281 Background: To analyze the effect of radiation dose escalation to the primary tumor on local control, locoregional control, survival and toxicity in definitive chemoradiation for esophageal cancer. Methods: Patients with clinical stage T2-4, N0-3, M0 carcinoma of the esophagus were randomized between a standard dose of 50.4 Gy/1.8 Gy/5,5 weeks to the tumor and regional lymph nodes (SD) versus the same dose combined with an integrated boost of 0,4 Gy per fraction (total 61,6 Gy) to the primary tumor (HD). Chemotherapy consisted of 6 weekly concurrent carboplatin (AUC 2) and paclitaxel (50 mg/m2) in both arms. The primary endpoint was local progression free survival (LPFS) and 260 patients were needed to detect a difference of 15% (power: 80%). Secondary endpoints were locoregional progression free survival (LRPFS), overall survival (OS) and toxicity. Patients were stratified for histological subtype. Results: Between September 2012 and June 2018, 260 patients were included. Reasons for inoperability were proximal localization and patient preference (44%), comorbidity (30%), unresectable lymph nodes (11%), T4 (5%), local recurrence 2% and combinations (7%). 61% of the patients had a squamous cell carcinoma (SCC) and 39% had an adenocarcinoma (AC). 94% completed radiation treatment and 85% had at least 5 courses chemotherapy. Median follow up time was 45 months. 3-year LPFS was 70% in the SD arm versus 76% in the HD arm (ns). LPFS for SCC and AC was 74% versus 81% and 62% versus 65% for SD and HD, resp. (ns). 3-year LRPFS was 53% and 63% for the SD and HD arm resp. (p = 0.08). 1 year any progression free survival was 60% for SCC and 50% for AC, without a significant difference between SD and HD (p = 0,5). 3-year OS was 41% versus 40% for SD and HD resp. Overall grade 4 and 5 CTC toxicity was 12% and 4% in the SD arm versus 14% and 10% in the HD arm, resp. Conclusions: In definitive chemoradiation for esophageal cancer, radiation dose escalation up to 61,6 Gy to the primary tumor did not result in a significant increase in local control over 50,4 Gy. Numerical improvement of locoregional control after HD was observed with an increase in toxicity and without improving OS. Clinical trial information: NL38343.018.11.
Background and purpose Treatment planning of radiotherapy is a time-consuming and planner dependent process that can be automated by dose prediction models. The purpose of this study was to evaluate the performance of two machine learning models for breast cancer radiotherapy before possible clinical implementation. Materials and methods An in-house developed model, based on U-net architecture, and a contextual atlas regression forest (cARF) model integrated in the treatment planning software were trained. Obtained dose distributions were mimicked to create clinically deliverable plans. For training and validation, 90 patients were used, 15 patients were used for testing. Treatment plans were scored on predefined evaluation criteria and percent errors with respect to clinical dose were calculated for doses to planning target volume (PTV) and organs at risk (OARs). Results The U-net plans before mimicking met all criteria for all patients, both models failed one evaluation criterion in three patients after mimicking. No significant differences (p < 0.05) were found between clinical and predicted U-net plans before mimicking. Doses to OARs in plans of both models differed significantly from clinical plans, but no clinically relevant differences were found. After mimicking, both models had a mean percent error within 1.5% for the average dose to PTV and OARs. The mean errors for maximum doses were higher, within 6.6%. Conclusions Differences between predicted doses to OARs of the models were small when compared to clinical plans, and not found to be clinically relevant. Both models show potential in automated treatment planning for breast cancer.
Background. Even in view of the recent findings of the MA.17R trial, the impact of prolonged aromatase inhibitor (AI) therapy after prior tamoxifen in hormone receptor-positive early breast cancer remains insufficiently clear. Methods. In this open-label phase III study, we randomly assigned 1912 postmenopausal women with hormone receptor-positive breast cancer after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole therapy. The primary endpoint was the adapted disease-free survival (ADFS). This was defined as the DFS beyond 3 years after randomization to AI therapy because initially all patients received the same AI therapy for 3 years. ADFS events included (non-) invasive breast cancer recurrences (local, regional, distant), second primary (non-) invasive (breast) cancers, and death of any cause. The study was designed to detect an increase of the ADFS in the 6-year versus the 3-year anastrozole group corresponding with a hazard ratio (HR) of 0.60. The HRs and the corresponding 95% confidence intervals (CIs) were estimated with stratified Cox proportional-hazard models according to intention-to-treat. Results. Patients were randomized from July 2006 till August 2009. Three years after randomization 1663 patients had no DFS events, with an equal distribution between the treatment arms. The patient and tumor characteristics were well balanced. The median age at randomization was 57 years (P5 = 45 years, P95 = 76 years), the median primary tumor size was 21 mm (P5 = 10 mm, P95 = 50 mm), 67% of the patients had node-positive disease, and in 2% the tumor was HER2-positive (14% unknown); 64% of the patients had received adjuvant chemotherapy and <1% adjuvant trastuzumab. The median adapted follow-up was 4.1 years (P5 = 2.9 years, P95 = 5.8 years). No unexpected safety issues were seen. The 5-year ADFS was 79% in the 3-year and 83% in the 6-year anastrozole treatment group, yielding a HR for ADFS-event of 0.78 (95% CI 0.61 to 1.00; p = 0.0528). In patients with node-positive disease (N = 1117), the HR for ADFS-event was 0.71 (95% CI 0.53 to 0.96; p=0.0232), in N0 disease (N=546) 1.01 (95% CI 0.62 to 1.63; p=0.9817) and in patients with both ER and PR positive breast cancer (N = 1264) 0.68 (95% CI 0.51 to 0.90; p=0.0072). The 5-year adapted overall survival was not different between the treatment groups. Conclusion. These findings do not yet support the use of extended adjuvant AI prescription after 5 years of sequential endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer, but suggest benefit for a selected group of patients. Continued follow-up is needed to assess long-term efficacy and safety. Funding. Funded by AstraZeneca NL, ClinicalTrials.gov number, NCT00301457. Citation Format: Tjan-Heijnen VC, Van Hellemond IE, Peer PG, Swinkels AC, Smorenburg CH, Van der Sangen M, Kroep JR, De Graaf H, Honkoop AH, Erdkamp F, Van den Berkmortel FW, Kitzen JJ, De Boer M, De Roos WK, Linn SC, Imholz AL, Seynaeve C. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-03.
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