Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.

BACKGROUND: Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. METHODS: Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. FINDINGS: Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). INTERPRETATION: A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. FUNDING: Fonds Cancer, Belgium.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.

BACKGROUND: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING: EORTC Charitable Trust.

Pathology-based validation of FDG PET segmentation tools for volume assessment of lymph node metastases from head and neck cancer.

PURPOSE: FDG PET is increasingly incorporated into radiation treatment planning of head and neck cancer. However, there are only limited data on the accuracy of radiotherapy target volume delineation by FDG PET. The purpose of this study was to validate FDG PET segmentation tools for volume assessment of lymph node metastases from head and neck cancer against the pathological method as the standard. METHODS: Twelve patients with head and neck cancer and 28 metastatic lymph nodes eligible for therapeutic neck dissection underwent preoperative FDG PET/CT. The metastatic lymph nodes were delineated on CT (NodeCT) and ten PET segmentation tools were used to assess FDG PET-based nodal volumes: interpreting FDG PET visually (PETVIS), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PETSUV), two segmentation tools with a fixed threshold of 40% and 50%, and two adaptive threshold based methods. The latter four tools were applied with the primary tumour as reference and also with the lymph node itself as reference. Nodal volumes were compared with the true volume as determined by pathological examination. RESULTS: Both NodeCT and PETVIS showed good correlations with the pathological volume. PET segmentation tools using the metastatic node as reference all performed well but not better than PETVIS. The tools using the primary tumour as reference correlated poorly with pathology. PETSUV was unsatisfactory in 35% of the patients due to merging of the contours of adjacent nodes. CONCLUSION: FDG PET accurately estimates metastatic lymph node volume, but beyond the detection of lymph node metastases (staging), it has no added value over CT alone for the delineation of routine radiotherapy target volumes. If FDG PET is used in radiotherapy planning, treatment adaptation or response assessment, we recommend an automated segmentation method for purposes of reproducibility and interinstitutional comparison.

The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R): Real-World Data on Stage III Non-Small Cell Lung Cancer Patients Treated With Curative Chemoradiation.

INTRODUCTION: Chemoradiotherapy (CRT) is the standard of care in inoperable non-small-cell lung cancer (NSCLC) patients, favoring concurrent (cCRT) over sequential CRT (seqCRT), with adjuvant immunotherapy in responders. Elderly and frail NSCLC patients have generally been excluded from trials in the past. In elderly patients however, the higher treatment related morbidity of cCRT, may outweigh the possible lower tumor control of seqCRT. For elderly patients with locally advanced NSCLC real-world data is essential to be able to balance treatment toxicity and treatment outcome. The aim of this study is to analyze acute toxicity and 3-month mortality of curative chemoradiation (CRT) in patients with stage III NSCLC and to analyze whether cCRT for elderly stage III NSCLC patients is safe. METHODS: The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national lung cancer audit that started in 2013 for patients treated with curative intent radiotherapy. All Dutch patients treated for stage III NSCLC between 2015 and 2018 with seqCRT or cCRT for (primary or recurrent) stage III lung cancer are included in this population-based study. Information was collected on patient, tumor- and treatment characteristics and the incidence and severity of acute non-hematological toxicity (CTCAE-4 version 4.03) and mortality within 3 months after the end of radiotherapy. To evaluate the association between prognostic factors and outcome (acute toxicity and mortality within 3 months), an univariable and multivariable analysis was performed. The definition of cCRT was:radiotherapy started within 30 days after the start of chemotherapy. RESULTS: Out of all 20 Dutch departments of radiation oncology, 19 centers participated in the registry. A total of 2942 NSCLC stage III patients were treated with CRT. Of these 67.2% (n = 1977) were treated with cCRT (median age 66 years) and 32.8% (n = 965) were treated with seqCRT (median age 69 years). Good performance status (WHO 0-1) was scored in 88.6% for patients treated with cCRT and in 71.0% in the patients treated with seqCRT. Acute nonhematological 3-month toxicity (CTCAE grade ≥3 or radiation pneumonitis grade ≥2) was scored in 21.9% of the patients treated with cCRT and in 17.7% of the patients treated with seqCRT. The univariable analysis for acute toxicity showed significantly increased toxicity for cCRT (P = .008), WHO ≥2 (P = .006), and TNM IIIC (P = .031). The multivariable analysis for acute toxicity was significant for cCRT (P = .015), WHO ≥2 (P = .001) and TNM IIIC (P = .016). The univariable analysis for 3-month mortality showed significance for seqCRT (P = .025), WHO ≥2 (P < .001), higher cumulative radiotherapy dose (P < .001), higher gross tumor volume total (P = .020) and male patients (p < .001). None of these variables reached significance in the multivariable analysis for 3-month mortality. CONCLUSION: In this national lung cancer audit of inoperable NSCLC patients, 3-month toxicity was significantly higher in patients treated with cCRT (21.9% vs. 17.7% for seqCRT) higher TNM stage IIIC, and poor performance (WHO≥2) patients.The 3-months mortality was not significantly different for tested parameters. Age was not a risk factor for acute toxicity, nor 3 months mortality.

Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer: 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial.

PURPOSE: The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life. METHODS: In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681). RESULTS: Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND. CONCLUSION: This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.

Can FDG PET predict radiation treatment outcome in head and neck cancer? Results of a prospective study.

PURPOSE: In head and neck cancer (HNC) various treatment strategies have been developed to improve outcome, but selecting patients for these intensified treatments remains difficult. Therefore, identification of novel pretreatment assays to predict outcome is of interest. In HNC there are indications that pretreatment tumour (18)F-fluorodeoxyglucose (FDG) uptake may be an independent prognostic factor. The aim of this study was to assess the prognostic value of FDG uptake and CT-based and FDG PET-based primary tumour volume measurements in patients with HNC treated with (chemo)radiotherapy. METHODS: A total of 77 patients with stage II-IV HNC who were eligible for definitive (chemo)radiotherapy underwent coregistered pretreatment CT and FDG PET. The gross tumour volume of the primary tumour was determined on the CT (GTV(CT)) and FDG PET scans. Five PET segmentation methods were applied: interpreting FDG PET visually (PET(VIS)), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PET(2.5)), using fixed thresholds of 40% and 50% (PET(40%), PET(50%)) of the maximum intratumoral FDG activity (SUV(MAX)) and applying an adaptive threshold based on the signal-to-background (PET(SBR)). Mean FDG uptake for each PET-based volume was recorded (SUV(mean)). Subsequently, to determine the metabolic volume, the integrated SUV was calculated as the product of PET-based volume and SUV(mean). All these variables were analysed as potential predictors of local control (LC), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS). RESULTS: In oral cavity/oropharynx tumours PET(VIS) was the only volume-based method able to predict LC. Both PET(VIS) and GTV(CT) were able to predict DMFS, DFS and OS in these subsites. Integrated SUVs were associated with LC, DMFS, DFS and OS, while SUV(mean) and SUV(MAX) were not. In hypopharyngeal/laryngeal tumours none of the variables was associated with outcome. CONCLUSION: There is no role yet for pretreatment FDG PET as a predictor of (chemo)radiotherapy outcome in HNC in daily routine. However, this potential application needs further exploration, focusing both on FDG PET-based primary tumour volume, integrated SUV and SUV(MAX) of the primary tumour.

Deep learning model for automatic contouring of cardiovascular substructures on radiotherapy planning CT images: Dosimetric validation and reader study based clinical acceptability testing.

BACKGROUND AND PURPOSE: Large radiotherapy (RT) planning imaging datasets with consistently contoured cardiovascular structures are essential for robust cardiac radiotoxicity research in thoracic cancers. This study aims to develop and validate a highly accurate automatic contouring model for the heart, cardiac chambers, and great vessels for RT planning computed tomography (CT) images that can be used for dose-volume parameter estimation. MATERIALS AND METHODS: A neural network model was trained using a dataset of 127 expertly contoured planning CT images from RT treatment of locally advanced non-small-cell lung cancer (NSCLC) patients. Evaluation of geometric accuracy and quality of dosimetric parameter estimation was performed on 50 independent scans with contrast and without contrast enhancement. The model was further evaluated regarding the clinical acceptability of the contours in 99 scans randomly sampled from the RTOG-0617 dataset by three experienced radiation oncologists. RESULTS: Median surface dice at 3 mm tolerance for all dedicated thoracic structures was 90% in the test set. Median absolute difference between mean dose computed with model contours and expert contours was 0.45 Gy averaged over all structures. The mean clinical acceptability rate by majority vote in the RTOG-0617 scans was 91%. CONCLUSION: This model can be used to contour the heart, cardiac chambers, and great vessels in large datasets of RT planning thoracic CT images accurately, quickly, and consistently. Additionally, the model can be used as a time-saving tool for contouring in clinic practice.

Can FDG-PET assist in radiotherapy target volume definition of metastatic lymph nodes in head-and-neck cancer?

BACKGROUND AND PURPOSE: The role of FDG-PET in radiotherapy target volume definition of the neck was evaluated by comparing eight methods of FDG-PET segmentation to the current CT-based practice of lymph node assessment in head-and-neck cancer patients. MATERIALS AND METHODS: Seventy-eight head-and-neck cancer patients underwent coregistered CT- and FDG-PET scans. Lymph nodes were classified as "enlarged" if the shortest axial diameter on CT was 10mm, and as "marginally enlarged" if it was 7-10mm. Subsequently, lymph nodes were assessed on FDG-PET applying eight segmentation methods: visual interpretation (PET(VIS)), applying fixed thresholds at a standardized uptake value (SUV) of 2.5 and at 40% and 50% of the maximum signal intensity of the primary tumor (PET(SUV), PET(40%), PET(50%)) and applying a variable threshold based on the signal-to-background ratio (PET(SBR)). Finally, PET(40%N), PET(50%N) and PET(SBRN) were acquired using the signal of the lymph node as the threshold reference. RESULTS: Of 108 nodes classified as "enlarged" on CT, 75% were also identified by PET(VIS), 59% by PET(40%), 43% by PET(50%) and 43% by PET(SBR). Of 100 nodes classified as "marginally enlarged", only a minority were visualized by FDG-PET. The respective numbers were 26%, 10%, 7% and 8% for PET(VIS), PET(40%), PET(50%) and PET(SBR). PET(40%N), PET(50%N) and PET(SBRN), respectively, identified 66%, 82% and 96% of the PET(VIS)-positive nodes. CONCLUSIONS: Many lymph nodes that are enlarged and considered metastatic by standard CT-based criteria appear to be negative on FDG-PET scan. Alternately, a small proportion of marginally enlarged nodes are positive on FDG-PET scan. However, the results are largely dependent on the PET segmentation tool used, and until proper validation FDG-PET is not recommended for target volume definition of metastatic lymph nodes in routine practice.

Interobserver variability in the delineation of the primary lung cancer and lymph nodes on different four-dimensional computed tomography reconstructions.

PURPOSE: The study compared interobserver variation in the delineation of the primary tumour (GTVp) and lymph nodes (GTVln) between three different 4DCT reconstruction types; Maximum Intensity Projection (MIP), Mid-Ventilation (Mid-V) and Mid-Position (Mid-P). MATERIAL AND METHODS: Seven radiation oncologists delineated the GTVp and GTVln on the MIP, Mid-V and Mid-P 4DCT image reconstructions of 10 lung cancer patients. The volumes, the mean standard deviation (SD) and distribution of SD (SD/area) over the median surface contour were compared for different tumour regions. RESULTS: The overall mean delineated volume on the MIP was significantly larger (p < 0.001) than the Mid-V and Mid-P. For the GTVp the Mid-P had the lowest interobserver variation (SD = 0.261 cm), followed by Mid-V (SD = 0.314 cm) and MIP (SD = 0.330 cm) For GTVln the Mid-V had the lowest interobserver variation (SD = 0.425 cm) followed by the MIP (SD = 0.477 cm) and Mid-P (SD = 0.543 cm). The SD/area distribution showed a statistically significant difference between the MIP versus Mid-P and Mid-P versus Mid-V for both GTVp and GTVln (p < 0.001), with outliers indicating interpretation differences for GTVp located close to the mediastinum and GTVln. CONCLUSION: The Mid-P reduced the interobserver variation for the GTVp. Delineation protocols must be improved to benefit from the improved image quality of Mid-P for the GTVln.

Predictors for poor cosmetic outcome in patients with early stage breast cancer treated with breast conserving therapy: Results of the Young boost trial.

PURPOSE: In the Young Boost trial (YBT), breast cancer patients ≤50 years of age, treated with breast conserving therapy (BCT) were randomized between a 26 Gy boost dose and a 16 Gy boost dose, with local recurrence as primary and cosmetic outcome (CO) as secondary endpoint. Data of the YBT was used to investigate which factors are related with worse cosmetic outcome after BCT. METHODS: From 2004 to 2011, 2421 cT1-2N0-2a breast cancer patients were randomized. CO was scored subjectively by the patient and physician, and objectively using BCCT.core: at baseline, one and four years after treatment. Associations between potential risk factors for worse cosmetic outcome, based on the objective BCCT.core, were investigated using a proportional odds model. RESULTS: At four years, CO was significantly better in the standard boost group for all three scoring methods (satisfied CO ±65% vs 55%). A photon boost, high boost dose, poor cosmesis before radiation therapy, large boost volume and adjuvant chemotherapy significantly deteriorated CO. CONCLUSION: Important risk factors for worse CO were the use of a photon boost instead of an electron boost, a high boost dose, cosmesis at baseline, adjuvant chemotherapy and boost volume. These results can be used to define strategies aimed at improving CO.

Comparison of five segmentation tools for 18F-fluoro-deoxy-glucose-positron emission tomography-based target volume definition in head and neck cancer.

PURPOSE: Target-volume delineation for radiation treatment to the head and neck area traditionally is based on physical examination, computed tomography (CT), and magnetic resonance imaging. Additional molecular imaging with (18)F-fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) may improve definition of the gross tumor volume (GTV). In this study, five methods for tumor delineation on FDG-PET are compared with CT-based delineation. METHODS AND MATERIALS: Seventy-eight patients with Stages II-IV squamous cell carcinoma of the head and neck area underwent coregistered CT and FDG-PET. The primary tumor was delineated on CT, and five PET-based GTVs were obtained: visual interpretation, applying an isocontour of a standardized uptake value of 2.5, using a fixed threshold of 40% and 50% of the maximum signal intensity, and applying an adaptive threshold based on the signal-to-background ratio. Absolute GTV volumes were compared, and overlap analyses were performed. RESULTS: The GTV method of applying an isocontour of a standardized uptake value of 2.5 failed to provide successful delineation in 45% of cases. For the other PET delineation methods, volume and shape of the GTV were influenced heavily by the choice of segmentation tool. On average, all threshold-based PET-GTVs were smaller than on CT. Nevertheless, PET frequently detected significant tumor extension outside the GTV delineated on CT (15-34% of PET volume). CONCLUSIONS: The choice of segmentation tool for target-volume definition of head and neck cancer based on FDG-PET images is not trivial because it influences both volume and shape of the resulting GTV. With adequate delineation, PET may add significantly to CT- and physical examination-based GTV definition.

Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical Trial.

IMPORTANCE: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy. OBJECTIVE: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years. INTERVENTIONS: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI. MAIN OUTCOMES AND MEASURES: Time to ipsilateral breast tumor recurrence (IBTR) as first event. RESULTS: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present). CONCLUSIONS AND RELEVANCE: The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02295033.

Correction of an image size difference between positron emission tomography (PET) and computed tomography (CT) improves image fusion of dedicated PET and CT.

AIM: Clinical work in software positron emission tomography/computed tomography (PET/CT) image fusion has raised suspicion that the image sizes of PET and CT differ slightly from each other, thus rendering the images suboptimal for image fusion. The aim of this study was to evaluate the extent of the relative image size difference between PET and CT and the impact of the correction of this difference on the accuracy of image fusion. METHODS: The difference in real image size between PET and CT was evaluated using a phantom study. Subsequently, 13 patients with cancer in the head/neck area underwent both CT and [(18)F]fluorodeoxyglucose PET in a custom-made mask for external beam radiotherapy, with multimodality markers for positional reference. The image size of PET relative to CT was determined by evaluating the distances between the markers in multiple directions in both scans. Rigid-body image fusion was performed using the markers as landmarks, with and without correction of the calculated image size difference. RESULTS: Phantom studies confirmed a difference in real image size between PET and CT, caused by an absolute error in PET image size calibration. The clinical scans demonstrated an average relative difference in image size of 2.0% in the transverse plane and 0.8% along the longitudinal axis, the PET images being significantly smaller. Image fusion using original images demonstrated an average registration error of 2.7 mm. This error was decreased to 1.4 mm after size correction of the PET images, a significant improvement of 48% (P<0.001). CONCLUSIONS: A significant deviation in PET image size may occur, either as a real image size deviation or as a relative difference from CT. Although possibly not clinically relevant in normal diagnostic procedures, correction of such a difference benefits image fusion accuracy. Therefore, it is advisable to calibrate the PET image size relative to CT before performing high-accuracy rigid-body image fusion.

Cardiovascular Disease Risk in a Large, Population-Based Cohort of Breast Cancer Survivors.

PURPOSE: To conduct a large, population-based study on cardiovascular disease (CVD) in breast cancer (BC) survivors treated in 1989 or later. METHODS AND MATERIALS: A large, population-based cohort comprising 70,230 surgically treated stage I to III BC patients diagnosed before age 75 years between 1989 and 2005 was linked with population-based registries for CVD. Cardiovascular disease risks were compared with the general population, and within the cohort using competing risk analyses. RESULTS: Compared with the general Dutch population, BC patients had a slightly lower CVD mortality risk (standardized mortality ratio 0.92, 95% confidence interval [CI] 0.88-0.97). Only death due to valvular heart disease was more frequent (standardized mortality ratio 1.28, 95% CI 1.08-1.52). Left-sided radiation therapy after mastectomy increased the risk of any cardiovascular event compared with both surgery alone (subdistribution hazard ratio (sHR) 1.23, 95% CI 1.11-1.36) and right-sided radiation therapy (sHR 1.19, 95% CI 1.04-1.36). Radiation-associated risks were found for not only ischemic heart disease, but also for valvular heart disease and congestive heart failure (CHF). Risks were more pronounced in patients aged <50 years at BC diagnosis (sHR 1.48, 95% CI 1.07-2.04 for left- vs right-sided radiation therapy after mastectomy). Left- versus right-sided radiation therapy after wide local excision did not increase the risk of all CVD combined, yet an increased ischemic heart disease risk was found (sHR 1.14, 95% CI 1.01-1.28). Analyses including detailed radiation therapy information showed an increased CVD risk for left-sided chest wall irradiation alone, left-sided breast irradiation alone, and internal mammary chain field irradiation, all compared with right-sided breast irradiation alone. Compared with patients not treated with chemotherapy, chemotherapy used ≥1997 (ie, anthracyline-based chemotherapy) increased the risk of CHF (sHR 1.35, 95% CI 1.00-1.83). CONCLUSION: Radiation therapy regimens used in BC treatment between 1989 and 2005 increased the risk of CVD, and anthracycline-based chemotherapy regimens increased the risk of CHF.

Factors associated with patient-reported cosmetic outcome in the Young Boost Breast Trial.

PURPOSE: To investigate which factors are related to patient reported cosmetic outcome (PRCO) after breast conserving therapy. METHODS: From 2004 to 2011, 2421 cT1-2N0-2a breast cancer patients were randomised in the Young Boost Trial between a 16 and a 26Gy boost to the tumour bed. Cosmesis was scored subjectively by the patient and physician, and objectively using BCCT.core, at baseline, one and four years after treatment. Presence of fibrosis, QoL and rib pain at four years were also scored. Data were complete for 864 patients. The relation between the separate components was investigated using a proportional odds model. RESULTS: Of the 7 BCCT.core parameters, the distance from nipple to inframammary fold and the length of the breast contour were significantly related to the overall PRCO at four years. Patients with more fibrosis and poorer QoL scored their cosmesis worse, while rib pain was not related. The agreement between the different scores was low (kappa 0.26-0.42). CONCLUSION: The distance from nipple to inframammary fold, the length of the breast contour and the severity of fibrosis were the main factors related to patient-reported cosmetic outcome. Patients with better QoL scored their cosmesis better.

Clinical evidence on PET-CT for radiation therapy planning in head and neck tumours.

The potential benefits of positron emission tomography (PET) imaging for the management of head and neck tumours are increasingly being recognized. Integrated PET-CT has found its way into the practice of radiation oncology providing both functional and anatomical tumour information for treatment planning and the implications for clinical practice are currently being investigated. First, it has been demonstrated that (18)F-fluorodeoxyglucose ((18)FDG)-PET can improve the accuracy of gross tumour volume delineation for radiation therapy planning. Next, PET using (18)FDG or more specific tracers may facilitate dose escalation to radioresistant tumour subvolumes. Finally, PET can provide tumour characterization prior to and during radiotherapy, facilitating adaptive radiotherapy and other tailored treatment strategies. Although these are promising prospects, unresolved issues remain and these applications are not yet ready for introduction into routine clinical practice.

Innovations in radiotherapy planning of head and neck cancers: role of PET.

Modern radiotherapy techniques heavily rely on high-quality medical imaging. PET provides biologic information about the tumor, complementary to anatomic imaging. Integrated PET/CT has found its way into the practice of radiation oncology, and (18)F-FDG PET is being introduced for radiotherapy planning. The functional information possibly augments accurate delineation and treatment of the tumor and its extensions while reducing the dose to surrounding healthy tissues. In addition to (18)F-FDG, other PET tracers are available for imaging specific biologic tumor characteristics determining radiation resistance. For head and neck cancer, the potential gains of PET are increasingly being recognized. This review describes the current role of PET and perspectives on its future use for selection and delineation of radiotherapy target volumes and for biologic characterization of this tumor entity. Furthermore, the potential role of PET for early response monitoring, treatment modification, and patient selection is addressed in this review.

External beam radiotherapy with endocavitary boost for nasopharyngeal cancer: treatment results and late toxicity after extended follow-up.

PURPOSE: To evaluate the long-term outcome after treatment of nasopharyngeal carcinoma and assess late toxicity in a multidisciplinary clinic. METHODS AND MATERIALS: A retrospective analysis of 117 patients treated for nasopharyngeal cancer in a single institute between 1985 and 2002 was performed. Fifty-one long-term survivors were evaluated for late toxicity by a multidisciplinary team comprising a radiation oncologist, otolaryngologist, neurologist, and oral and maxillofacial surgeon. RESULTS: The 5-year local control rate for T1 to T2 and T3 to T4 tumors was 97% and 76%, respectively. Five-year disease-free survival and overall survival were 82% and 88% for Stage I to IIb disease and 46% and 52% for Stage III to IVb, respectively. Late morbidity evaluation revealed Radiation Therapy Oncology Group (RTOG) Grade III to IV toxicity in 71% of patients. A high incidence of cranial nerve palsies (47%) and mandibular osteolysis (82%) was found, although these complications had limited clinical impact. CONCLUSIONS: The multidisciplinary late morbidity clinic revealed an unexpected high incidence of cranial nerve palsies and mandibular osteolysis and overall an RTOG Grade III to IV toxicity in 71% of patients treated for nasopharyngeal cancer. External beam radiotherapy with endocavitary brachytherapy produces excellent rates of local control for T1 to T2 tumors, but the high incidence of late toxicity suggests an overtreatment.

Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial.

PURPOSE: To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT). PATIENTS AND METHODS: In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed. RESULTS: The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively. CONCLUSION: Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.