Long-term Renal Function Outcomes After Stereotactic Ablative Body Radiotherapy for Primary Renal Cell Carcinoma Including Patients with a Solitary Kidney: A Report from the International Radiosurgery Oncology Consortium of the Kidney.

BACKGROUND AND OBJECTIVE: Renal function preservation is particularly important following nonoperative treatment of localized renal cell carcinoma (RCC) since patients are often older with medical comorbidities. Our objective was to report long-term renal function outcomes after stereotactic ablative radiotherapy (SABR) including patients with a solitary kidney. METHODS: Patients with primary RCC treated with SABR with ≥2 yr of follow-up at 12 International Radiosurgery Consortium for Kidney institutions were included. Renal function was measured by estimated glomerular filtration rate (eGFR). KEY FINDINGS AND LIMITATIONS: In total, 190 patients (56 with a solitary kidney) underwent SABR and were followed for a median of 5.0 yr (interquartile range [IQR]: 3.4-6.8). In patients with a solitary kidney versus bilateral kidneys, pre-SABR eGFR (mean [standard deviation]) was 61.1 (23.2) versus 58.0 (22.3) ml/min (p = 0.32) and the median tumor size was 3.65 cm (IQR: 2.59-4.50 cm) versus 4.00 cm (IQR: 3.00-5.00 cm; p = 0.026). At 5 yr after SABR, eGFR decreased by -14.5 (7.6) and -13.3 (15.9) ml/min (p = 0.67), respectively, and there were similar rates of post-SABR dialysis (3.6% [n = 2/56] vs 3.7% [n = 5/134]). A multivariable analysis demonstrated that increasing tumor size (odds ratio [OR] per 1 cm: 1.57; 95% confidence interval [CI]: 1.14-2.16, p = 0.0055) and baseline eGFR (OR per 10 ml/min: 1.30; 95% CI: 1.02-1.66, p = 0.034) were associated with an eGFR decline of ≥15 ml/min at 1 yr. CONCLUSIONS AND CLINICAL IMPLICATIONS: With long-term follow-up after SABR, kidney function decline remains moderate, with no observed difference between patients with a solitary kidney and bilateral kidneys. Tumor size and baseline eGFR are dominant factors predictive of long-term renal function decline. PATIENT SUMMARY: With long-term follow-up, stereotactic ablative radiotherapy (SABR) yields moderate long-term renal function decline and low dialysis rates even in patients with a solitary kidney. SABR thus represents a promising noninvasive, nephron-sparing option for patients with localized renal cell carcinoma.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

National Patterns of Early Adoption of Magnetic Resonance Imaging-Guided Linear Accelerators in 2018 to 2019.

Purpose: Adaptive magnetic resonance imaging-guided linear accelerators (aMRI-LINACs) are an emerging technology with the potential to improve radiation treatment for cancer through improved visualization and adaptive treatment. Given the competing forces of the increased cost, knowledge, and staff required for aMRI-LINAC therapy, it is unpredictable how rapidly and for whom aMRI-LINAC therapy is being adopted. Therefore, given that aMRI-LINAC therapy was granted approval from the Food and Drug Administration in late 2017, we evaluated the National Cancer Database (NCDB) to obtain a nationwide view of early aMRI-LINAC adoption in 2018 to 2019. Methods and Materials: Forty-three disease sites were aggregated. A sample of patients who underwent intensity modulated radiation therapy (IMRT) from 2018 to 2019 were matched 1:1 by stage for the top 4 cancer sites. We then compared 9 characteristics of interest (age, % White [vs non-White], % residing in metro areas, % living in the greatest income quartile, % insured by Medicare, % uninsured or unknown insurance status, % treated at a comprehensive cancer center or academic center, % with no recorded Charlson-Deyo comorbidities, and % residing in an area with highest educational) between the 2 samples (aMRI-LINAC and matched IMRT). Results: Only 171 patients were recorded as having been treated with aMRI-LINACs in the NCDB in 2018 to 2019. Fifty-six percent were male, 89% White, and 54% enrolled in Medicare. The most common sites of disease treated were lung (33 patients), pancreas (30 patients), prostate (29 patients), and breast (23 patients). There were no significant differences between aMRI-LINAC- and IMRT-matched patients except that patients with lung or breast cancer treated with aMRI-LINAC were significantly more likely to be treated at a comprehensive cancer center or academic center. Conclusions: aMRI-LINAC adoption recorded in the NCDB after Food and Drug Administration approval was potentially underreported, slow, and attributed to academic sites of practice. Further longitudinal study will be needed to assess how practice patterns evolve with greater adoption.

5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney).

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for primary renal cell carcinoma, for which long-term data are awaited. The primary aim of this study was to report on long-term efficacy and safety of SABR for localised renal cell carcinoma. METHODS: This study was an individual patient data meta-analysis, for which patients undergoing SABR for primary renal cell carcinoma across 12 institutions in five countries (Australia, Canada, Germany, Japan, and the USA) were eligible. Eligible patients had at least 2 years of follow-up, were aged 18 years or older, had any performance status, and had no previous local therapy. Patients with metastatic renal cell carcinoma or upper-tract urothelial carcinoma were excluded. SABR was delivered as a single or multiple fractions of greater than 5 Gy. The primary endpoint was investigator-assessed local failure per the Response Evaluation Criteria in Solid Tumours version 1.1, and was evaluated using cumulative incidence functions. FINDINGS: 190 patients received SABR between March 23, 2007, and Sept 20, 2018. Single-fraction SABR was delivered in 81 (43%) patients and multifraction SABR was delivered in 109 (57%) patients. Median follow-up was 5·0 years (IQR 3·4-6·8). 139 (73%) patients were men, and 51 (27%) were women. Median age was 73·6 years (IQR 66·2-82·0). Median tumour diameter was 4·0 cm (IQR 2·8-4·9). 96 (75%) of 128 patients with available operability details were deemed inoperable by the referring urologist. 56 (29%) of 190 patients had a solitary kidney. Median baseline estimated glomerular filtration rate (eGFR) was 60·0 mL/min per 1·73 m2 (IQR 42·0-76·0) and decreased by 14·2 mL/min per 1·73 m2 (IQR 5·4-22·5) by 5 years post-SABR. Seven (4%) patients required dialysis post-SABR. The cumulative incidence of local failure at 5 years was 5·5% (95% CI 2·8-9·5) overall, with single-fraction SABR yielding fewer local failures than multifraction (Gray's p=0·020). There were no grade 3 toxic effects or treatment-related deaths. One (1%) patient developed an acute grade 4 duodenal ulcer and late grade 4 gastritis. INTERPRETATION: SABR is effective and safe in the long term for patients with primary renal cell carcinoma. Single-fraction SABR might yield less local failure than multifraction, but further evidence from randomised trials is needed to elucidate optimal treatment schedules. These mature data lend further support for renal SABR as a treatment option for patients unwilling or unfit to undergo surgery. FUNDING: None.

Focal Prostate Stereotactic Body Radiation Therapy With Correlative Pathological and Radiographic-Based Treatment Planning.

INTRODUCTION: Advances in multiparametric MRI (mpMRI) combining anatomic and functional imaging can accurately identify foci of adenocarcinoma within the prostate, offering the possibility of partial gland therapy. We performed tandem prospective pilot trials to investigate the feasibility of focal prostate SBRT (f-SBRT) based on correlating diagnostic mpMRI and biopsies with confirmatory pathology in treatment planning. MATERIALS AND METHODS: Patients with pathologic focal Gleason 6-7 disease and a corresponding PIRADS 4-5 lesion on mpMRI underwent targeted and comprehensive biopsies using MRI/ultrasound fusion under electromagnetic sensor navigation. After rigorous analysis for imaging biopsy concordance, five of 18 patients were eligible to proceed to f-SBRT. Chi-squared test was used for differences from expected outcomes, and concordance was estimated with binomial distribution theory and Wilson's method. RESULTS: Six patients had Gleason 6 and 12 had Gleason 3 + 4 disease (mean PSA: 5.8 ng/ml, range: 2.2-8.4). Absolute concordance was 43.8% (95% CI: 0.20, 0.64). Patterns of discordance included additional sites of ipsilateral disease, bilateral disease, and negative target. Five were upstaged to a new NCCN risk category necessitating treatment escalation. The five patients with concordant pathology completed three-fraction f-SBRT with sparing of the surrounding normal structures (including contralateral neurovascular bundle), with no reported grade 2+ toxicities and favorable PSA responses (mean: 41% decrease). CONCLUSIONS: On our pilot trials of f-SBRT planning using rigorous imaging and pathology concordance, image-guided confirmatory biopsies frequently revealed additional disease, suggesting the need for caution in partial-gland therapy. For truly focal disease, f-SBRT provided excellent dosimetry, minimal toxicity, and encouraging biochemical response. Clinical Trial Registration: www.clinicaltrials.gov, NCT02681614; NCT02163317.

Synthetic CT Generation of the Pelvis in Patients With Cervical Cancer: A Single Input Approach Using Generative Adversarial Network.

Multi-modality imaging constitutes a foundation of precision medicine, especially in oncology where reliable and rapid imaging techniques are needed in order to insure adequate diagnosis and treatment. In cervical cancer, precision oncology requires the acquisition of 18F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), magnetic resonance (MR), and computed tomography (CT) images. Thereafter, images are co-registered to derive electron density attributes required for FDG-PET attenuation correction and radiation therapy planning. Nevertheless, this traditional approach is subject to MR-CT registration defects, expands treatment expenses, and increases the patient's radiation exposure. To overcome these disadvantages, we propose a new framework for cross-modality image synthesis which we apply on MR-CT image translation for cervical cancer diagnosis and treatment. The framework is based on a conditional generative adversarial network (cGAN) and illustrates a novel tactic that addresses, simplistically but efficiently, the paradigm of vanishing gradient vs. feature extraction in deep learning. Its contributions are summarized as follows: 1) The approach -termed sU-cGAN-uses, for the first time, a shallow U-Net (sU-Net) with an encoder/decoder depth of 2 as generator; 2) sU-cGAN's input is the same MR sequence that is used for radiological diagnosis, i.e. T2-weighted, Turbo Spin Echo Single Shot (TSE-SSH) MR images; 3) Despite limited training data and a single input channel approach, sU-cGAN outperforms other state of the art deep learning methods and enables accurate synthetic CT (sCT) generation. In conclusion, the suggested framework should be studied further in the clinical settings. Moreover, the sU-Net model is worth exploring in other computer vision tasks.

Transforming UTE-mDixon MR Abdomen-Pelvis Images Into CT by Jointly Leveraging Prior Knowledge and Partial Supervision.

Computed tomography (CT) provides information for diagnosis, PET attenuation correction (AC), and radiation treatment planning (RTP). Disadvantages of CT include poor soft tissue contrast and exposure to ionizing radiation. While MRI can overcome these disadvantages, it lacks the photon absorption information needed for PET AC and RTP. Thus, an intelligent transformation from MR to CT, i.e., the MR-based synthetic CT generation, is of great interest as it would support PET/MR AC and MR-only RTP. Using an MR pulse sequence that combines ultra-short echo time (UTE) and modified Dixon (mDixon), we propose a novel method for synthetic CT generation jointly leveraging prior knowledge as well as partial supervision (SCT-PK-PS for short) on large-field-of-view images that span abdomen and pelvis. Two key machine learning techniques, i.e., the knowledge-leveraged transfer fuzzy c-means (KL-TFCM) and the Laplacian support vector machine (LapSVM), are used in SCT-PK-PS. The significance of our effort is threefold: 1) Using the prior knowledge-referenced KL-TFCM clustering, SCT-PK-PS is able to group the feature data of MR images into five initial clusters of fat, soft tissue, air, bone, and bone marrow. Via these initial partitions, clusters needing to be refined are observed and for each of them a few additionally labeled examples are given as the partial supervision for the subsequent semi-supervised classification using LapSVM; 2) Partial supervision is usually insufficient for conventional algorithms to learn the insightful classifier. Instead, exploiting not only the given supervision but also the manifold structure embedded primarily in numerous unlabeled data, LapSVM is capable of training multiple desired tissue-recognizers; 3) Benefiting from the joint use of KL-TFCM and LapSVM, and assisted by the edge detector filter based feature extraction, the proposed SCT-PK-PS method features good recognition accuracy of tissue types, which ultimately facilitates the good transformation from MR images to CT images of the abdomen-pelvis. Applying the method on twenty subjects' feature data of UTE-mDixon MR images, the average score of the mean absolute prediction deviation (MAPD) of all subjects is 140.72 ± 30.60 HU which is statistically significantly better than the 241.36 ± 21.79 HU obtained using the all-water method, the 262.77 ± 42.22 HU obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method, and the 197.05 ± 76.53 HU obtained via the conventional SVM method. These results demonstrate the effectiveness of our method for the intelligent transformation from MR to CT on the body section of abdomen-pelvis.

Final results of a dose escalation protocol of stereotactic body radiotherapy for poor surgical candidates with localized renal cell carcinoma.

BACKGROUND AND PURPOSE: We previously demonstrated the safety of doses up to 48 Gy in 4 fractions with stereotactic body radiotherapy (SBRT) in poor surgical candidates with localized renal cell carcinoma (RCC). In an additional expansion cohort, we aimed to assess the safety of further dose escalation to 48-60 Gy in 3 fractions. MATERIAL AND METHODS: Patients were required to have localized RCC and be poor surgical candidates due to medical comorbidities. Dose-limiting toxicity (DLT) was defined as acute (<180 days) grade ≥3 gastrointestinal/genitourinary toxicity by CTCAEv4. Tumor response was assessed using RECIST 1.1 criteria measurements every 6 months for 3 years and optional percutaneous biopsy. RESULTS: Groups of 4, 4, and 3 patients received 48, 54, and 60 Gy in 3 fractions, respectively from 2012 to 2016. Median follow-up was 34.3 months. Zero DLTs were observed. Acute toxicities were limited to grade 1 fatigue and nausea in 45.5% and 18.1%. Late grade 2+ and grade 3+ possibly treatment-related events occurred in 18.1% and 9.1%, respectively. Three-year local control was 90% by RECIST 1.1 criteria. Five of 5 post-treatment biopsies in the expansion cohort were positive by Hematoxylin and Eosin staining. Three of the 5 patients with positive biopsies have been observed for 1.2-3.9 years without evidence of progression. CONCLUSION: Dose escalation to 60 Gy in 3 fractions was achieved without DLTs. Favorable local control rates were observed, and the interpretation of post-SBRT biopsies remains uncertain. Further studies comparing SBRT to percutaneous ablation for poor surgical candidates with RCC are warranted.

Refining complex re-irradiation dosimetry through feasibility benchmarking and analysis for informed treatment planning.

PURPOSE/OBJECTIVES: The purpose of this study is to dually evaluate the effectiveness of PlanIQ in predicting the viability and outcome of dosimetric planning in cases of complex re-irradiation as well as generating an equivalent plan through Pinnacle integration. The study also postulates that a possible strength of PlanIQ lies in mitigating pre-optimization uncertainties tied directly to dose overlap regions where re-irradiation is necessary. METHODS: A retrospective patient selection (n = 20) included a diverse range of re-irradiation cases to be planned using Pinnacle auto-planning with PlanIQ integration. A consistent planning template was developed and applied across all cases. Direct plan comparisons of manual plans against feasibility-produced plans were performed by physician(s) with dosimetry recording relevant proximal OAR and planning timeline data. RESULTS AND DISCUSSION: All re-irradiation cases were successfully predicted to be achievable per PlanIQ analyses with three cases (3/20) necessitating 95% target coverage conditions, previously exhibited in the manually planned counterparts, and determined acceptable under institutional standards. At the same time, PlanIQ consistently produced plans of equal or greater quality to the previously manually planned re-irradiation across all (20/20) trials (P = 0.05). Proximal OAR exhibited similar to slightly improved maximum point doses from feasibility-based planning with the largest advantages gained found within the subset of cranial and spine overlap cases, where improvements upward of 10.9% were observed. Mean doses to proximal tissues were found to be a statistically significant (P < 0.05) 5.0% improvement across the entire study. Documented planning times were markedly less than or equal to the time contributed to manual planning across all cases. CONCLUSION: Initial findings indicate that PlanIQ effectively provides the user clear feasibility feedback capable of facilitating decision-making on whether re-irradiation dose objectives and prescription dose coverage are possible at the onset of treatment planning thus eliminating possible trial and error associated with some manual planning. Introducing model-based prediction tools into planning of complex re-irradiation cases yielded positive outcomes on the final treatment plans.

Ultrahypofractionated versus hypofractionated and conventionally fractionated radiation therapy for localized prostate cancer: A systematic review and meta-analysis of phase III randomized trials.

INTRODUCTION: To characterize the efficacy (5-year disease-free survival [DFS]) and safety (incidence of grade 2+ late gastrointestinal or genitourinary toxicity) of ultrahypofractionated radiation therapy (UHRT) versus hypofractionated radiation therapy (HFRT) and conventionally fractionated radiation therapy (CFRT) by comparing patients treated on phase III protocols. METHODS: A PICOS/PRISMA/MOOSE protocol was used to identify eligible studies. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method. Wald-type tests were used to compare treatment modalities for each outcome, where the null hypothesis was rejected for p < 0.05. RESULTS: Seven studies were included that consisted of 6795 patients (2849 CFRT, 3357 HFRT, and 589 UHRT). Median age was 68 years. Summary effect sizes for 5-year DFS were 85.1% (95% CI: 82.1%-87.8%) for CFRT, 86% (95% CI: 83%-88.7%) for HFRT, and 85% (95% CI: 80%-87%) for UHRT (p = 0.66 and p = 0.8 for CFRT vs. HFRT and CFRT versus UHRT, respectively). Summary effect sizes for late grade 2+ gastrointestinal toxicity were 12.1% (95% CI: 9.2%-15.4%) for CFRT, 14.6% (95% CI: 9.9%-20%) for HFRT, and 10% (95% CI: 7%-13%) for UHRT (p = 0.41 and p = 0.09 for CFRT versus HFRT and CFRT versusus UHRT, respectively). Summary effect sizes for late grade 2+ genitourinary toxicity were 19.4% (95% CI: 10.7-29.9%) for CFRT, 20.4% (95% CI: 10.2%-32.9%) for HFRT, and 18% (95% CI: 15%-22%) for UHRT (p = 0.89 and p = 0.92 for CFRT versus HFRT and CFRT versus UHRT, respectively). CONCLUSION: Ultrahypofrationated regimens appear to offer similar levels of safety and efficacy to CFRT and HFRT. These findings are hypothesis-generating and require further validation by ongoing prospective trials.

Stereotactic Ablative Radiotherapy for ≥T1b Primary Renal Cell Carcinoma: A Report From the International Radiosurgery Oncology Consortium for Kidney (IROCK).

PURPOSE: Patients with larger (T1b, >4 cm) renal cell carcinoma (RCC) not suitable for surgery have few treatment options because thermal ablation is less effective in this setting. We hypothesize that SABR represents an effective, safe, and nephron-sparing alternative for large RCC. METHODS AND MATERIALS: Individual patient data from 9 institutions in Germany, Australia, USA, Canada, and Japan were pooled. Patients with T1a tumors, M1 disease, and/or upper tract urothelial carcinoma were excluded. Demographics, treatment, oncologic, and renal function outcomes were assessed using descriptive statistics. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes. RESULTS: Ninety-five patients were included. Median follow-up was 2.7 years. Median age was 76 years, median tumor diameter was 4.9 cm, and 81.1% had Eastern Cooperative Oncology Group performance status of 0 to 1 (or Karnofsky performance status ≥70%). In patients for whom operability details were reported, 77.6% were defined as inoperable as determined by the referring urologist. Mean baseline estimated glomerular filtration rate (eGFR) was 57.2 mL/min (mild-to-moderate dysfunction), with 30% of the cohort having moderate-to-severe dysfunction (eGFR <45mL/min). After SABR, eGFR decreased by 7.9 mL/min. Three patients (3.2%) required dialysis. Thirty-eight patients (40%) had a grade 1 to 2 toxicity. No grade 3 to 5 toxicities were reported. Cancer-specific survival, overall survival, and progression-free survival were 96.1%, 83.7%, and 81.0% at 2 years and 91.4%, 69.2%, 64.9% at 4 years, respectively. Local, distant, and any failure at 4 years were 2.9%, 11.1%, and 12.1% (cumulative incidence function with death as competing event). On multivariable analysis, increasing tumor size was associated with inferior cancer-specific survival (hazard ratio per 1 cm increase: 1.30; P < .001). CONCLUSIONS: SABR for larger RCC in this older, largely medically inoperable cohort, demonstrated efficacy and tolerability and had modest impact on renal function. SABR appears to be a viable treatment option in this patient population.

Reducing the Toxicity of Radiotherapy for Pancreatic Cancer With Magnetic Resonance-guided Radiotherapy.

Pancreatic cancer is a highly fatal malignancy for which surgery is currently considered to be the only curative treatment. However, less than a quarter of patients have disease amenable to definitive surgical resection. Local treatment with radiation therapy is a promising alternative to surgery for those patients with unresectable disease. However, conventional radiation techniques with computed tomography (CT)-guided therapy have yielded disappointing results due to the inability to deliver ablative doses of ionizing radiation, while sparing the radiosensitive adjacent organs at risk. Magnetic resonance-guided radiotherapy (MRgRT) has emerged as an alternative to CT-guided radiation treatment which allows for the delivery of higher doses of radiation with low toxicity to surrounding structures. Further study into the use of MRgRT and dose escalation for locally advanced unresectable pancreatic cancer is needed.

Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial.

PURPOSE: Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. METHODS AND MATERIALS: Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. RESULTS: Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. CONCLUSIONS: There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

mDixon-Based Synthetic CT Generation for PET Attenuation Correction on Abdomen and Pelvis Jointly Using Transfer Fuzzy Clustering and Active Learning-Based Classification.

We propose a new method for generating synthetic CT images from modified Dixon (mDixon) MR data. The synthetic CT is used for attenuation correction (AC) when reconstructing PET data on abdomen and pelvis. While MR does not intrinsically contain any information about photon attenuation, AC is needed in PET/MR systems in order to be quantitatively accurate and to meet qualification standards required for use in many multi-center trials. Existing MR-based synthetic CT generation methods either use advanced MR sequences that have long acquisition time and limited clinical availability or use matching of the MR images from a newly scanned subject to images in a library of MR-CT pairs which has difficulty in accounting for the diversity of human anatomy especially in patients that have pathologies. To address these deficiencies, we present a five-phase interlinked method that uses mDixon MR acquisition and advanced machine learning methods for synthetic CT generation. Both transfer fuzzy clustering and active learning-based classification (TFC-ALC) are used. The significance of our efforts is fourfold: 1) TFC-ALC is capable of better synthetic CT generation than methods currently in use on the challenging abdomen using only common Dixon-based scanning. 2) TFC partitions MR voxels initially into the four groups regarding fat, bone, air, and soft tissue via transfer learning; ALC can learn insightful classifiers, using as few but informative labeled examples as possible to precisely distinguish bone, air, and soft tissue. Combining them, the TFC-ALC method successfully overcomes the inherent imperfection and potential uncertainty regarding the co-registration between CT and MR images. 3) Compared with existing methods, TFC-ALC features not only preferable synthetic CT generation but also improved parameter robustness, which facilitates its clinical practicability. Applying the proposed approach on mDixon-MR data from ten subjects, the average score of the mean absolute prediction deviation (MAPD) was 89.78±8.76 which is significantly better than the 133.17±9.67 obtained using the all-water (AW) method (p=4.11E-9) and the 104.97±10.03 obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method (p=0.002). 4) Experiments in the PET SUV errors of these approaches show that TFC-ALC achieves the highest SUV accuracy and can generally reduce the SUV errors to 5% or less. These experimental results distinctively demonstrate the effectiveness of our proposed TFCALC method for the synthetic CT generation on abdomen and pelvis using only the commonly-available Dixon pulse sequence.

Relationships between expression of BCS1L, mitochondrial bioenergetics, and fatigue among patients with prostate cancer.

Introduction: Cancer-related fatigue (CRF) is the most debilitating symptom with the greatest adverse side effect on quality of life. The etiology of this symptom is still not understood. The purpose of this study was to examine the relationship between mitochondrial gene expression, mitochondrial oxidative phosphorylation, electron transport chain complex activity, and fatigue in prostate cancer patients undergoing radiotherapy (XRT), compared to patients on active surveillance (AS). Methods: The study used a matched case-control and repeated-measures research design. Fatigue was measured using the revised Piper Fatigue Scale from 52 patients with prostate cancer. Mitochondrial oxidative phosphorylation, electron-transport chain enzymatic activity, and BCS1L gene expression were determined using patients' peripheral mononuclear cells. Data were collected at three time points and analyzed using repeated measures ANOVA. Results: The fatigue score was significantly different over time between patients undergoing XRT and AS (P<0.05). Patients undergoing XRT experienced significantly increased fatigue at day 21 and day 42 of XRT (P<0.01). Downregulated mitochondrial gene (BC1, ubiquinol-cytochrome c reductase, synthesis-like, BCS1L, P<0.05) expression, decreased OXPHOS-complex III oxidation (P<0.05), and reduced activity of complex III were observed over time in patients with XRT. Moreover, increased fatigue was significantly associated with downregulated BCS1L and decreased complex III oxidation in patients undergoing XRT. Conclusion: Our results suggest that BCS1L and complex III in mitochondrial mononuclear cells are potential biomarkers and feasible therapeutic targets for acute XRT-induced fatigue in this clinical population.

Appropriate Methodology for EBRT and HDR Intracavitary/Interstitial Brachytherapy Dose Composite and Clinical Plan Evaluation for Patients With Cervical Cancer.

PURPOSE: This study assessed the appropriateness of full parameter addition (FPA) methods with respect to the 3-dimensional deformable dose composite method for evaluating combined external beam radiation therapy (EBRT) and intracavitary brachytherapy (ICBT). METHODS AND MATERIALS: A total of 22 patients who received EBRT and high-dose-rate ICBT were retrospectively evaluated. Split-ring and tandem applicators were used for all patients. Additional interstitial needles were used for 5 patients to supplement the implant. Deformable image registrations were performed to deform the secondary EBRT and ICBT planning computed tomography (CT) images onto the reference CT from the third fraction of ICBT. The Dice similarity coefficient was used to evaluate the quality of deformable registration. Doses were transferred to the reference CT, scaled to the equivalent dose in 2-Gy fractions and combined to create the dose composite. Eight dose-accumulation methods were evaluated and compared. D2cc and D0.1cc for organs at risk were investigated. RESULTS: The differences in D2cc for rectum, bladder, sigmoid, and bowel between the FPA method for whole-pelvis EBRT and ICBT, calculated using an old American Brachytherapy Society worksheet (FPA_Eh + I_old) and deformable composite for EBRT with boosts and ICBT (Def_E + B + I) were -2.19 ± 1.37 Gyα/ß = 3, -0.64 ± 1.13 Gyα/ß = 3, -2.06 ± 2.71 Gyα/ß = 3, and -1.59 ± 0.89 Gyα/ß = 3, respectively. The differences in D2cc for rectum, bladder, sigmoid, and bowel between the new ABS worksheet (FPA_Eh + B + I_abs) and the Def_E + B + I method were 1.21 ± 1.22 Gy α/ß = 3, 1.93 ± 1.38 Gyα/ß = 3, 0.72 ± 1.12 Gyα/ß = 3, and 1.19 ± 1.46 Gyα/ß = 3, respectively. Differences in dose-volume histogram parameter values among Def_E + B + I and other FPA methods were not statistically significant (P > .05). CONCLUSIONS: Compared with the FPA-based method, deformable registration-based dose composites demonstrated lower OAR D2cc and D0.1cc values; however, the differences were not statistically significant. The current ABS-recommended FPA-based sheet can serve as an acceptable plan evaluation tool for clinical purposes.

The Emerging Role of Stereotactic Ablative Radiotherapy for Primary Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

CONTEXT: Stereotactic ablative radiotherapy (SABR) is an emerging treatment option for primary renal cell carcinoma (RCC). OBJECTIVE: To systematically review the literature on SABR for primary RCC and perform a meta-analysis evaluating local control (LC), toxicity, and renal function. EVIDENCE ACQUISITION: A PROSPERO-registered (#115573), Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA)-based systematic review of the literature was conducted (1995-2019). Studies of SABR targeting primary RCC tumors were included, while those targeting only metastases were excluded. The primary outcome was LC defined as tumor size reduction and/or absence of local progression. Secondary outcomes included toxicity (Common Terminology Criteria for Adverse Events) and renal function (change in estimated glomerular filtration rate [eGFR]). Weighted random-effect meta-analyses using the DerSimonian and Laird method were conducted for primary and secondary outcomes. The I2 statistic and Cochran's Q test were used to assess heterogeneity. EVIDENCE SYNTHESIS: From 2386 PubMed entries and 924 meeting abstracts, 26 studies were identified (11 prospective trials), including 383 tumors in 372 patients, most of whom were deemed inoperable. Weighted averages (ranges) of median follow-up, median age, and mean tumor size were 28.0 (5.8-79.2)mo, 70.4 (62-83)yr, and 4.6 (2.3-9.5)cm, respectively. RCC histology was confirmed in 78.9% of patients who underwent pretreatment biopsy. Dose fractionation varied, but 26Gy in one fraction and 40Gy in five fractions were most common. The random-effect estimates for LC, grade 3-4 toxicity, and post-SABR eGFR change were 97.2% (95% confidence interval [CI]: 93.9-99.5%, I2=20%), 1.5% (95% CI: 0-4.3%, I2=0%), and -7.7ml/min (95% CI: -12.5 to -2.8, I2=2%), respectively, and heterogeneity was minimal. Six patients with pre-existing renal dysfunction (2.9%) required dialysis. CONCLUSIONS: Renal SABR is locally effective and associated with low toxicity rates for primary RCC, despite treatment of larger tumors in older, mostly medically inoperable patients. PATIENT SUMMARY: Stereotactic ablative radiotherapy is a high-precision, noninvasive radiation treatment requiring few outpatient visits, and represents a safe and effective management option for primary renal cell carcinoma.

Evaluating radiotherapy treatment delay using Failure Mode and Effects Analysis (FMEA).

PURPOSE: This study identified and evaluated the factors that are responsible for delay in the clinical workflow of radiation therapy, starting from the CT simulation (CT-Sim) to the first fraction of treatment delivery using the Failure Mode and Effects Analysis (FMEA) methodology. MATERIALS AND METHODS: A total of 1106 patient cases were retrospectively analyzed using FMEA methodology. For each failure mode (FM), the following factors were rated and discussed by the group: occurrence (O), severity (S), detectability (D), and methods of improvement or mitigation. In addition, two new factors, namely social effect (SE) and economic effect (EE), were introduced to evaluate the impact of FM on the department or hospital. Risk priority number (RPN) and the product of RPN, SE, and EE (i.e. RPNSE-EE) were calculated for each FM. RESULTS: Average delay caused by identified FM was 8 days while 76% of the FMs resulted in delay of less than 5 days. The RPN of all the FMs ranged from 4 to 60 with an average value of 18. "Tumor volume, prescription and objective" had the highest average RPN of 23. The majority of FMs with high RPN were identified in "CT-Sim" (RPN: 21.5 ±â€¯11.1; RPNSE-EE: 97.0 ±â€¯46.4) and "treatment planning" (RPN: 20.1 ±â€¯8.1, RPNSE-EE: 152.9 ±â€¯76.5) stages. CONCLUSION: The FMEA enabled identification of the factors that caused delay in the pre-treatment process of radiation therapy. "CT-Sim" and "treatment planning" stages had more FMs with high RPN values which have higher priority for future improvement. Two new factors, SE and EE, were introduced and appeared to be valuable in evaluating the impact of FMs on radiation oncology department or hospital in general.

UTE-mDixon-based thorax synthetic CT generation.

PURPOSE: Accurate photon attenuation assessment from MR data remains an unmet challenge in the thorax due to tissue heterogeneity and the difficulty of MR lung imaging. As thoracic tissues encompass the whole physiologic range of photon absorption, large errors can occur when using, for example, a uniform, water-equivalent or a soft-tissue-only approximation. The purpose of this study was to introduce a method for voxel-wise thoracic synthetic CT (sCT) generation from MR data attenuation correction (AC) for PET/MR or for MR-only radiation treatment planning (RTP). METHODS: Acquisition: A radial stack-of-stars combining ultra-short-echo time (UTE) and modified Dixon (mDixon) sequence was optimized for thoracic imaging. The UTE-mDixon pulse sequence collects MR signals at three TE times denoted as UTE, Echo1, and Echo2. Three-point mDixon processing was used to reconstruct water and fat images. Bias field correction was applied in order to avoid artifacts caused by inhomogeneity of the MR magnetic field. ANALYSIS: Water fraction and R2* maps were estimated using the UTE-mDixon data to produce a total of seven MR features, that is UTE, Echo1, Echo2, Dixon water, Dixon fat, Water fraction, and R2*. A feature selection process was performed to determine the optimal feature combination for the proposed automatic, 6-tissue classification for sCT generation. Fuzzy c-means was used for the automatic classification which was followed by voxel-wise attenuation coefficient assignment as a weighted sum of those of the component tissues. Performance evaluation: MR data collected using the proposed pulse sequence were compared to those using a traditional two-point Dixon approach. Image quality measures, including image resolution and uniformity, were evaluated using an MR ACR phantom. Data collected from 25 normal volunteers were used to evaluate the accuracy of the proposed method compared to the template-based approach. Notably, the template approach is applicable here, that is normal volunteers, but may not be robust enough for patients with pathologies. RESULTS: The free breathing UTE-mDixon pulse sequence yielded images with quality comparable to those using the traditional breath holding mDixon sequence. Furthermore, by capturing the signal before T2* decay, the UTE-mDixon image provided lung and bone information which the mDixon image did not. The combination of Dixon water, Dixon fat, and the Water fraction was the most robust for tissue clustering and supported the classification of six tissues, that is, air, lung, fat, soft tissue, low-density bone, and dense bone, used to generate the sCT. The thoracic sCT had a mean absolute difference from the template-based (reference) CT of less than 50 HU and which was better agreement with the reference CT than the results produced using the traditional Dixon-based data. CONCLUSION: MR thoracic acquisition and analyses have been established to automatically provide six distinguishable tissue types to generate sCT for MR-based AC of PET/MR and for MR-only RTP.