Redefining radiotherapy for early-stage breast cancer with single dose ablative treatment: a study protocol

Contains fulltext : 181789.pdf (publisher's version ) (Open Access

Tumor-Infiltrating Lymphocytes in Low-Risk Patients With Breast Cancer Treated With Single-Dose Preoperative Partial Breast Irradiation

Contains fulltext : 232805.pdf (Publisher’s version ) (Open Access)PURPOSE: Preoperative partial breast irradiation (PBI) has the potential to induce tumor regression. We evaluated the differences in the numbers of preirradiation tumor infiltrating lymphocytes (TILs) between responders and nonresponders after preoperative PBI in low-risk patients with breast cancer. Furthermore, we evaluated the change in number of TILs before and after irradiation. METHODS AND MATERIALS: In the prospective ABLATIVE study, low-risk patients with breast cancer underwent treatment with single-dose preoperative PBI (20 Gy) to the tumor and breast-conserving surgery after 6 or 8 months. In the preirradiation diagnostic biopsy and postirradiation resection specimen, numbers of TILs in 3 square regions of 450 x 450 mum were counted manually. TILs were visualized with CD3, CD4, and CD8 immunohistochemistry. Differences in numbers of preirradiation TILs between responders and nonresponders were tested using Mann-Whitney U test. Responders were defined as pathologic complete or near-complete response, and nonresponders were defined "as all other response." Changes in numbers of TILs after preoperative PBI was evaluated with the Wilcoxon signed rank test. RESULTS: Preirradiation tissue was available from 28 patients, postirradiation tissue from 29 patients, resulting in 22 pairs of preirradiation and postirradiation tissue. In these 35 patients, 15 had pathologic complete response (43%), 11 had a near-complete response (31%), 7 had a partial response (20%), and 2 had stable disease (6%). The median numbers of CD3(+) TILs, CD4(+) TILs, and CD8(+) TILs in the preirradiation tumor tissue were 49 (interquartile range [IQR], 36-80), 45 (IQR, 28-57), and 19 (IQR, 8-35), respectively. The number of preirradiation TILs did not differ significantly between responders and nonresponders. The median numbers of CD3(+) TILs, CD4(+) TILs, and CD8(+) TILs in postirradiation tumor tissue were 17 (IQR, 13-31), 26 (IQR, 16-35), and 7 (IQR, 5-11), respectively. CONCLUSIONS: After preoperative PBI in this limited cohort, the number of TILs in tumor tissue decreased. No differences in numbers of preirradiation TILs between responders and nonresponders were observed

Treatment constraints for single dose external beam preoperative partial breast irradiation in early-stage breast cancer

Background: Following breast-conserving surgery and post-operative 3D-conformal accelerated partial breast irradiation (APBI), suboptimal cosmetic results have been reported. Preoperative radiation delivery to the intact tumor enables better target visualization and treatment volume reduction. Single dose preoperative APBI has the potential to improve toxicity profiles, reduce treatment burden and enable in vivo exploration of breast cancer radiogenomics. Purpose: Develop practical guidelines for single dose external beam preoperative APBI. Methods: Recommended dose constraints were derived from pooled dosimetry estimates from 2 clinical trials. In an American dose escalation trial, a uniform 15, 18 or 21 Gy dose has previously been evaluated for non-lobular cT1N0 or low/intermediate grade DCIS <2 cm in prone position (n = 32). In the Netherlands, the feasibility of ablative APBI (20 Gy to GTV, 15 Gy to CTV) to non-lobular cT1N0 in supine position, is currently being explored (n = 15). The dosimetric adherence to the developed constraints was evaluated in new APBI plans with a 21 Gy uniform dose but an extended CTV margin (n = 32). Results: Dosimetric data pooling enabled the development of practical guidelines for single dose preoperative APBI. Conclusion: The developed guidelines will allow further explorations in the promising field of single dose preoperative external beam APBI for breast cancer treatment

Health-related quality of life of early-stage breast cancer patients after different radiotherapy regimens

PURPOSE: To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. METHODS: Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 × 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 × 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 × 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21-26 × 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 × 2.3 Gy; n = 475). Women ≥ 60 years with invasive/in situ carcinoma ≤ 30 mm, cN0 and pN0-1a were included. Validated EORTC QLQ-C30/BR23 questionnaires were used to asses HRQL. Multivariable linear regression models adjusted for confounding (age, comorbidity, pT, locoregional treatment, systemic therapy) were used to compare the impact of the RT regimens on HRQL at 12 and 24 months. Differences in HRQL over time (3-24 months) were evaluated using linear mixed models. RESULTS: There were no significant differences in HRQL at 12 months between groups except for breast symptoms which were better after IORT and EB-APBI compared to hypo-WBI at 12 months (p < 0.001). Over time, breast symptoms, fatigue, global health status and role functioning were significantly better after IORT and EB-APBI than hypo-WBI. At 24 months, HRQL was comparable in all groups. CONCLUSION: In women with early-stage breast cancer, the radiotherapy regimen did not substantially influence long-term HRQL with the exception of breast symptoms. Breast symptoms are more common after WBI than after IORT or EB-APBI and improve slowly until no significant difference remains at 2 years posttreatment

Single dose partial breast irradiation using an MRI linear accelerator in the supine and prone treatment position

Background: In selected patients with early-stage and low-risk breast cancer, an MRI-linac based treatment might enable a radiosurgical, non-invasive alternative for current standard breast conserving therapy. Aim: To investigate whether single dose accelerated partial breast (APBI) to the intact tumor in both the prone and supine radiotherapy positions on the MRI-linac is dosimetrically feasible with respect to predefined coverage and organs at risk (OAR) constraints. Material & methods: For 20 patients with cTis or low-risk cT1N0M0 non-lobular breast carcinoma, previously treated with single dose preoperative APBI in the supine (n = 10) or prone (n = 10) position, additional intensity modulated radiotherapy plans with 7 coplanar beams in the presence of a 1.5T magnetic field were generated. A 20 Gy and 15 Gy dose was prescribed to the gross tumor and clinical target volume, respectively. The percentage of plans achieving predefined organ at risk (OAR) constraints, currently used in clinical practice, was assessed. Dosimetry differences between the prone versus supine approach and the MRI-linac versus clinically delivered plans were evaluated. Results: All MRI-linac plans met the coverage and predefined OAR constraints. The prone approach appeared to be more favorable with respect to the chest wall, and ipsilateral lung dose compared to the supine position. No dosimetric differences were observed for the ipsilateral breast. No treatment position was clearly more beneficial for the skin or heart, since dosimetry varied among parameters. Overall, the MRI-linac and clinical plans were comparable, with minor absolute dosimetric differences. Conclusion: MRI-linac based single dose APBI to the intact tumor is a promising and a dosimetrically feasible strategy in patients with low-risk breast cancer. Preliminary OAR dosimetry favored the prone radiotherapy position

Synthetic CT for single-fraction neoadjuvant partial breast irradiation on an MRI-linac

A synthetic computed tomography (sCT) is required for daily plan optimization on an MRI-linac. Yet, only limited information is available on the accuracy of dose calculations on sCT for breast radiotherapy. This work aimed to (1) evaluate dosimetric accuracy of treatment plans for single-fraction neoadjuvant partial breast irradiation (PBI) on a 1.5 T MRI-linac calculated on a) bulk-density sCT mimicking the current MRI-linac workflow and b) deep learning-generated sCT, and (2) investigate the number of bulk-density levels required. For ten breast cancer patients we created three bulk-density sCTs of increasing complexity from the planning-CT, using bulk-density for: (1) body, lungs, and GTV (sCTBD1); (2) volumes for sCTBD1 plus chest wall and ipsilateral breast (sCTBD2); (3) volumes for sCTBD2 plus ribs (sCTBD3); and a deep learning-generated sCT (sCTDL) from a 1.5 T MRI in supine position. Single-fraction neoadjuvant PBI treatment plans for a 1.5 T MRI-linac were optimized on each sCT and recalculated on the planning-CT. Image evaluation was performed by assessing mean absolute error (MAE) and mean error (ME) in Hounsfield Units (HU) between the sCTs and the planning-CT. Dosimetric evaluation was performed by assessing dose differences, gamma pass rates, and dose-volume histogram (DVH) differences. The following results were obtained (median across patients for sCTBD1/sCTBD2/sCTBD3/sCTDL respectively): MAE inside the body contour was 106/104/104/75 HU and ME was 8/9/6/28 HU, mean dose difference in the PTVGTV was 0.15/0.00/0.00/-0.07 Gy, median gamma pass rate (2%/2 mm, 10% dose threshold) was 98.9/98.9/98.7/99.4%, and differences in DVH parameters were well below 2% for all structures except for the skin in the sCTDL. Accurate dose calculations for single-fraction neoadjuvant PBI on an MRI-linac could be performed on both bulk-density and deep learning sCT, facilitating further implementation of MRI-guided radiotherapy for breast cancer. Balancing simplicity and accuracy, sCTBD2 showed the optimal number of bulk-density levels for a bulk-density approach

Dynamic Contrast-enhanced and Diffusion-weighted Magnetic Resonance Imaging for Response Evaluation After Single-Dose Ablative Neoadjuvant Partial Breast Irradiation

PURPOSE: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. METHODS AND MATERIALS: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (<10% vs ≥10% residual tumor cells). The semiquantitative MRI parameters evaluated were time to enhancement (TTE), 1-minute relative enhancement (RE(1min)), percentage of enhancing voxels (%EV), distribution of washout curve types, and apparent diffusion coefficient (ADC). RESULTS: In general, the enhancement increased 1 week after NA-PBI (baseline vs 1 week median - TTE: 15s vs 10s; RE(1min): 161% vs 197%; %EV: 47% vs 67%) and decreased from 2 months onward (6 months median - TTE: 25s; RE(1min): 86%; %EV: 12%). Median ADC increased from 0.83 × 10(-3) mm(2)/s at baseline to 1.28 × 10(-3) mm(2)/s at 6 months. TTE, RE(1min), and %EV showed the most potential to differentiate between radiologic responses, and TTE, RE(1min), and ADC between pathologic responses. CONCLUSIONS: Semiquantitative analyses of DCE and DW-MRI showed changes in relative enhancement and ADC 1 week after NA-PBI, indicating acute inflammation, followed by changes indicating tumor regression from 2 to 6 months after radiation therapy. A relation between the MRI parameters and radiologic and pathologic responses could not be proven in this exploratory study

Tumor Response After Neoadjuvant Magnetic Resonance Guided Single Ablative Dose Partial Breast Irradiation

Contains fulltext : 219916.pdf (Publisher’s version ) (Closed access)PURPOSE: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs). METHODS AND MATERIALS: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, >/=70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software). RESULTS: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed. CONCLUSIONS: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients