Dosimetric Comparison of Ultra-Hypofractionated and Conventionally Fractionated Radiation Therapy Boosts for Patients with High-Risk Prostate Cancer.

Recent comparison of an ultra-hypofractionated radiotherapy (UF-RT) boost to a conventionally fractionated (CF-RT) option showed similar toxicity and disease control outcomes. An analysis of the treatment plans for these patients is needed for evaluating calculated doses for different organs, treatment beam-on time, and requirements for human and financial resources. Eighty-six plans for UF-RT and 93 plans for CF-RT schemes were evaluated. The biologically equivalent dose, EQD2, summed for the first phase and the boost, was calculated for dose-volume parameters for organs at risk (OARs), as well as for the PTV1. ArcCHECK measurements for the boost plans were used for a comparison of planned and delivered doses. Monitor units and beam-on times were recorded by the Eclipse treatment planning system. Statistical analysis was performed with a significance level of 0.05. Dosimetric parameter values for OARs were well within tolerance for both groups. EQD2 for the PTV1 was on average 84 Gy for UF-RT patients and 76 Gy for CF-RT patients. Gamma passing rate for planned/delivered doses comparison was above 98% for both groups with 3 mm/3% distance to agreement/dose difference criteria. Total monitor units per fraction were 647 ± 94 and 2034 ± 570 for CF-RT and UF-RT, respectively. The total delivery time for boost radiation for the patients in the UF-RT arm was, on average, four times less than the total time for a conventional regimen with statistically equal clinical outcomes for the two arms in this study.

Proliferation saturation index in an adaptive Bayesian approach to predict patient-specific radiotherapy responses.

Purpose: Radiotherapy prescription dose and dose fractionation protocols vary little between individual patients having the same tumor grade and stage. To personalize radiotherapy a predictive model is needed to simulate radiation response. Previous modeling attempts with multiple variables and parameters have been shown to yield excellent data fits at the cost of non-identifiability and clinically unrealistic results. Materials and methods: We develop a mathematical model based on a proliferation saturation index (PSI) that is a measurement of pre-treatment tumor volume-to-carrying capacity ratio that modulates intrinsic tumor growth and radiation response rates. In an adaptive Bayesian approach, we utilize an increasing number of data points for individual patients to predict patient-specific responses to subsequent radiation doses. Results: Model analysis shows that using PSI as the only patient-specific parameter, model simulations can fit longitudinal clinical data with high accuracy (R2=0.84). By analyzing tumor response to radiation using daily CT scans early in the treatment, response to the remaining treatment fractions can be predicted after two weeks with high accuracy (c-index = 0.89). Conclusion: The PSI model may be suited to forecast treatment response for individual patients and offers actionable decision points for mid-treatment protocol adaptation. The presented work provides an actionable image-derived biomarker prior to and during therapy to personalize and adapt radiotherapy.

A Phase II Multi-institutional Clinical Trial Assessing Fractionated Simultaneous In-Field Boost Radiotherapy for Brain Oligometastases.

Purpose/Objective Published preclinical and phase I clinical trial data suggest that fractionated lesional radiotherapy with 60 Gy in 10 fractions can serve as an alternative approach to single fraction radiosurgical boost for brain oligometastases.  Methods and Materials A phase II clinical trial (NCT01543542) of a total of 60 Gy in 10 fractions of lesional (one to three) radiotherapy (given simultaneously with whole-brain helical tomotherapy with 30 Gy in 10 fractions) was conducted at five institutions. We hypothesized that fractionated radiotherapy would be considered unsuitable if the median overall survival (OS) was degraded by two months or if six-month intracranial control (ICC) and intracranial lesion (ILC) were inferior by 10% compared with the published RTOG 9508 results. Results A total of 87 patients were enrolled over a 4.5-year accrual period. Radiological lesion and extralesional central nervous system progression were documented in 15/87 (17%) and 11/87 (13%) patients, respectively. Median OS for all patients was 5.4 months. Six-month actuarial estimates of ICC and ILC were 78% and 89%, respectively. However, only the ILC estimate achieved statistical significance (p=0.02), demonstrating non-inferiority to the a priori historical controls (OS: p=0.09, ICC=0.31). Two patients developed suspected asymptomatic radionecrosis. Conclusions The phase II estimates of ILC were demonstrated to be non-inferior to the results of the RTOG 9508.

Online daily assessment of dose change in head and neck radiotherapy without dose-recalculation.

BACKGROUND: Head and neck cancers are commonly treated with radiation therapy, but due to possible volume changes, plan adaptation may be required during the course of treatment. Currently, plan adaptations consume significant clinical resources. Existing methods to evaluate the need for plan adaptation requires deformable image registration (DIR) to a new CT simulation or daily cone beam CT (CBCT) images and the recalculation of the dose distribution. In this study, we explore a tool to assist the decision for plan adaptation using a CBCT without re-computation of dose, allowing for rapid online assessment. METHODS: This study involved 18 head and neck cancer patients treated with CBCT image guidance who had their treatment plan modified based on a new CT simulation (ReCT). Dose changes were estimated using different methods and compared to the current gold standard of using DIR between the planning CT scan (PCT) and ReCT with recomputed dose. The first and second methods used DIR between the PCT and daily CBCT with the planned dose or recalculated dose from the ReCT respectively, with the dose transferred to the CBCT using rigid registration. The necessity of plan adaptation was assessed by the change in dose to 95% of the planning target volume (D95) and mean dose to the parotids. RESULTS: The treatment plans were adapted clinically for all 18 patients but only 7 actually needed an adaptation yielding 11 unnecessary adaptations. Applying a method using the daily CBCT with the planned dose distribution would have yielded only four unnecessary adaptations and no missed adaptations: a significant improvement from that done clinically. CONCLUSION: Using the DIR between the planning CT and daily CBCT can flag cases for plan adaptation before every fraction while not requiring a new re-planning CT scan and dose recalculation.

Prognostic Significance of Tumor Location for Liver Cancer Radiotherapy.

Introduction According to the Surveillance, Epidemiology and End Results (SEER) data, cancerous involvement of the liver is on an increase over the last three decades. It occurs worldwide in all races and carries a poor prognosis. Currently, considerable progress has been made in patient selection, staging, surgery, chemotherapy agents, and stereotactic radiotherapy in both primary and metastatic liver cancers with improved outcomes. While there is evidence of the prognostic factors of liver function, the involvement of the portal vein, inferior vena cava thrombosis, lesion size, radiation dose, number of fractions, and SBRT techniques, there is no study evaluating outcomes with the location of the lesion. Our aim in this retrospective study was to explore the correlation of tumor location from the portal vein bifurcation (vascular wall) and the radiotherapy outcome (survival) in hepatocellular cancer. Methods Contrast-enhanced computed tomography (CT) studies in 86 patients with liver cancer were retrospectively reviewed in an institutional review board (IRB)-approved database to determine the distance to the bifurcation point of the portal vein from tumor's centre of mass (distance tumor bifurcation: DTB) and from the edge point of the planning target volume closest to the bifurcation (distance edge bifurcation: DEB). The mean dose to the sphere of 1 cm diameter around the bifurcation point (mean dose at bifurcation: MDB) was calculated. These parameters were tested as predictors of patient outcomes using univariate and multivariate analysis as two groups of patients. Results Only the DEB correlation with survival for hepatocellular carcinoma (HCC) was found to be significant (P = 0.028). A larger MDB is caused by a smaller DTB and a smaller DEB. The hazard ratio for DTB, DEB, and MDB were 0.48, 0.41, and 1.05, respectively. The DEB was found to be a better predictor of outcomes (overall survival) compared to the DTB and MDB parameters. The close proximity of the tumor to the blood supply vessels was a decisive factor. The DTB parameter is also dependent on the size of the tumor and this factor weakens the correlation of this parameter on survival data. The inclusion of the dosimetric and geometric location, as well as distance parameters in predictive models for liver cancer patients, was shown to benefit the pre-selection of treatment options for liver cancer patients treated with radiotherapy. Conclusion For hepatocellular cancer patients, the distance between the edge point of the planning treatment volume (PTV) to the portal vein bifurcation (DEB) of more than 2 cm was found to be a predictor of survival.

Performance Characteristics of an Independent Dose Verification Program for Helical Tomotherapy.

Helical tomotherapy with its advanced method of intensity-modulated radiation therapy delivery has been used clinically for over 20 years. The standard delivery quality assurance procedure to measure the accuracy of delivered radiation dose from each treatment plan to a phantom is time-consuming. RadCalc®, a radiotherapy dose verification software, has released specifically for beta testing a module for tomotherapy plan dose calculations. RadCalc®'s accuracy for tomotherapy dose calculations was evaluated through examination of point doses in ten lung and ten prostate clinical plans. Doses calculated by the TomoHDA™ tomotherapy treatment planning system were used as the baseline. For lung cases, RadCalc® overestimated point doses in the lung by an average of 13%. Doses within the spinal cord and esophagus were overestimated by 10%. Prostate plans showed better agreement, with overestimations of 6% in the prostate, bladder, and rectum. The systematic overestimation likely resulted from limitations of the pencil beam dose calculation algorithm implemented by RadCalc®. Limitations were more severe in areas of greater inhomogeneity and less prominent in regions of homogeneity with densities closer to 1 g/cm3. Recommendations for RadCalc® dose calculation algorithms and anatomical representation were provided based on the results of the study.

Secondary Cutaneous Involvement in Follicular Diffuse Lymphoma Treated with Helical Tomotherapy.

Non-Hodgkin's lymphoma is a complex heterogeneous group of disease entities that involves nodal and extranodal tissues. Cutaneous involvement can occur either as a primary or secondary in course of disease. Radiation therapy with either total body or localized treatments is often used for local control and symptom relief, depending on the target volume. We describe a 60-year-old male with a remote history of stage IA left neck follicular lymphoma treated with radiation 20 years ago and previous relapses aggressively treated by chemotherapy. Treatment to a large volume of back and posterior shoulders on a helical tomotherapy radiotherapy system is reported. The skin lesions responded completely with no toxicity. Palliative radiotherapy to a fairly large and complex volume of skin with modest dose avoiding underlying critical tissues on tomotherapy is feasible, well tolerated with an excellent durable response, without compromising future chemotherapy and stem cell transplant for systemic relapse.

Representing the dosimetric impact of deformable image registration errors.

Deformable image registration (DIR) is emerging as a tool in radiation therapy for calculating the cumulative dose distribution across multiple fractions of treatment. Unfortunately, due to the variable nature of DIR algorithms and dependence of performance on image quality, registration errors can result in dose accumulation errors. In this study, landmarked images were used to characterize the DIR error throughout an image space and determine its impact on dosimetric analysis. Ten thoracic 4DCT images with 300 landmarks per image study matching the end-inspiration and end-expiration phases were obtained from 'dir-labs'. DIR was performed using commercial software MIM Maestro. The range of dose uncertainty (RDU) was calculated at each landmark pair as the maximum and minimum of the doses within a sphere around the landmark in the end-expiration phase. The radius of the sphere was defined by a measure of DIR error which included either the actual DIR error, mean DIR error per study, constant errors of 2 or 5 mm, inverse consistency error, transitivity error or the distance discordance metric (DDM). The RDUs were evaluated using the magnitude of dose uncertainty (MDU) and inclusion rate (IR) of actual error lying within the predicted RDU. The RDU was calculated for 300 landmark pairs on each 4DCT study for all measures of DIR error. The most representative RDU was determined using the actual DIR error with a MDU of 2.5 Gy and IR of 97%. Across all other measures of DIR error, the DDM was most predictive with a MDU of 2.5 Gy and IR of 86%, closest to the actual DIR error. The proposed method represents the range of dosimetric uncertainty of DIR error using either landmarks at specific voxels or measures of registration accuracy throughout the volume.

Technical Note: Comparison of megavoltage, dual-energy, and single-energy CT-based µ-maps for a four-channel breast coil in PET/MRI.

PURPOSE: The purpose of this study was to describe and evaluate methods for calculating a megavoltage computed tomography (MVCT)-derived MR hardware attenuation map (µ-map) and dual-energy CT (DECT) for 511 keV photons. METHODS: Phantom measurements were acquired on a whole-body hybrid PET/MRI system, using a four-channel receive-only MR radiofrequency (RF) breast coil. Two acquisitions were performed: with the phantoms positioned in the four-channel RF breast coil, and without the breast coil. PET attenuation from the breast coil was corrected using three different CT-derived hardware µ-maps: (a) Single-energy CT (SECT), (b) DECT, and (c) MVCT. Each attenuation-corrected (AC) PET volume was evaluated and compared with the acquisition performed without the breast coil. RESULTS: The breast coil attenuated PET photons by 10% overall. Threshold values were applied to the SECT µ-map to reduce the effects of metal artifacts, but overcorrection occurred in more highly attenuated regions. The DECT-derived virtual monochromatic image reduced beam-hardening artifacts, but other metal artifacts remained. Despite the remaining metal artifacts in the DECT image, it led to an improvement in the more attenuated regions. The MVCT images appear to be free from metal artifacts leading to an artifact-free µ-map and a further improvement AC-PET images. CONCLUSIONS: Our MVCT-based approach for creating µ-maps for MR RF coils greatly reduces artifacts produced by metal in a SECT approach. This eliminates the need for other artifact reduction methods, including the application of a threshold of narrow beam attenuation coefficients, or disassembling hardware to remove high-Z components before imaging with a kilovoltage source.

Optimization of brain metastases radiotherapy with TomoHDA.

An upgrade of the helical tomotherapy technology by introducing variable fan-field width (dynamic jaws) reduced the penumbra in superior-inferior direction for the target. Possible implementation of this upgrade even for the cases of the targets with different dose prescriptions is proposed. An example of brain metastasis in proximity to the optical apparatus in need of the whole brain irradiation of 30 Gy and higher dose to the lesion is considered.

A multivariable model to predict survival for patients with hepatic carcinoma or liver metastasis receiving radiotherapy.

AIM: New parameters that correlate with overall survival were identified in patients with liver lesions treated with radiation therapy. METHODS: Pretreatment information and parameters of radiation treatment plans for 129 metastatic and 66 hepatocellular carcinoma liver cancer patients were analyzed. Study end points included overall survival collected from patient charts and electronic records. RESULTS: Two practical nomograms were constructed for primary hepatocellular carcinoma and liver metastasis patients. For patients with a Child-Pugh A, radiation dose escalation provided a significant survival benefit. However, for those with Child-Pugh B or C, increasing dose does not impact on survival. CONCLUSION: The developed models can potentially guide dose selection and provide prognostic information but still require external validation.

Target margins in radiotherapy of prostate cancer.

We reviewed the literature on the use of margins in radiotherapy of patients with prostate cancer, focusing on different options for image guidance (IG) and technical issues. The search in PubMed database was limited to include studies that involved external beam radiotherapy of the intact prostate. Post-prostatectomy studies, brachytherapy and particle therapy were excluded. Each article was characterized according to the IG strategy used: positioning on external marks using room lasers, bone anatomy and soft tissue match, usage of fiducial markers, electromagnetic tracking and adapted delivery. A lack of uniformity in margin selection among institutions was evident from the review. In general, introduction of pre- and in-treatment IG was associated with smaller planning target volume (PTV) margins, but there was a lack of definitive experimental/clinical studies providing robust information on selection of exact PTV values. In addition, there is a lack of comparative research regarding the cost-benefit ratio of the different strategies: insertion of fiducial markers or electromagnetic transponders facilitates prostate gland localization but at a price of invasive procedure; frequent pre-treatment imaging increases patient in-room time, dose and labour; online plan adaptation should improve radiation delivery accuracy but requires fast and precise computation. Finally, optimal protocols for quality assurance procedures need to be established.

Quantitative Perfusion and Permeability Biomarkers in Brain Cancer from Tomographic CT and MR Images.

Dynamic contrast-enhanced perfusion and permeability imaging, using computed tomography and magnetic resonance systems, are important techniques for assessing the vascular supply and hemodynamics of healthy brain parenchyma and tumors. These techniques can measure blood flow, blood volume, and blood-brain barrier permeability surface area product and, thus, may provide information complementary to clinical and pathological assessments. These have been used as biomarkers to enhance the treatment planning process, to optimize treatment decision-making, and to enable monitoring of the treatment noninvasively. In this review, the principles of magnetic resonance and computed tomography dynamic contrast-enhanced perfusion and permeability imaging are described (with an emphasis on their commonalities), and the potential values of these techniques for differentiating high-grade gliomas from other brain lesions, distinguishing true progression from posttreatment effects, and predicting survival after radiotherapy, chemotherapy, and antiangiogenic treatments are presented.

Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1-3 metastases.

We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1-3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32-59 % for FACT-Br and 0-16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.

Evaluation of CT Perfusion Biomarkers of Tumor Hypoxia.

BACKGROUND: Tumor hypoxia is associated with treatment resistance to cancer therapies. Hypoxia can be investigated by immunohistopathologic methods but such procedure is invasive. A non-invasive method to interrogate tumor hypoxia is an attractive option as such method can provide information before, during, and after treatment for personalized therapies. Our study evaluated the correlations between computed tomography (CT) perfusion parameters and immunohistopathologic measurement of tumor hypoxia. METHODS: Wistar rats, 18 controls and 19 treated with stereotactic radiosurgery (SRS), implanted with the C6 glioma tumor were imaged using CT perfusion on average every five days to monitor tumor growth. A final CT perfusion scan and the brain were obtained on average 14 days (8-22 days) after tumor implantation. Tumor hypoxia was detected immunohistopathologically with pimonidazole. The tumor, necrotic, and pimonidazole-positive areas on histology samples were measured. Percent necrotic area and percent hypoxic areas were calculated. Tumor volume (TV), blood flow (BF), blood volume (BV), and permeability-surface area product (PS) were obtained from the CT perfusion studies. Correlations between CT perfusion parameters and histological parameters were assessed by Spearman's ρ correlation. A Bonferroni-corrected P value < 0.05 was considered significant. RESULTS: BF and BV showed significant correlations with percent hypoxic area ρ = -0.88, P < 0.001 and ρ = -0.81, P < 0.001, respectively, for control animals and ρ = -0.7, P < 0.001 and ρ = -0.6, P = 0.003, respectively, for all animals, while TV and BV were correlated (ρ = -0.64, P = 0.01 and ρ = -0.43, P = 0.043, respectively) with percent necrotic area. PS was not correlated with either percent necrotic or percent hypoxic areas. CONCLUSIONS: Percent hypoxic area provided significant correlations with BF and BV, suggesting that CT perfusion parameters are potential non-invasive imaging biomarkers of tumor hypoxia.

Survival prediction in high-grade gliomas using CT perfusion imaging.

Patients with high-grade gliomas usually have heterogeneous response to surgery and chemoirradiation. The objectives of this study were (1) to evaluate serial changes in tumor volume and perfusion imaging parameters and (2) to determine the value of these data in predicting overall survival (OS). Twenty-nine patients with World Health Organization grades III and IV gliomas underwent magnetic resonance (MR) and computed tomography (CT) perfusion examinations before surgery, and 1, 3, 6, 9, and 12 months after radiotherapy. Serial measurements of tumor volumes and perfusion parameters were evaluated by receiver operating characteristic analysis, Cox proportional hazards regression, and Kaplan-Meier survival analysis to determine their values in predicting OS. Higher trends in blood flow (BF), blood volume (BV), and permeability-surface area product in the contrast-enhancing lesions (CEL) and the non-enhancing lesions (NEL) were found in patients with OS < 18 months compared to those with OS ≥ 18 months, and these values were significant at selected time points (P < 0.05). Only CT perfusion parameters yielded sensitivities and specificities of ≥ 70% in predicting 18 and 24 months OS. Pre-surgery BF in the NEL and BV in the CEL and NEL 3 months after radiotherapy had sensitivities and specificities >80% in predicting 24 months OS in patients with grade IV gliomas. Our study indicated that CT perfusion parameters were predictive of survival and could be useful in assessing early response and in selecting adjuvant treatment to prolong survival if verified in a larger cohort of patients.