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This study aimed to highlight the value and key findings of on-site proton audits.The authors performed 38 on-site measurement-based peer reviews of proton centers participating in National Cancer Institute-funded clinical trials. The reviews covered beam calibration, lateral and depth measurements, mechanical checks, treatment planning and clinical practice, and quality assurance (QA) practices. Program deficiencies were noted, and recommendations were made about ways institutions could improve their practices.Institutions received an average of 3 (range, 1-8) recommendations for practice improvements. The number of deficiencies did not decrease over time, highlighting the continued need for this type of peer review. The most common deficiencies were for Task Group-recommended QA compliance (97% of centers), computed tomography number (CTN) to relative linear stopping power conversion (59%), and QA procedures (53%). In addition, 32% of institutions assessed failed at least 1 lateral beam profile measurement (90% of pixels passing 3% [global]/3 mm; 10% threshold), despite passing internal QA measurements. These failures occurred for several different plan configurations (large, small, shallow, and deep targets) and at different depths in the beam path (proximal to target, central, and distal). CTN to relative linear stopping power conversion curves showed deviations at low, mid, and high CTNs and highlighted areas of inconsistency between proton centers, with many centers falling outside of 2 sigma of the mean curve of their peers. All deficiencies from the peer review were discussed with the institutions, and many implemented dosimetric treatment planning and practice changes to improve the accuracy of their system and consistency with other institutions.This peer review program has been integral in confirming and promoting consistency and best practice across proton centers for clinical trials, minimizing deviations for outcomes data.

PurposeTo test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer.Methods and materialsIn an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS.ResultsIn total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P=.048) and in the combined cohort (13% vs 35%, χ2P=.01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P=.216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group.ConclusionsPET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.

PURPOSE: Sparing active bone marrow (ABM) can reduce acute hematologic toxicity in patients undergoing chemoradiotherapy for cervical cancer, but ABM segmentation based on positron emission tomography/computed tomography (PET/CT) is costly. We sought to develop an atlas-based ABM segmentation method for implementation in a prospective clinical trial. METHODS AND MATERIALS: A multiatlas was built on a training set of 144 patients and validated in 32 patients from the NRG-GY006 clinical trial. ABM for individual patients was defined as the subvolume of pelvic bone greater than the individual mean standardized uptake value on registered (18)F-fluorodeoxyglucose PET/CT images. Atlas-based and custom ABM segmentations were compared using the Dice similarity coefficient and mean distance to agreement and used to generate ABM-sparing intensity modulated radiation therapy plans. Dose-volume metrics and normal tissue complication probabilities of the two approaches were compared using linear regression. RESULTS: Atlas-based ABM volumes (mean [standard deviation], 548.4 [88.3] cm(3)) were slightly larger than custom ABM volumes (535.1 [93.2] cm(3)), with a Dice similarity coefficient of 0.73. Total pelvic bone marrow V(20) and D(mean) were systematically higher and custom ABM V(10) was systematically lower with custom-based plans (slope: 1.021 [95% confidence interval (CI), 1.005-1.037], 1.014 [95% CI, 1.006-1.022], and 0.98 [95% CI, 0.97-0.99], respectively). We found no significant differences between atlas-based and custom-based plans in bowel, rectum, bladder, femoral heads, or target dose-volume metrics. CONCLUSIONS: Atlas-based ABM segmentation can reduce pelvic bone marrow dose while achieving comparable target and other normal tissue dosimetry. This approach may allow ABM sparing in settings where PET/CT is unavailable.

Purpose To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. Methods and Materials We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. Results From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data ( P =.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ 2 P =.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P =.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P =.25). Conclusions IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Purpose To present issues to be considered in, and make proposals for, image-based brachytherapy for cervical cancer. Methods and materials The Image-Guided Brachytherapy Working Group, consisting of representatives from the Gynecology Oncology Group (GOG), Radiologic Physics Center (RPC), American Brachytherapy Society (ABS), American College of Radiology (ACR), American College of Radiology Imaging Network (ACRIN), American Association of Physicists in Medicine (AAPM), Radiation Therapy Oncology Group (RTOG), and American Society for Therapeutic Radiology and Oncology (ASTRO), proposed guidelines for image-based brachytherapy for cervical cancer. This report was based on their aggregate clinical experience and a review of the literature. It reflects only the personal opinions of the authors and is not meant to be an endorsement from any of the above organizations. Results The Group recommended T 2 -weighted MRI using a pelvic surface coil with MRI-compatible brachytherapy applicators in place for image-based intracavitary brachytherapy for cervical cancer. Imaging must be performed with the patient in the treatment position, with all other treatment conditions duplicated as closely as possible. Future use of positron emission tomography or positron emission tomography/CT may obviate the need for special applicators. The group proposed the following terminology for image-based brachytherapy. The GTV (I) is defined as the gross tumor volume as defined through imaging, GTV is defined as the GTV (I) plus any clinically visualized or palpable tumor extensions, and GTV + cx is defined as the GTV plus the entire cervix. The dose–volume histograms (DVH) of the GTV, GTV (I) , GTV + cx should be performed, and the dose to 100%, 95%, or 90% of the GTV (D 100 , D 95 , and D 90 , respectively) and the percentage of the GTV covered by Point A dose (V 100 ) should be reported. Similarly, the DVH of the bladder and rectum wall should be performed, and the maximal dose at any point within the bladder and rectal wall should be reported, along with the maximal dose to a contiguous 1, 2, and 5 cm 3 volume of the bladder and rectum, respectively. In addition, the dose at the International Commission on Radiation Units and Measurements reference point for the bladder and rectum should be reported. The Group thought that the current dose prescription method in use for cervical cancer brachytherapy (i.e., to prescribe to Point A in most institutions) should not be changed as yet, because image-based dosimetry is not ready for routine practice. The Group proposes that for research purposes, individual centers and cooperative groups (e.g., GOG, RTOG, ACRIN) collect image-based dosimetry information and perform DVHs and correlate these data with the clinical outcome to determine which of the above parameters are relevant. The Group encourages external funding for image-based dosimetry and recommends that brachytherapy manufacturers develop image-compatible applicators. Conclusion Although current institutional brachytherapy prescription for cervical cancer should continue, image-based data collection and analysis are needed to optimize cervical cancer brachytherapy. Proposals are made for research in image-based brachytherapy for cervical cancer.