PREVLAR: Phase 2a Randomized Trial to Assess the Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Head and Neck Chemoradiotherapy.

PURPOSE: No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study. METHODS AND MATERIALS: This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients' blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria. RESULTS: Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient. CONCLUSIONS: Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy.

Executive summary of the American Radium Society appropriate use criteria for management of uterine clear cell and serous carcinomas.

BACKGROUND: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies. OBJECTIVE: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of current published literature from peer-reviewed journals. A well-established methodology (modified Delphi) was used to rate the appropriate use of diagnostic and therapeutic procedures for the management of uterine clear cell and serous carcinomas. RESULTS: The primary treatment for non-metastatic uterine clear cell and serous carcinomas is complete surgical staging, with total hysterectomy, salpingo-oophorectomy, omentectomy, and lymph node staging. Even in early-stage disease, patients with uterine clear cell and serous carcinomas have a worse prognosis than those with type I endometrial cancers, warranting consideration for adjuvant therapy regardless of the stage. Given the aggressive nature of these malignancies, and until further research determines the most appropriate adjuvant therapy, it may be reasonable to counsel patients about combined-modality treatment with systemic chemotherapy and radiotherapy. CONCLUSION: Patients diagnosed with uterine clear cell and serous carcinomas should undergo complete surgical staging. Multimodal adjuvant therapies should be considered in the treatment of both early-stage and advanced-stage disease. Further prospective studies or multi-institutional retrospective studies are warranted to determine optimal sequencing of therapy and appropriate management of patients based on their unique risk factors. Long-term surveillance is indicated due to the high risk of locoregional and distant recurrence.

Skin dose in radiation treatment of the left breast: Analysis in the context of prone versus supine treatment technique.

PURPOSE: To determine how the skin dose varies in patients receiving radiation treatment for breast cancer in the prone and supine positions. METHODS: Fifty patients were scanned in the prone and supine positions. A radiation treatment plan was created for the left breast using a 6-MV beam for a prescribed dose of 42.66 Gy in 16 fractions. The dose was calculated using 1- and 2.5-mm calculation grid sizes and the surface dose was compared in both techniques. RESULTS: The median gantry angles relative to the skin surface at the central axis were 8 and 52 degrees for treatment in the prone and supine positions, respectively. The mean dose difference between the prone and supine techniques was statistically significant from 3- to 5-mm depth for both grid sizes. For the 1-mm calculation grid size, the doses at 3-, 4-, and 5-mm depths in the prone and supine techniques were 87.80% and 89.10% (P < 0.003), 91.92% and 94.50% (P < 0.00), and 95.30% and 98.20% (P < 0.00), respectively; for the 2.5-mm grid size, the respective doses were 87.10% and 88.59% (P < 0.00), 91.60% and 94.63% (P < 0.00), and 95.10% and 97.80% (P < 0.00), respectively. CONCLUSIONS: This study demonstrates that the prone technique facilitates a relatively lower skin dose than the supine technique. This observation is probably due to the beam angle. The beam is more perpendicular to the skin surface in the prone technique, whereas it is more tangential in the supine technique, which may deliver a higher skin dose. Thus, the dose to the skin should be evaluated in the prone technique, and if desired, the skin dose could be carefully augmented via a bolus or beam spoiler.

Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS. RESULTS: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival. CONCLUSION: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.

Biological Indices Evaluation of Various Treatment Techniques for Left-Sided Breast Treatment.

PURPOSE: To compare dose to organs at risk (OARs) and biological evaluation using normal tissue complication probability (NTCP) for left-sided breast radiation therapy in 4 techniques: supine free breathing (SFB), supine deep inspiration breath hold (SDIBH), prone free breathing (PFB), and prone deep inspiration breath hold (PDIBH). METHODS AND MATERIALS: Twenty-five patients with left-sided breast cancer suitable for this study underwent a computed tomography scan using SFB, SDIBH, PFB, and PDIBH. One radiation oncologist contoured the planning target volume and OAR (cardiac components). Dose-volume histograms and NTCPs for the heart, left ventricle (LV), left anterior descending artery (LAD), and left lung were calculated for all 4 techniques. RESULTS: The mean heart dose in PDIBH is 0.77 Gy, which is statistically significantly lower than in SFB (1.88 Gy, P < .0001), SDIBH (0.97 Gy, P < .001), and PFB (0.85 Gy, P < .001). The mean left lung dose is 0.69 Gy in PFB and 0.88 Gy in PDIBH. PFB and PDIBH have statistically significantly lower doses compared with SFB (6.09 Gy, P < .0001) and SDIBH (5.41 Gy, P < .0001). The mean NTCP in SFB for the heart, LV, and LAD is 0.27%, 0.62%, and 4.23%, respectively, and it is negligible for other techniques. CONCLUSIONS: We found that PDIBH had a dosimetrically lower mean dose for the heart and LV compared with the other 3 techniques. In addition, SDIBH, PFB and PDIBH had statistically significantly lower NTCP for the heart, LV, and LAD compared with SFB. NTCP for the left lung was statistically significantly lower for prone techniques compared with supine techniques. Therefore we concluded that, compared with SDIBH, PDIBH provides the added benefit of sparing the heart while keeping the benefit of sparing the lung as in the prone technique.

Incorporating Routine Magnetic Resonance Imaging-based Planning for the Delivery of High-dose-rate Brachytherapy for Prostate Cancer: An Evaluation of Clinical Feasibility and Dosimetric Outcomes.

Introduction To evaluate the implementation and dosimetric outcomes of magnetic resonance imaging (MRI) planning for improved target and normal tissue definition for the treatment of prostate cancer with high-dose-rate brachytherapy (HDRBT). Methods From August 2015 to October 2017, 137 unique patients with newly diagnosed localized prostate cancer underwent a total of 174 outpatient brachytherapy procedures using MRI-based treatment planning. Patients receiving brachytherapy as monotherapy underwent two separate procedures while those receiving brachytherapy as a boost after external beam radiation therapy underwent a single procedure. The target volume was defined as the prostate +/- seminal vesicles as clinically appropriate without any additional margin. Pre-treatment dose-volume histogram (DVH) goals to the target were: D90≥95%, V90≥95%, V100≥90%, V150≤30%, V200≤15%. DVH goals to organs-at-risk (OARs): urethra D.01cc ≤115%, bladder D1cc ≤75%, rectum D1cc ≤75%, neurovascular bundle D0.1cc ≤100%, penile bulb D1cc ≤100%. Procedure times were recorded at each step of the procedure, from catheter insertion to removal. Results The median target volume was 45.9 cc, the median volume receiving the prescription dose was 53.0 cc, and the median selectivity index was 0.9. The median values for target dosimetry were as follows: D90=99.9%, V90=95.7%, V100=90.1%, V150=28.1%, V200=10.5%. The median values for OAR dosimetry were: urethra D.01cc=114.3%, bladder D1cc=68.3%, rectum D1cc=51.8%, left neurovascular bundle D0.1cc=86.8%, right neurovascular bundle D0.1cc=88.5%, penile bulb D1cc=31.7%. The median time from catheter insertion to end of HDRBT delivery was four hours 14 minutes (range 2:56-9:08); total treatment package time was five hours 32 minutes (range 3:31-9:45). Conclusion Routine MRI-based treatment planning is feasible for the delivery of HDRBT for prostate cancer. We met stringent dosimetric criteria despite more objective target and normal tissue definition with MRI imaging. Treatment package time remains reasonable. We have adopted MRI as our standard imaging modality for HDRBT for prostate cancer.

GammaKnife versus VMAT radiosurgery plan quality for many brain metastases.

The purpose of this work was to compare dose distributions between two radiosurgery modalities, single-isocenter volumetric modulated arc therapy (VMAT), and GammaKnife Perfexion (GK), in the treatment of a large number (≥7) of brain metastases. Twelve patients with 103 brain metastases were analyzed. The median number of targets per patient was 8 (range: 7-14). GK plans were compared to noncoplanar VMAT plans using both 6-MV flattening filter-free (FFF) and 10-MV FFF modes. Parameters analyzed included radiation therapy oncology group conformity index (CI), 12, 6, and 3 Gy isodose volumes (V12 Gy, V6 Gy, V3 Gy), mean and maximum hippocampal dose, and maximum skin dose. There were statistically significant differences in CI (2.5 ± 1.6 vs 1.6 ± 0.8 and 1.7 ± 0.9, P < 0.001, P < 0.001), V12 Gy (2.8 ± 6.1 cc vs 3.0 ± 5.2 cc and 3.1 ± 5.4 cc, P = 0.003, P < 0.001), and V3 Gy (323.0 ± 294.8 cc vs, 880.1 ± 369.1 cc and 937.9 ±  vs 361.9 cc, P = 0.005, P = 0.001) between GK versus both 6-MV FFF and 10-MV FFF. No significant differences existed for maximum hippocampal or skin doses. In conclusion, highly optimized VMAT produced improved conformity at the expense of a higher V12 Gy and V3 Gy volume when compared with highly optimized GK.

SPECT/CT image-based dosimetry for Yttrium-90 radionuclide therapy: Application to treatment response.

This work demonstrates the efficacy of voxel-based 90 Y microsphere dosimetry utilizing post-therapy SPECT/CT imaging and applies it to the prediction of treatment response for the management of patients with hepatocellular carcinoma (HCC). A 90 Y microsphere dosimetry navigator (RapidSphere) within a commercial platform (Velocity, Varian Medical Systems) was demonstrated for three microsphere cases that were imaged using optimized bremsstrahlung SPECT/CT. For each case, the 90 Y SPECT/CT was registered to follow-up diagnostic MR/CT using deformable image registration. The voxel-based dose distribution was computed using the local deposition method with known injected activity. The system allowed the visualization of the isodose distributions on any of the registered image datasets and the calculation of dose-volume histograms (DVHs). The dosimetric analysis illustrated high local doses that are characteristic of blood-flow directed brachytherapy. In the first case, the HCC mass demonstrated a complete response to treatment indicated by a necrotic region in follow-up MR imaging. This result was dosimetrically predicted since the gross tumor volume (GTV) was well covered by the prescription isodose volume (V150 Gy = 85%). The second case illustrated a partial response to treatment which was characterized by incomplete necrosis of an HCC mass and a remaining area of solid enhancement in follow-up MR imaging. This result was predicted by dosimetric analysis because the GTV demonstrated incomplete coverage by the prescription isodose volume (V470 Gy = 18%). The third case demonstrated extrahepatic activity. The dosimetry indicated that the prescription (125 Gy) isodose region extended outside of the liver into the duodenum (178 Gy maximum dose). This was predictive of toxicity as the patient later developed a duodenal ulcer. The ability to predict outcomes and complications using deformable image registration, calculated isodose distributions, and DVHs, points to the clinical utility of patient-specific dose calculations for 90 Y radioembolization treatment planning.

Evaluation of sparing organs at risk (OARs) in left-breast irradiation in the supine and prone positions and with deep inspiration breath-hold.

PURPOSE: To compare doses to organs at risk (OARs) for left-sided whole-breast radiation therapy with comparable planning target volume (PTV) coverage using three techniques: free breathing in a supine position (SFB), deep inspirational breath-hold in a supine position (SDIBH), and free breathing in prone position (PFB). MATERIALS AND METHODS: Thirty-three patients with left-sided early-stage breast cancer underwent CT simulation following SFB, SDIBH, and PFB protocols for whole-breast radiation therapy. One radiation oncologist contoured the breast PTV, heart, left ventricle (LV), and left anterior descending artery (LAD). Treatment plans were optimized using field-in-field technique with the AAA algorithm. Each plan was optimized to provide identical coverage to the PTV such that a reasonable comparison for OAR dosimetry could be evaluated. All plans were prescribed 42.56 Gy in 16 fractions to the left-breast PTV. RESULTS: The mean dose in SFB for the heart, LV, and LAD was 1.92, 3.19, and 21.73 Gy, respectively, which were significantly higher than the mean dose in SDIBH for the heart (1.08 Gy, P ≤ 0.0001), LV (1.50 Gy, P ≤ 0.0001), and LAD (6.3 Gy, P ≤ 0.0001) and in PFB for the heart (0.98 Gy, P ≤ 0.0001), LV (1.34 Gy, P ≤ 0.0001), and LAD (6.57 Gy, P ≤ 0.0001). Similar findings were noted for the cardiac components in SFB for V2.5, V5, V10, V20, and V30 compared with values in SDIBH and PFB. The mean dose for the left lung in PFB was 0.61 Gy that was significantly lower than in SFB (5.63 Gy, P ≤ 0.0001) and SDIBH (5.54 Gy, P ≤ 0.0001). Mean dose and dosimetric values for each OAR increased in SFB and SDIBH for patients with a large breast volume compared with values for patients with a small breast volume. CONCLUSIONS: SFB results in higher heart, LAD, and LV doses than the other techniques. Both PFB and SDIBH are more advantageous for these OARs irrespective of breast volume. PFB results in significantly lower lung doses than SFB and SDIBH. PFB always provided better results than SFB for the heart, LV, LAD, and lung. This conclusion contrasts with some published studies concluding that the prone position has no benefit for heart sparing.

Investigating multi-radiomic models for enhancing prediction power of cervical cancer treatment outcomes.

Quantitative image features, also known as radiomic features, have shown potential for predicting treatment outcomes in several body sites. We quantitatively analyzed 18Fluorine-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) uptake heterogeneity in the Metabolic Tumor Volume (MTV) of eighty cervical cancer patients to investigate the predictive performance of radiomic features for two treatment outcomes: the development of distant metastases (DM) and loco-regional recurrent disease (LRR). We aimed to fit the highest predictive features in multiple logistic regression models (MLRs). To generate such models, we applied backward feature selection method as part of Leave-One-Out Cross Validation (LOOCV) within a training set consisting of 70% of the original patient cohort. The trained MLRs were tested on an independent set consisted of 30% of the original cohort. We evaluated the performance of the final models using the Area under the Receiver Operator Characteristic Curve (AUC). Accordingly, six models demonstrated superior predictive performance for both outcomes (four for DM and two for LRR) when compared to both univariate-radiomic feature models and Standard Uptake Value (SUV) measurements. This demonstrated approach suggests that the ability of the pre-radiochemotherapy PET radiomics to stratify patient risk for DM and LRR could potentially guide management decisions such as adjuvant systemic therapy or radiation dose escalation.

Reproducibility of F18-FDG PET radiomic features for different cervical tumor segmentation methods, gray-level discretization, and reconstruction algorithms.

Site-specific investigations of the role of radiomics in cancer diagnosis and therapy are emerging. We evaluated the reproducibility of radiomic features extracted from 18 Flourine-fluorodeoxyglucose (18 F-FDG) PET images for three parameters: manual versus computer-aided segmentation methods, gray-level discretization, and PET image reconstruction algorithms. Our cohort consisted of pretreatment PET/CT scans from 88 cervical cancer patients. Two board-certified radiation oncologists manually segmented the metabolic tumor volume (MTV1 and MTV2 ) for each patient. For comparison, we used a graphical-based method to generate semiautomated segmented volumes (GBSV). To address any perturbations in radiomic feature values, we down-sampled the tumor volumes into three gray-levels: 32, 64, and 128 from the original gray-level of 256. Finally, we analyzed the effect on radiomic features on PET images of eight patients due to four PET 3D-reconstruction algorithms: maximum likelihood-ordered subset expectation maximization (OSEM) iterative reconstruction (IR) method, fourier rebinning-ML-OSEM (FOREIR), FORE-filtered back projection (FOREFBP), and 3D-Reprojection (3DRP) analytical method. We extracted 79 features from all segmentation method, gray-levels of down-sampled volumes, and PET reconstruction algorithms. The features were extracted using gray-level co-occurrence matrices (GLCM), gray-level size zone matrices (GLSZM), gray-level run-length matrices (GLRLM), neighborhood gray-tone difference matrices (NGTDM), shape-based features (SF), and intensity histogram features (IHF). We computed the Dice coefficient between each MTV and GBSV to measure segmentation accuracy. Coefficient values close to one indicate high agreement, and values close to zero indicate low agreement. We evaluated the effect on radiomic features by calculating the mean percentage differences (d¯) between feature values measured from each pair of parameter elements (i.e. segmentation methods: MTV1 -MTV2 , MTV1 -GBSV, MTV2 -GBSV; gray-levels: 64-32, 64-128, and 64-256; reconstruction algorithms: OSEM-FORE-OSEM, OSEM-FOREFBP, and OSEM-3DRP). We used |d¯| as a measure of radiomic feature reproducibility level, where any feature scored |d¯| ±SD ≤ |25|% ± 35% was considered reproducible. We used Bland-Altman analysis to evaluate the mean, standard deviation (SD), and upper/lower reproducibility limits (U/LRL) for radiomic features in response to variation in each testing parameter. Furthermore, we proposed U/LRL as a method to classify the level of reproducibility: High- ±1% ≤ U/LRL ≤ ±30%; Intermediate- ±30% < U/LRL ≤ ±45%; Low- ±45 < U/LRL ≤ ±50%. We considered any feature below the low level as nonreproducible (NR). Finally, we calculated the interclass correlation coefficient (ICC) to evaluate the reliability of radiomic feature measurements for each parameter. The segmented volumes of 65 patients (81.3%) scored Dice coefficient >0.75 for all three volumes. The result outcomes revealed a tendency of higher radiomic feature reproducibility among segmentation pair MTV1 -GBSV than MTV2 -GBSV, gray-level pairs of 64-32 and 64-128 than 64-256, and reconstruction algorithm pairs of OSEM-FOREIR and OSEM-FOREFBP than OSEM-3DRP. Although the choice of cervical tumor segmentation method, gray-level value, and reconstruction algorithm may affect radiomic features, some features were characterized by high reproducibility through all testing parameters. The number of radiomic features that showed insensitivity to variations in segmentation methods, gray-level discretization, and reconstruction algorithms was 10 (13%), 4 (5%), and 1 (1%), respectively. These results suggest that a careful analysis of the effects of these parameters is essential prior to any radiomics clinical application.

Investigating multi-objective fluence and beam orientation IMRT optimization.

Radiation Oncology treatment planning requires compromises to be made between clinical objectives that are invariably in conflict. It would be beneficial to have a 'bird's-eye-view' perspective of the full spectrum of treatment plans that represent the possible trade-offs between delivering the intended dose to the planning target volume (PTV) while optimally sparing the organs-at-risk (OARs). In this work, the authors demonstrate Pareto-aware radiotherapy evolutionary treatment optimization (PARETO), a multi-objective tool featuring such bird's-eye-view functionality, which optimizes fluence patterns and beam angles for intensity-modulated radiation therapy (IMRT) treatment planning. The problem of IMRT treatment plan optimization is managed as a combined monolithic problem, where all beam fluence and angle parameters are treated equally during the optimization. To achieve this, PARETO is built around a powerful multi-objective evolutionary algorithm, called Ferret, which simultaneously optimizes multiple fitness functions that encode the attributes of the desired dose distribution for the PTV and OARs. The graphical interfaces within PARETO provide useful information such as: the convergence behavior during optimization, trade-off plots between the competing objectives, and a graphical representation of the optimal solution database allowing for the rapid exploration of treatment plan quality through the evaluation of dose-volume histograms and isodose distributions. PARETO was evaluated for two relatively complex clinical cases, a paranasal sinus and a pancreas case. The end result of each PARETO run was a database of optimal (non-dominated) treatment plans that demonstrated trade-offs between the OAR and PTV fitness functions, which were all equally good in the Pareto-optimal sense (where no one objective can be improved without worsening at least one other). Ferret was able to produce high quality solutions even though a large number of parameters, such as beam fluence and beam angles, were included in the optimization.

Rectal dose to prostate cancer patients treated with proton therapy with or without rectal spacer.

The purpose of this study was to evaluate whether a spacer inserted in the prerectal space could reduce modeled rectal dose and toxicity rates for patients with prostate cancer treated in silico with pencil beam scanning (PBS) proton therapy. A total of 20 patients were included in this study who received photon therapy (12 with rectal spacer (DuraSeal™ gel) and 8 without). Two PBS treatment plans were retrospectively created for each patient using the following beam arrangements: (1) lateral-opposed (LAT) fields and (2) left and right anterior oblique (LAO/RAO) fields. Dose volume histograms (DVH) were generated for the prostate, rectum, bladder, and right and left femoral heads. The normal tissue complication probability (NTCP) for ≥grade 2 rectal toxicity was calculated using the Lyman-Kutcher-Burman model and compared between patients with and without the rectal spacer. A significantly lower mean rectal DVH was achieved in patients with rectal spacer compared to those without. For LAT plans, the mean rectal V70 with and without rectal spacer was 4.19 and 13.5%, respectively. For LAO/RAO plans, the mean rectal V70 with and without rectal spacer was 5.07 and 13.5%, respectively. No significant differences were found in any rectal dosimetric parameters between the LAT and the LAO/RAO plans generated with the rectal spacers. We found that ≥ 9 mm space resulted in a significant decrease in NTCP modeled for ≥grade 2 rectal toxicity. Rectal spacers can significantly decrease modeled rectal dose and predicted ≥grade 2 rectal toxicity in prostate cancer patients treated in silico with PBS. A minimum of 9 mm separation between the prostate and anterior rectal wall yields the largest benefit.

ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

ACR Appropriateness Criteria® Management of Recurrent Endometrial Cancer.

OBJECTIVES: In women with endometrial carcinoma (EC), tumor recurrences tend to occur in the 2- to 3-year period following surgical staging. Management of disease recurrence in EC poses significant challenges. These patients represent a heterogenous group where histologic subtypes, previous adjuvant management, interval since completion of adjuvant therapy, and size and site(s) of disease recurrence all have important implications on salvage therapies and prognosis. No randomized controlled trials have been published to determine optimal management in this group of patients. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. RESULTS: Five clinical variants were developed to address common scenarios in the management of women with recurrent EC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. CONCLUSIONS: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with recurrent EC.

Implications of staged reconstruction and adjuvant brachytherapy in the treatment of recurrent soft tissue sarcoma.

PURPOSE: Prior studies illustrated a reduction in wound complications with the use of staged reconstruction (SR) and negative pressure wound therapy when treating soft tissue sarcoma (STS) with surgical resection followed by high-dose-rate adjuvant brachytherapy. The purpose of this study is to compare the outcomes of SR and immediate reconstruction (IR) brachytherapy in recurrent STS. METHODS AND MATERIALS: A retrospective review of 40 patients with recurrent STS of the local extremity and trunk treated with resection followed by adjuvant brachytherapy alone. Margin status was defined as positive (SM(+)) if there was microscopic involvement (R1) or ≤1 mm margin and negative (SM(-)) if >1 mm margin was obtained. SR and IR were compared regarding toxicity, local control, and limb preservation. RESULTS: Median followup was 27 months. When comparing the SR (n = 22) and IR (n = 18) cohorts, there was a significantly lower final SM(+) rate in SR (32% vs. 83%, p < 0.01). A 2-year local control benefit seen with SR (80% vs. 34%; p = 0.012) and a final SM(-) (81% vs. 39%; p = 0.023). SR was associated with less toxicity on multivariate analysis, including a 90% decrease in persistent edema, an 80% decrease in wound dehiscence, and a 94% decrease in nonhealing wounds, when compared to IR. Ten of 31 (32%) extremity cases required eventual amputation from either chronic wound complications (n = 4) or local recurrence (n = 6). SR predicted for a benefit in 2-year limb preservation (88% vs. 50%; p = 0.008). CONCLUSION: In our series, the treatment with SR brachytherapy resulted in less morbidity and an improved final SM(-) rate. This technique translated to an improvement in both local control and limb preservation of recurrent STS.

Role of Gamma Knife® Radiosurgery for the Treatment of Brain Metastases from Gynecological Cancers.

OBJECTIVE: Gamma Knife® (GK) (Elekta Instruments, Stockholm, Sweden) radiosurgery is well established for treatment of brain metastases. There are limited data on patients treated with GK from gynecological cancers. The authors sought to determine the effectiveness of the GK in patients with brain metastases from gynecological cancers. METHODS: An IRB-approved database was queried for patients with gynecologic cancers treated with GK between June 1996 and May 2016. Imaging studies were reviewed post-SRS (stereotactic radiosurgery) to evaluate local control (LC) and distant brain control (DC). Overall survival (OS), local control, and distant brain control were calculated using the Kaplan-Meier (KM) method and log-rank test.  Results: Thirty-three patients underwent SRS for 73 separate cranial lesions. The median age was -58.5 years, and 17 (52%) also had extracranial metastases. Ten (30%) patients had previously received whole brain radiotherapy (WBRT), and 11 (33%) underwent concurrent WBRT. The median tumor volume was 0.96 cm3. Median radiographic follow-up was 11 months. At the time of treatment, 39% of patients were categorized as recursive partitioning analysis (RPA) Class I, 55% as RPA Class II, and 6% as RPA Class III. The local failure rate was 8%. Five patients (15%) developed new brain lesions outside the radiation field with a median progression-free survival (PFS) of seven (range: 3-9) months. Median OS was 15 months from GK treatment. One-year OS was 72.9% from GK treatment. Primary cancer histology was a significant predictor of OS, favoring ovarian and endometrial cancer (p = 0.03). CONCLUSIONS: Gamma Knife stereotactic radiosurgery for gynecologic brain metastases leads to excellent control rates of treated lesions. Primary histology may have a significant impact on OS following GK, with improved survival seen with ovarian and cervical cancer following Gamma Knife radiosurgery (p = 0.03).

ACR Appropriateness Criteria® Adjuvant Therapy in Vulvar Cancer.

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

Dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with high-dose-rate brachytherapy for large prostate volumes.

PURPOSE: To evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes. MATERIALS AND METHODS: One hundred and two prostate cancer patients with prostate volumes >50 mL (range: 5-29 mL) were treated with high-dose-rate (HDR) brachytherapy ± intensity modulated radiation therapy (IMRT) to 4,500 cGy in 25 daily fractions between 2009 and 2013. HDR brachytherapy monotherapy doses consisted of two 1,350-1,400 cGy fractions separated by 2-3 weeks, and HDR brachytherapy boost doses consisted of two 950-1,150 cGy fractions separated by 4 weeks. Twelve of 32 (38%) unfavorable intermediate risk, high risk, and very high risk patients received androgen deprivation therapy. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4. RESULTS: Median follow-up was 14 months. Dosimetric goals were achieved in over 90% of cases. Three of 102 (3%) patients developed Grade 2 acute proctitis. No variables were significantly associated with Grade 2 acute proctitis. Seventeen of 102 (17%) patients developed Grade 2 acute urinary retention. American Urological Association (AUA) symptom score was the only variable significantly associated with Grade 2 acute urinary retention (p=0.04). There was no ≥ Grade 3 acute toxicity. CONCLUSIONS: Dosimetric coverage of the prostate and normal tissue sparing were adequate in patients with prostate volumes >50 mL. Higher pre-treatment AUA symptom scores increased the relative risk of Grade 2 acute urinary retention. However, the overall incidence of acute toxicity was acceptable in patients with large prostate volumes.

Dosimetric Coverage of the Prostate, Normal Tissue Sparing, and Acute Toxicity with High-Dose-Rate Brachytherapy for Large Prostate Volumes

To evaluate dosimetric coverage of the prostate, normal tissue sparing, and acute toxicity with HDR brachytherapy for large prostate volumes.