Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Variability of Target Volumes and Organs at Risk Delineation in Breast Cancer Radiation Therapy: Quality Assurance Results of the Pretrial Benchmark Case for the POTENTIAL Trial.

PURPOSE: To estimate the variations in clinical target volumes (CTVs) and organs at risk delineation within the quality assurance (QA) program of the POTENTIAL trial, which is a multicenter, randomized phase 3 trial evaluating postmastectomy radiation therapy (RT), with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. METHODS AND MATERIALS: The simulating computed tomography scan data set of a benchmark case was sent to the participating centers, and the delineation of CTVs and organs at risk was required to be completed by the investigators following protocol guidelines. All submitted contours were reviewed and compared with the reference contours created by the QA team, using quantitative geometric analysis regarding volume and the Jaccard Index (JCI), Dice similarity coefficient, Geographic Miss Index, Discordance Index, and mean distance to agreement. In addition to the whole-volume analysis of all structures, the combination contour of the supraclavicular fossa and level III and II axilla (CTVsc + axIII + axII) was further analyzed on a slice-by-slice basis. RESULTS: The contours from 26 centers were reviewed and variations were observed between submission and reference. The variations of the CTV of the chest wall, contralateral breast, and heart were small, for which the mean JCI values were 0.62, 0.68, and 0.87, respectively. However, the mean JCI values of the CTV of the internal mammary nodal region, ipsilateral brachial plexus, left anterior descending coronary artery, and right coronary artery were 0.38, 0.21, 0.29, and 0.18, respectively, suggesting marked variations. In addition, marked under- and overoutlining variations were identified on 4 slices of CTVsc + axIII + axII on slice-by-slice analysis. CONCLUSIONS: There were residual contouring variations despite a detailed protocol being provided, confirming the importance of pretrial QA in RT and highlighting the need for education and consideration of a real-time central review of the target delineation before the trial participants begin RT.

Mapping of Level I Axillary Lymph Nodes in Patients with Newly Diagnosed Breast Cancer: Optimal Target Delineation and Treatment Techniques for Breast and Level I Axilla Irradiation.

PURPOSE: To map the locations of level I axilla (Ax-L1) lymph nodes (LNs), evaluate the clinical target volume (CTV) coverage defined by the Radiation Therapy Oncology Group (RTOG) Breast Cancer Atlas, and assess the optimal techniques for whole-breast and Ax-L1 irradiation (WBI + Ax-L1). METHODS AND MATERIALS: We identified 76 patients newly diagnosed with breast cancer with 1 to 4 positive LNs confirmed by axillary dissection. The locations of 116 involved Ax-L1 LNs on diagnostic computed tomography (CT) were mapped onto simulated CT images of a standard patient. Ax-L1 LN coverage by the RTOG atlas was evaluated, and a modified Ax-L1 CTV with better coverage was proposed. Treatment plans were designed for WBI + Ax-L1 with high tangential simplified intensity modulated radiation therapy (HT-sIMRT) and volumetric modulated arc therapy (VMAT) and for WBI + RTOG Ax-L1 with VMAT with a prescription dose of 50 Gy in 25 fractions, respectively. The differences in dosimetric parameters were compared. RESULTS: The RTOG Atlas missed 29.3% of LNs. Modification by extending 1 cm caudal and 0.5 cm anterior to the RTOG-defined CTV borders allowed the modified Ax-L1 CTV to encompass 90.5% of LNs. All plans met the required prescription dose to WBI and Ax-L1. The mean dose and the V20 and V5 (percentage volume receiving 20 Gy and 5 Gy) of the ipsilateral lung were 11.7 Gy, 23.0%, and 38.1% for HT-sIMRT WBI + Ax-L1 and 8.9 Gy, 16.4%, and 32.5% for VMAT WBI + Ax-L1 plans, respectively. The mean heart doses in the left-sided plans were 3.2 Gy and 3.0 Gy, respectively. The V30 of the humeral head and the minimum dose to the axillary-lateral thoracic vessel junction were 2.0% versus 1.8% and 45.5 Gy versus 45.7 Gy for VMAT WBI + Ax-L1 and VMAT WBI + RTOG Ax-L1 plans, respectively. CONCLUSIONS: A modified Ax-L1 CTV with expansion of the caudal and anterior borders might provide better coverage. Compared with HT-sIMRT WBI + Ax-L1, VMAT WBI + Ax-L1 provided an adequate dose to the Ax-L1 while decreasing the doses to most normal tissues. Coverage of the modified Ax-L1 did not increase the dose to organs at risk compared with coverage of RTOG Ax-L1.

POstmastectomy radioThErapy in Node-posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a study protocol for a multicenter prospective phase III randomized controlled trial.

BACKGROUND: Various randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques. METHODS: POTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1-3 vs. 4-9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed. DISCUSSION: This trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy. TRIAL REGISTRATION: ClinicalTrails.gov , NCT04320979 . Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979.