Spatial organization of tumor phenotype is of great interest to radiotherapy target definition and outcome prediction. We characterized tumor phenotype in patients with cancers of the oropharynx through voxel-based correlation of PET images of metabolism, proliferation, and hypoxia.
Patients with oropharyngeal cancer received 18F-fluorodeoxyglucose (FDG) PET/CT, 18F-fluorothymidine (FLT) PET/CT, and 61Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) PET/CT. Images were co-registered and standardized uptake values (SUV) were calculated for all modalities. Voxel-based correlation was evaluated with Pearson’s correlation coefficient in tumor regions. Additionally, sensitivity studies were performed to quantify the effects of image segmentation, registration, noise, and segmentation on R.
On average, FDG PET and FLT PET images were most highly correlated (RFDG:FLT=0.76, range 0.53–0.85), while Cu-ATSM PET showed greater heterogeneity in correlation to other tracers (RFDG:Cu-ATSM=0.64, range 0.51–0.79; RFLT:Cu-ATSM=0.61, range 0.21–0.80). Of the tested parameters, correlation was most sensitive to image registration. Misregistration of one voxel lead to ΔRFDG=0.25, ΔRFLT=0.39, and ΔRCu-ATSM=0.27. Image noise and reconstruction also had quantitative effects on correlation. No significant quantitative differences were found between GTV, expanded GTV, or CTV regions.
Voxel-based correlation represents a first step into understanding spatial organization of tumor phenotype. These results have implications for radiotherapy target definition and provide a framework to test outcome prediction based on pretherapy distribution of phenotype.
Correlation; FDG; FLT; Cu-ATSM; PET
Background and purpose
PET imaging with 18F-fluorothymidine (18F-FLT) can potentially be used to identify tumour subvolumes for selective dose escalation in radiation therapy. The purpose of this study is to analyse the co-localization of intratumoural patterns of cell proliferation with 18F-FLT tracer uptake.
Materials and methods
Mice bearing FaDu or SQ20B xenograft tumours were injected with 18F-FLT, and bromodeoxyuridine (proliferation marker). Ex vivo images of the spatial pattern of intratumoural 18F-FLT uptake and that of bromodeoxyuridine DNA incorporation were obtained from thin tumour tissue sections. These images were segmented by thresholding and relative operating characteristic (ROC) curves and Dice similarity indices were evaluated.
The thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation were significantly different for the two xenograft tumour models, whereas the median Dice values were not. However, ROC analysis indicated that segmented FLT images were more specific at detecting the proliferation pattern in FaDu tumours than in SQ20B tumours.
Highly dispersed patterns of cell proliferation observed in certain tumours can affect the perceived spatial concordance between the spatial pattern of 18F-FLT uptake and that of cell proliferation even when a high-resolution ex vivo autoradiography imaging is used for 18F-FLT imaging.
FLT; tumour cell proliferation; mouse tumour; autoradiography; image-guided radiotherapy
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 [18F]FDG (FDGpre), [18F]FLT (FLTpre), and [61Cu]Cu-ATSM (Cu-ATSMpre). Following radiotherapy regimens of 50 Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at three months (FDGpost). Regression of standardized uptake values in baseline FDGpre, FLTpre and Cu-ATSMpre tumour voxels to those in FDGpost images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R2. Hypothesis testing of coefficients over the patient population was performed.
Multivariate linear model fits of FDGpre to FDGpost were significantly positive over the population (FDGpost~0.17 FDGpre, 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 FDGpre to FDGpost by a linear power law (FDGpost~FDGpre0.93, p<0.001). Univariate mixture model fits of FDGpre improved R2 from 0.17 to 0.52. Neither baseline FLT PET nor Cu-ATSM PET uptake contributed statistically significant multivariate regression coefficients.
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.
PET; FDG; FLT; Cu-ATSM; dose painting; regression analysis; sinonasal cancer
To investigate whether hypoxia targeted bifunctional suicide gene expression-cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) with 5-FC treatments can enhance radiotherapy.
Material and Methods
Stable transfectant of R3327-AT cells were established which express a triple-fusion-gene: CD, UPRT and monomoric DsRed (mDsRed) controlled by a hypoxia inducible promoter. Hypoxia-induced expression/function of CDUPRTmDsRed was varified by western blot, flow cytometry, fluorescent microscopy, and cytotoxicity assay of 5-FU and 5-FC. Tumor-bearing mice were treated with 5-FC and locally radiation. Tumor volume were monitored and compared with those treated with 5-FC or radiation alone. In addition, the CDUPRTmDsRed distribution in hypoxic regions of tumor sections was visualized with fluorescent microscopy.
Hypoxic induction of CDUPRTmDsRed protein correlated with increased sensitivity to 5-FC and 5-FU. Significant radiosensitization effects were detected after 5-FC treatments under hypoxic conditions. In the tumor xenografts, the distribution of CDUPRTmDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC to mice in combined with local irradiation resulted in significant tumor regression, as comparison with 5-FC or radiation treatments alone.
Our data suggest that the hypoxia-inducible CDUPRT/5-FC gene therapy strategy has the ability to specifically target hypoxic cancer cells and significantly improves the tumor control in combination with radiotherapy.
hypoxia; radiosensitization; cytosine deaminase; uracil phosphoribosyltransferase; 5-flurocytosine
Background and Purpose
We previously demonstrated that radiation may arrest tumor cells at G2 phase, which in turn prevents the cytotoxicity of antimicrotubule drugs and results in antagonistic interaction between these two modalities. Herein we tested whether G2 abrogators would attenuate the above antagonistic interaction and improve the therapeutic efficacy of combination therapy between radiation and antimicrotubule drugs.
Materials and Methods
Breast cancer BCap37 and epidermoid carcinoma KB cell lines were administered with radiation, UCN-01 (a model drug of G2 abrogator), paclitaxel or vincristine, alone or in combinations. The antitumor activities of single and combined treatments were analyzed by a series of cytotoxic, apoptosis, cell cycle, morphological and biochemical assays.
UCN-01 significantly enhanced the cytotoxicity of radiation, antimitotic drugs, and their combined treatments in vitro. Further investigations demonstrated that UCN-01 attenuated radiation-induced G2 arrest, and subsequently repressed the inhibitory effect of radiation on drug-induced mitotic arrest and apoptosis.
This is the first report demonstrating that G2 checkpoint abrogation represses the inhibitory effect of radiation on antimicrotubule drugs, which may be implicated in cancer combination therapy. Considering that G2 abrogators are under extensive evaluation for cancer treatment, our findings provide valuable information for this class of promising compounds.
radiation therapy; antimicrotubule drugs; UCN-01; breast cancer; apoptosis; cell cycle arrest
Background and Purpose
Dose effects of intrafraction motion during prone prostate radiotherapy are unknown. We compared prone and supine treatment using real-time tracking data to model dose coverage.
Material and Methods
Electromagnetic tracking data was analyzed for 10 patients treated prone, and 15 treated supine, with IMRT for localized prostate cancer. Plans were generated using 0, 3, and 5 mm PTV expansions. Manual beam-hold interventions were applied to reposition the patient when translations exceeded a predetermined threshold. A custom software application (SWIFTER) used intrafraction tracking data acquired during beam-on to model delivered prostate dose, by applying rigid body transformations to the prostate structure contoured at simulation within the planned dose cloud. The delivered minimum prostate dose as a percentage of planned dose (Dmin%), and prostate volume covered by the prescription dose as a percentage of the planned volume (VRx%) were compared for prone and supine treatment.
Dmin% was reduced for prone treatment for 0 (p=0.02) and 3 mm (p=0.03) PTV margins. VRx% was reduced for prone treatment only for 0 mm margins (p=0.002). No significant differences were found using 5 mm margins.
Intrafraction motion has a greater impact on target coverage for prone compared to supine prostate radiotherapy. PTV margins of 3 mm or less correlate with a significant decrease in delivered dose for prone treatment.
Prostate; Radiotherapy; Prone; Tracking; Calypso
Background and purpose
To examine the role of adjuvant chemoradiation (CRT) in patients with resected ampullary adenocarcinoma.
Materials and methods
The records of patients who underwent curative surgery for ampullary adenocarcinoma at a single institution between 1992 and 2007 were reviewed. Final analysis included 111 patients, 45% of which also received adjuvant CRT.
Median overall survival (OS) was 36.2 months for all patients. Adverse prognostic factors for OS included T stage (T3/4 vs. T1/T2, p = 0.046), node status (positive vs. negative, p < 0.001), and histological grade (grade 3 vs. 1/2, p = 0.09). Patients receiving CRT were more likely to have advanced T-stage (p = 0.001), node positivity (p < 0.001), and poor histologic grade (p = 0.015). Patients who received CRT were also significantly younger (p = 0.001). On univariate analysis, adjuvant CRT failed to result in a significant difference in survival when compared to surgery alone (median OS: 33.4 vs. 36.2 months, p = 0.969). Patients with node-positive resections who underwent CRT had a non-significant improvement in survival (median OS: 21.6 vs. 13.0 months, p = 0.092). Thirty-three percent of patients developed distant metastasis. Common sites of distant metastasis included liver (23%) and peritoneum (7%).
Adjuvant chemoradiation following curative resection for ampullary adenocarcinoma did not lead to a statistically significant benefit in overall survival. A significant proportion of patients still developed distant metastatic disease suggesting a need for more effective systemic adjuvant therapy.
Ampulla of Vater; Ampullary cancer; Radiotherapy; Adjuvant therapy; Chemoradiation
To determine factors associated with symptomatic cardiac toxicity in patients with esophageal cancer treated with chemoradiotherapy.
Material and Methods
We retrospectively evaluated 102 patients treated with chemoradiotherapy for locally advanced esophageal cancer. Our primary endpoint was symptomatic cardiac toxicity. Radiation dosimetry, patient demographic factors, and myocardial changes seen on 18F-FDG PET were correlated with subsequent cardiac toxicity. Cardiac toxicity measured by RTOG and CTCAE v3.0 criteria was identified by chart review.
During the follow up period, 12 patients were identified with treatment related cardiac toxicity, 6 of which were symptomatic. The mean heart V20 (79.7% vs. 67.2%, p=0.05), V30 (75.8% vs. 61.9%, p=0.04), and V40 (69.2% vs. 53.8%, p=0.03) were significantly higher in patients with symptomatic cardiac toxicity than those without. We found the threshold for symptomatic cardiac toxicity to be a V20, V30 and V40 above 70%, 65% and 60%, respectively. There was no correlation between change myocardial SUV on PET and cardiac toxicity, however, a greater proportion of women suffered symptomatic cardiac toxicity compared to men (p=0.005).
A correlation did not exist between percent change in myocardial SUV and cardiac toxicity. Patients with symptomatic cardiac toxicity received significantly greater mean V20, 30 and 40 values to the heart compared to asymptomatic patients. These data need validation in a larger independent data set.
Chemoradiotherapy; Esophageal cancer; Cardiac Toxicity
Background and Purpose
For toxicities occurring during the course of radiotherapy, it is conceptually inaccurate to perform normal-tissue complication probability analyses using the complete dose-volume histogram. The goal of this study was to analyze acute rectal toxicity using a novel approach in which the fit of the Lyman-Kutcher-Burman (LKB) model is based on the fractional rectal dose-volume histogram (DVH).
Materials and Methods
Grade ≥2 acute rectal toxicity was analyzed in 509 patients treated on Radiation Therapy Oncology Group (RTOG) protocol 94-06. These patients had no field reductions or treatment-plan revisions during therapy, allowing the fractional rectal DVH to be estimated from the complete rectal DVH based on the total number of dose fractions delivered.
The majority of patients experiencing Grade ≥2 acute rectal toxicity did so before completion of radiotherapy (70/80=88%). Acute rectal toxicity depends on fractional mean rectal dose, with no significant improvement in the LKB model fit when the volume parameter differs from n=1. The incidence of toxicity was significantly lower for patients who received hormone therapy (P=0.024).
Variations in fractional mean dose explain the differences in incidence of acute rectal toxicity, with no detectable effect seen here for differences in numbers of dose fractions delivered.
prostate cancer; acute rectal toxicity; dose-volume histogram; normal-tissue complication probability; Lyman model
To quantify the post-radiotherapy 2-[18F]-fluoro-2-deoxyglucose (FDG) pulmonary uptake dose-response in lung cancer patients and determine its relationship with radiation pneumonitis symptoms.
Methods and Materials
The data from 24 patients treated for lung cancer with thoracic radiotherapy who received restaging PET/CT imaging between 4 and 12 weeks after radiotherapy completion were evaluated. Their radiation dose distribution was registered with the post-treatment restaging PET/CT. Using histogram analysis, the voxel average FDG-PET uptake versus radiation dose was obtained for each case and linear regression was performed. The resulting slope, the pulmonary metabolic radiation response (PMRR), was used to characterize the dose-response. The Common Toxicity Criteria version 3 was used to score clinical pulmonary toxicity symptoms. Receiver operating characteristic (ROC) curves were used to determine the level of FDG uptake v. dose, MLD, V5, V10, V20, and V30 that can best predict symptomatic and asymptomatic patients.
The median time between radiotherapy completion and FDG-PET imaging was 59 days (range, 26–70 days). The median of the mean SUV from lung that received 0–5 Gy was 1.00 (range, 0.37–1.48), 5–10 Gy was 1.01 (range, 0.37–1.77), 10 –20 Gy was 1.04 (0.42–1.53), and > 20 Gy was 1.29 (range, 0.41–8.01). Using the dose range of 0 Gy to the maximum dose minus 10 Gy, hierarchical linear regression model of the radiation dose and normalized FDG uptake per case found an adequate fit with the linear model. Pneumonitis scores were: Grade 0 for 13, Grade 1 for 5, Grade 2 for 6, and Grade 3, 4 or 5 for none. Using a PMRR threshold of 0.017 yields an associated true positive rate of 0.67 and false positive rate of 0.15 with average error of 30%. A V5 threshold of 57.6 gives an associated true positive rate of 0.67 and false positive rate of 0.05 with a 20% average error.
The metabolic radiation pneumonitis dose response was evaluated from post-treatment FDG-PET/CT imaging. Statistical modeling found a linear relationship. The FDG uptake dose response and V5 correlated with symptomatic radiation pneumonitis.
Radiation pneumonitis; Pulmonary injury; Computed tomography; Positron emission tomography
To assess patterns of H&N IMRT practice with particular emphasis on elective target delineation.
Materials and methods
Twenty institutions with established H&N IMRT expertise were solicited to design clinical target volumes for the identical H&N cancer case. To limit contouring variability, a primary tonsil GTV and ipsilateral level II node were pre-contoured. Participants were asked to accept this GTV, and contour their recommended CTV and PTV. Dose prescriptions, contouring time, and recommendations regarding chemotherapy were solicited.
All 20 institutions responded. Remarkable heterogeneity in H&N IMRT design and practice was identified. Seventeen of 20 centers recommended treatment of bilateral necks whereas 3/20 recommended treatment of the ipsilateral neck only. The average CTV volume was 250 cm3 (range 37–676 cm3). Although there was high concordance in coverage of ipsilateral neck levels II and III, substantial variation was identified for levels I, V, and the contralateral neck. Average CTV expansion was 4.1 mm (range 0–15 mm). Eight of 20 centers recommended chemotherapy (cisplatin), whereas 12/20 recommended radiation alone. Responders prescribed on average 69 and 68 Gy to the tumor and metastatic node GTV, respectively. Average H&N target volume contouring time was 102.5 min (range 60–210 min).
This study identifies substantial heterogeneity in H&N IMRT target definition, prescription, neck treatment, and use of chemotherapy among practitioners with established H&N IMRT expertise. These data suggest that continued efforts to standardize and simplify the H&N IMRT process are desirable for the safe and effective global advancement of H&N IMRT practice.
IMRT; Head and neck; Target design; CTV definition; Contouring
Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches.
Materials and methods
In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC).
We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of one hour. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2–15 minutes following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement.
Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gambogic amide produced radiation sensitization.
kinomics; Trk; DNA repair; radiation; tumor microvasculature
Prospective analysis was performed of self-reported and biochemically confirmed tobacco use in 50 head and neck cancer patients during treatment. With 93.5% compliance to complete weekly self-report and biochemical confirmatory tests, 29.4% of smokers required biochemical assessment for identification. Accuracy increased by 14.9% with weekly vs. baseline self-reported assessments. Data confirm that head and neck cancer patients misrepresent true tobacco use during treatment.
tobacco; smoking; head/neck; radiotherapy; cotinine
Background and purpose
To compare the dosimetric impact of organ and target variations relative to the applicator for intracavitary brachytherapy by a multicentre analysis with different application techniques and fractionation schemes.
Material and methods
DVH data from 363 image/contour sets (120 patients, 6 institutions) were included for 1–6 fractions per patient, with imaging intervals ranging from several hours to ∼20 days. Variations between images acquired within one (intra-application) or between consecutive applicator insertions (inter-application) were evaluated. Dose plans based on a reference MR or CT image series were superimposed onto subsequent image sets and D2cm3 for the bladder, rectum and sigmoid and D90 for HR CTV were recorded.
For the whole sample, the systematic dosimetric variations for all organs at risk, i.e. mean variations of D2cm3, were found to be minor (<5%), while random variations, i.e. standard deviations were found to be high due to large variations in individual cases. The D2cm3 variations (mean ± 1SD) were 0.6 ± 19.5%, 4.1 ± 21.7% and 1.6 ± 26.8%, for the bladder, rectum and sigmoid. For HR CTV, the variations of D90 were found to be −1.1 ± 13.1% for the whole sample.
Grouping of the results by intra- and inter-application variations showed that random uncertainties for bladder and sigmoid were 3–7% larger when re-implanting the applicator for individual fractions. No statistically significant differences between the two groups were detected in dosimetric variations for the HR CTV.
Using 20% uncertainty of physical dose for OAR and 10% for HR CTV, the effects on total treatment dose for a 4 fraction HDR schedule at clinically relevant dose levels were found to be 4–8 Gy EQD2 for OAR and 3 Gy EQD2 for HR CTV.
Substantial variations occur in fractionated cervix cancer BT with higher impact close to clinical threshold levels. The treatment approach has to balance uncertainties for individual cases against the use of repetitive imaging, adaptive planning and dose delivery.
Image guided brachytherapy; Cervix cancer brachytherapy; Interfraction variations; Adaptive brachytherapy
To investigate and test the feasibility of adaptive 3D image based BT planning for cervix cancer patients in settings with limited access to MRI, using a combination of MRI for the first BT fraction and planning of subsequent fractions on CT.
Material and methods
For 20 patients treated with EBRT and HDR BT with tandem/ring applicators two sets of treatment plans were compared. Scenario one is based on the “gold standard” with individual MRI-based treatment plans (applicator reconstruction, target contouring and dose optimization) for two BT applications with two fractions each. Scenario two is based on one initial MRI acquisition with an applicator in place for the planning of the two fractions of the first BT application and reuse of the target contour delineated on MRI for subsequent planning of the second application on CT. Transfer of the target from MRI of the first application to the CT of the second one was accomplished by use of an automatic applicator-based image registration procedure. Individual dose optimization of the second BT application was based on the transferred MRI target volume and OAR structures delineated on CT.
DVH parameters were calculated for transferred target structures (virtual dose from MRI/CT plan) and CT-based OAR.
The quality of the MRI/CT combination method was investigated by evaluating the CT-based dose distributions on MRI-based target and OAR contours of the same application (real dose from MRI/CT plan).
The mean difference between the MRI based target volumes (HR CTVMRI2) and the structures transferred from MRI to CT (HR CTVCT2) was −1.7 ± 6.6 cm3 (−2.9 ± 20.4%) with a median of −0.7 cm3.
The mean difference between the virtual and the real total D90, based on the MRI/CT combination technique was −1.5 ± 4.3 Gy EQD2. This indicates a small systematic underestimation of the real D90.
A combination of MRI for first fraction and subsequent CT based planning is feasible and easy when automatic applicator-based image registration and target transfer are technically available. The results show striking similarity to fully MRI-based planning in cases of small tumours and intracavitary applications, both in terms of HR CTV coverage and respecting of OAR dose limits. For larger tumours and complex applications, as well as situations with unfavourable OAR topography, especially for the sigmoid, MRI based adaptive BT planning remains the superior method.
Cervical cancer; Image guided adaptive brachytherapy; MRI-based brachytherapy
Background and purpose
Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-β1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies.
Materials and methods
TGFB1 SNP rs1800469 c.-1347T>C (previously known as C-509T) genotype, treatment- related data, and clinically-assessed fibrosis (measured at least 2 years after therapy) were available in 2782 participants from 11 cohorts. All received adjuvant breast radiotherapy. Associations between late fibrosis or overall toxicity, reported by STAT (Standardised Total Average Toxicity) score, and rs1800469 genotype were assessed.
No statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed with univariate or multivariate regression analysis. The multivariate odds ratio (OR), obtained from meta-analysis, for an increase in late fibrosis grade with each additional rare allele of rs1800469 was 0.98 (95% Confidence Interval (CI) 0.85–1.11). This CI is sufficiently narrow to rule out any clinically relevant effect on toxicity risk in carriers vs. non-carriers with a high probability.
This meta-analysis has not confirmed previous reports of association between fibrosis or overall toxicity and rs1800469 genotype in breast cancer patients. It has demonstrated successful collaboration within the Radiogenomics Consortium.
Meta-analysis; Radiotherapy; Toxicity; Adverse effects
To develop a model to assess the quality of an IMRT treatment plan using data of prior patients with pancreatic adenocarcinoma.
The dose to an organ at risk (OAR) depends in large part on its orientation and distance to the planning target volume (PTV). A database of 33 previously treated patients with pancreatic cancer was queried to find patients with less favorable PTV-OAR configuration than a new case. The minimal achieved dose among the selected patients should also be achievable for the OAR of the new case. This way the achievable doses to the OARs of 25 randomly selected pancreas cancer patients were predicted. The patients were replanned to verify if the predicted dose could be achieved. The new plans were compared to their original clinical plans.
The predicted doses were achieved within 1 and 2 Gy for more than 82% and 94% of the patients, respectively, and were a good approximation of the minimal achievable doses. The improvement after replanning was 1.4 Gy (range 0–4.6 Gy) and 1.7 Gy (range 0–6.3 Gy) for the mean dose to the liver and the kidneys, respectively, without compromising target coverage or increasing radiation dose to the bowel. cord or stomach.
The model could accurately predict the achievable doses, leading to a considerable decrease in dose to the OARs and an increase in treatment planning efficiency.
Pancreatic cancer; Intensity modulated radiotherapy (IMRT); Treatment plan prediction and optimization; Overlap volume histogram (OVH); Pancreas; Quality control
To quantify the rotational offsets and estimate the dose effect of rotation on the target volume and normal tissues in children with brain tumor.
Twenty-one pediatric patients with brain tumors were included in this study. Cone-beam CT was performed before each treatment and at the end of every other treatment. Translational offsets were corrected before the treatment. An offline analysis was performed to quantify rotational errors. The treatment plans were altered and recalculated to simulate a rotation of 2° and 4°, and the dose changes were quantified.
1016 CBCT datasets were analyzed for this report. The mean of the rotations were not meaningfully different from zero. 18.1% of the fractions had rotations with a magnitude ≥2°, 5.0% had rotations ≥3° and 0.9% had rotations ≥4°. For the 2° rotational simulation, the gEUD values of the PTV and critical structures changed by less than 2%. For the 4° simulation, parallel type normal structures had minor changes (<2%), but serial type normal structures and the PTV had changes of 10% and 5%, respectively.
The majority of rotational errors observed were less than 1°. A rotational error of 2° produced negligible changes in the gEUD to critical structures or target volumes. Rotational errors ≥4° produced undesirable results, therefore, at a minimum, errors >2° should be corrected.
Pediatric; Brain tumor; Rotation errors; Set-up errors; CBCT
Evidence-based medicine has become a cornerstone in the development of radiation oncology and the randomized controlled phase III trial remains the gold standard for assessing differential benefits in clinical outcome between therapies. Health technologies aimed at improving treatment quality should primarily be tested using process measures or operational characteristics, the reason being that the sensitivity and specificity of clinical outcome is low for detecting quality improvements. The ongoing discussion of the relative merits of intensity modulated photon vs. proton radiotherapy is used to illustrate these concepts. Concerns over clinical and individual equipoise as well as the potential limitations of health economics considerations in this setting are also discussed. Working in a technology and science based medical discipline, radiation oncology researchers need to further develop methodology for critical assessment of health technologies as a complement to randomized controlled trials.
Background and Purpose
Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN.
Materials and Methods
Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n=40 plans) and dose volume histograms were generated.
The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p=0.020) and mean doses to the contralateral parotid gland (p=0.049) and larynx (p=0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lower the maximum doses to the spinal cord (p<0.002 for both) and brainstem (p<0.002 for both) and mean doses to the larynx (p<0.002 for both) and ipsilateral (p=0.004 IMRT, p=0.050 adaptive) and contralateral (p<0.002 IMRT, p=0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT.
Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage.
head and neck cancer; proton therapy; adaptive radiotherapy; IMRT; treatment planning
To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer.
Materials and Methods
Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques.
Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R2 range 0.29–0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R2 = 0.63).
Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.
head-and-neck cancer; positron emission tomography; metabolic tumor volume
Background and Purpose
Positron emission tomography (PET) imaging with [F-18] fluoromisonidazole (FMISO) has been validated as a hypoxic tracer [1, 2]. Head and neck cancer exhibits hypoxia, inducing aggressive biologic traits that impart resistance to treatment. Delivery of modestly higher radiation doses to tumors with stable areas of chronic hypoxia can improve tumor control . Advanced radiation treatment planning (RTP) and delivery techniques such as Intensity Modulated Radiation Therapy (IMRT) can deliver higher doses to a small volume without increasing morbidity. We investigated the utility of co-registered FMISO-PET and CT images to develop clinically feasible RTPs with higher tumor control probabilities (TCP).
FMISO-PET images were used to determine hypoxic sub-volumes for boost planning. Example plans were generated for ten of the patients in the study who exhibited significant hypoxia. We created an IMRT plan for each patient with a simultaneous integrated boost (SIB) to the hypoxic sub-volumes. We also varied the boost for two patients.
A significant (mean 17%, median 15%) improvement in TCP is predicted when the modest additional boost dose to the hypoxic sub-volume is included.
Combined FMISO-PET imaging and IMRT planning permits delivery of higher doses to hypoxic regions, increasing the predicted TCP (mean 17%) without increasing expected complications.
Hypoxia; FDG-PET; IMRT; FMISO-PET
It is widely believed that younger prostate cancer patients are at greater risk of recurrence following radiotherapy (RT).
From 1992–2007, 2168 (395 age ≤60) men received conformal RT alone for prostate cancer at our institution (median dose = 76 Gy, range:72–80). Multivariable analysis (MVA) was used to identify significant predictors for BF and PCSM. Cumulative incidence was estimated using the competing risk method (Fine and Gray) for BF (Phoenix definition) and PCSM to account for the competing risk of death.
With a median follow-up of 72.2 months (range:24.0–205.1), 8-year BF was 27.1% for age ≤60 vs. 23.7% for age >60 (p=0.29). 8-year PCSM was 3.0% for age ≤60 vs. 2.0% for age >60 (p=0.52). MVA for BF identified initial PSA [adjusted HR=1.7(PSA 10–20), 2.6(PSA>20), p<0.01], Gleason score [adjusted HR=2.1(G7),1.9(G8-10), p<0.01)], T-stage [adjusted HR=1.7(T2b-c),2.6(T3-4), p<0.01], and initial androgen deprivation therapy (ADT) [adjusted HR=0.38(ADT >12 mo), p<0.01] as significant, but not age or ADT <12 months. MVA for PCSM identified Gleason score [adjusted HR=3.0(G8-10), p=0.01] and T-stage [adjusted HR=8.7(T3-4), p<0.01] as significant, but not age, PSA, or ADT.
This is the largest, most mature study of younger men treated with RT for prostate cancer that confirms young age is not prognostic for BF.
prostatic neoplasms; prostate; radiotherapy; conformal; age factors
We have demonstrated that soy isoflavones radiosensitize cancer cells. Prostate cancer patients receiving radiotherapy (RT) and soy tablets had reduced radiation toxicity to surrounding organs. We have now investigated the combination of soy with RT in lung cancer (NSCLC), for which RT is limited by radiation-induced pneumonitis.
Human A549 NSCLC cells were injected i. v. in nude mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with left lung RT at 12 Gy and with oral soy treatments at 1mg/day for 30 days. Lung tissues were processed for histology.
Compared to lung tumor nodules treated with soy isoflavones or radiation, lung tissues from mice treated with both modalities showed that soy isoflavones augmented radiation-induced destruction of A549 lung tumor nodules leading to small residual tumor nodules containing degenerating tumor cells with large vacuoles. Soy isoflavones decreased the hemorrhages, inflammation and fibrosis caused by radiation in lung tissue, suggesting protection of normal lung tissue.
Soy isoflavones augment destruction of A549 lung tumor nodules by radiation, and also mitigate vascular damage, inflammation and fibrosis caused by radiation injury to normal lung tissue. Soy could be used as a non-toxic complementary approach to improve RT in NSCLC.
Lung cancer; soy isoflavones; radiation
Radiation and other types of DNA damaging agents induce a plethora of signaling events simultaneously originating from the nucleus, cytoplasm, and plasma membrane. As a result, this presents a dilemma when seeking to determine causal relationships and provide better insight into the intricacies of stress signaling. ATM plays critical roles in both nuclear and cytoplasmic signaling, of which, the DNA damage response (DDR) is the best characterized. We have recently created experimental conditions where the DNA damage signal alone can be studied while minimizing the influence from the extranuclear compartment. We have been able to document pro-survival and growth promoting signaling (via ATM-AKT-ERK) resulting from low levels of DSBs (equivalent to •2 Gy). More extensive DSBs (>2 Gy eq.) result in phosphatase-mediated ERK dephosphorylation, and thus shutdown of ERK signaling. In contrast, radiation does not result in such dephosphorylation even at very high doses. We propose that phosphatases are inactivated perhaps as a result of reactive oxygen species, which does not occur in response to ‘pure’ DNA damage. Our findings suggest that clinically relevant radiation doses, intended to halt tumor growth and induce cell death, are unable to inhibit tumor pro-survival signaling via ERK dephosphorylation.
ATM; AKT; DNA repair; EGFR; ERK; MAP kinase; phosphatase; ROS