resolved regression analysis of pre-treatment FDG, FLT and Cu-ATSM PET from post-treatment FDG PET: An exploratory study

PURPOSE To quantify associations between pre-radiotherapy and post-radiotherapy PET parameters via spatially resolved regression. MATERIALS AND METHODS Ten canine sinonasal cancer patients underwent PET/CT scans of [(18)F]FDG (FDG(pre)), [(18)F]FLT (FLT(pre)), and [(61)Cu]Cu-ATSM (Cu-ATSM(pre)). Following radiotherapy regimens of 50 Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at 3 months (FDG(post)). Regression of standardized uptake values in baseline FDG(pre), FLT(pre) and Cu-ATSM(pre) tumour voxels to those in FDG(post) images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R(2). Hypothesis testing of coefficients over the patient population was performed. RESULTS Multivariate linear model fits of FDG(pre) to FDG(post) were significantly positive over the population (FDG(post) ~ 0.17 · FDG(pre), p = 0.03), and classified slopes of RECIST non-responders and responders to be different (0.37 vs. 0.07, p = 0.01). Generalized-linear model fits related FDG(pre) to FDG(post) by a linear power law (FDG(post) ~ FDG(pre)(0.93),p<0.001). Univariate mixture model fits of FDG(pre) improved R(2) from 0.17 to 0.52. Neither baseline FLT PET nor Cu-ATSM PET uptake contributed statistically significant multivariate regression coefficients. CONCLUSIONS Spatially resolved regression analysis indicates that pre-treatment FDG PET uptake is most strongly associated with three-month post-treatment FDG PET uptake in this patient population, though associations are histopathology-dependent.

Dosimetric evaluation of a commercial proton spot scanning Monte-Carlo dose algorithm: comparisons against measurements and simulations

RaySearch Americas Inc. (NY) has introduced a commercial Monte Carlo dose algorithm (RS-MC) for routine clinical use in proton spot scanning. In this report, we provide a validation of this algorithm against phantom measurements and simulations in the GATE software package. We also compared the performance of the RayStation analytical algorithm (RS-PBA) against the RS-MC algorithm. A beam model (G-MC) for a spot scanning gantry at our proton center was implemented in the GATE software package. The model was validated against measurements in a water phantom and was used for benchmarking the RS-MC. Validation of the RS-MC was performed in a water phantom by measuring depth doses and profiles for three spread-out Bragg peak (SOBP) beams with normal incidence, an SOBP with oblique incidence, and an SOBP with a range shifter and large air gap. The RS-MC was also validated against measurements and simulations in heterogeneous phantoms created by placing lung or bone slabs in a water phantom. Lateral dose profiles near the distal end of the beam were measured with a microDiamond detector and compared to the G-MC simulations, RS-MC and RS-PBA. Finally, the RS-MC and RS-PBA were validated against measured dose distributions in an Alderson-Rando (AR) phantom. Measurements were made using Gafchromic film in the AR phantom and compared to doses using the RS-PBA and RS-MC algorithms. For SOBP depth doses in a water phantom, all three algorithms matched the measurements to within  ±3% at all points and a range within 1 mm. The RS-PBA algorithm showed up to a 10% difference in dose at the entrance for the beam with a range shifter and  >30 cm air gap, while the RS-MC and G-MC were always within 3% of the measurement. For an oblique beam incident at 45°, the RS-PBA algorithm showed up to 6% local dose differences and broadening of distal fall-off by 5 mm. Both the RS-MC and G-MC accurately predicted the depth dose to within  ±3% and distal fall-off to within 2 mm. In an anthropomorphic phantom, the gamma index (dose tolerance  =  3%, distance-to-agreement  =  3 mm) was greater than 90% for six out of seven planes using the RS-MC, and three out seven for the RS-PBA. The RS-MC algorithm demonstrated improved dosimetric accuracy over the RS-PBA in the presence of homogenous, heterogeneous and anthropomorphic phantoms. The computation performance of the RS-MC was similar to the RS-PBA algorithm. For complex disease sites like breast, head and neck, and lung cancer, the RS-MC algorithm will provide significantly more accurate treatment planning.

Differential hepatic avoidance radiation therapy: Proof of concept in hepatocellular carcinoma patients

PURPOSE To evaluate the feasibility of a novel planning concept that differentially redistributes RT dose away from functional liver regions as defined by (99m)Tc-sulphur colloid (SC) uptake on patient SPECT/CT images. MATERIALS AND METHODS Ten HCC patients with different Child-Turcotte-Pugh scores (A5-B9) underwent SC SPECT/CT scans in treatment position prior to RT that were registered to planning CT scans. Proton pencil beam scanning (PBS) therapy plans were optimized to deliver 37.5-60.0Gy (RBE) over 5-15 fractions using single field uniform dose technique robust to range and setup uncertainty. Photon volumetrically modulated arc therapy (VMAT) plans were optimized to the same prescribed dose and minimum target coverage. For both treatment modalities, differential hepatic avoidance RT (DHART) plans were generated to decrease dose to functional liver volumes (FLV) defined by a range of thresholds relative to maximum SC uptake (43-90%) in the tumor-subtracted liver. Radiation dose was redistributed away from regions of increased SC uptake in each FLV by linearly scaling mean dose objectives during PBS or VMAT optimization. DHART planning feasibility was assessed by a significantly negative Spearmans rank correlation (RS) between dose difference and SC uptake. Patient, tumor, and treatment planning characteristics were tested for association to DHART planning feasibility using non-parametric Kruskal-Wallis ANOVA. RESULTS Compared to conventional plans, DHART plans achieved a 3% FLV dose reduction for every 10% SC uptake increase. DHART planning was feasible in the majority of patients with 60% of patients having RS<-0.5 (p<0.01, range -1.0 to 0.2) and was particularly effective in 30% of patients (RS<-0.9). Mean dose to FLV was reduced by up to 20% in these patients. Only fractionation regimen was associated with DHART planning feasibility: 15 fraction courses were more feasible than 5-6 fraction courses (RS<-0.93 vs. RS>-0.60, p<0.02). CONCLUSION Differential avoidance of functional liver regions defined on sulphur colloid SPECT/CT is achievable with either photon VMAT or proton PBS therapy. Further investigation with phantom studies and in a larger cohort of patients may validate the utility of DHART planning for HCC radiotherapy.