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Objectives: Botulinum neurotoxin (BoNT) injections in the salivary glands and radiotherapy (RT) on these glands are commonly used to alleviate severe drooling in patients with amyotrophic lateral sclerosis (ALS). This study compares BoNT type A with RT based on patient-rated evaluations., Materials & Methods: A prospective randomized controlled pilot study to compare RT (n = 10; on the parotid and the posterior part of the submandibular glands) with BoNT-A treatment (n = 10; in the parotid glands only, because of the risk of increasing oropharyngeal weakness) in patients with ALS. The primary outcome was the drooling status (burden of drooling), and our secondary interests were the degree of salivation, global change of drooling after treatment, and level of satisfaction with the treatment and negative experiences., Results: There were no statistically significant between-treatment differences for the drooling status after treatment. Only at twelve weeks more saliva reduction was achieved by RT (P = 0.02). Patients treated with RT also described more transient negative experiences (like pain in mandible) directly after treatment. Subgroup analysis showed that patients with very severe dysphagia (no oral intake) were less satisfied and experienced a lower global change of drooling after treatment., Conclusions: This pilot study showed no significant difference in the burden of drooling between the treatments. However, with RT more saliva reduction was achieved, including negative experiences directly after treatment, but without the risk of decreasing oropharyngeal function. In addition, patients with very severe dysphagia do not seem to benefit from either treatment., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

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.

Background: Axillary recurrence after negative sentinel lymph node biopsy (SLNB) in patients with invasive breast carcinoma remains a concern. Previous investigations to identify prognostic factors for axillary recurrence identified that a disproportionate number of patients with an axillary recurrence after negative SLNB were not treated with external beam radiation therapy (EBRT) of the breast as part of initial treatment. This finding prompted a systematic review to test the hypothesis that EBRT to the breast reduces the risk of axillary recurrence after negative SLNB., Methods: A literature search was performed in PubMed, the Cochrane Library and the Spanish-language database LILACS to identify articles publishing data regarding follow-up of sentinel lymph node (SLN)-negative patients. Reports and articles lacking information on the initial treatment were excluded., Results: Forty-five articles were accepted for review. A total of 23,357 SLN-negative patients were identified with median follow-up ranging from 15 to 102 months. Some 18,878 patients were treated with EBRT to the breast as part of their initial treatment. One hundred and twenty-seven patients with an axillary recurrence were identified, of whom 73 had EBRT as part of their initial treatment. Meta-analysis showed that EBRT was associated with a lower rate of axillary recurrence (P < 0·001), but this finding was subject to heterogeneity., Conclusion: This review and meta-analysis showed that EBRT is associated with a significantly lower axillary recurrence rate after negative SLNB., (Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 European Society for Therapeutic Radiology and Oncology and European Association of Nuclear Medicine. Published by Elsevier Ireland Ltd.. All rights reserved.)

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.

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.

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.

Aim: Integration of positron emission tomography (PET) information into computer tomography (CT)- based intensity modulated external beam radiation therapy (IMRT) allows adaptation of the target volume to functional parameters, but only when the image registration procedure is reliable. The aim of this study was to select the optimal method for software fusion of dedicated PET and CT, and to validate the procedure for IMRT head-neck area., Method: Fifteen patients with head and neck squamous cell carcinoma underwent separate CT and F-18-fluorodeoxyglucose positron emission tomography(FDG-PET), both in a custom-moulded rigid mask fitted with 4 multimodality fiducial markers. Five image registration methods were applied . PET emission and CT were registered manually (ME) and using the landmarks (LM). PET transmission and CT were registered manually (MT) using a mutual information-based method (MI) and an iterative closest point method (ICP). The error in image registration of each method was determined by evaluating the markers., Results: LM showed an average registration error of 1.4 mm at the location of the markers, and 0.3mm in the planning area. However, this method proved to be laborious. Apart from LM, the best method was ICP, with registration errors of 3 and 2mm, respectively. The respective errors were 4.7 and 3.5 mm with ME, 3.6 and 2.7 mm with MT, and 5.3 and 4.1mm with MI., Conclusion: Image fusion of dedicated PET and CT of the head-neck area can be performed reliably using the operator-independent ICP method with no need for laborious markers. The achieved accuracy permits implementation of dedicated PET images in external beam radiation therapy.

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.

Progress in radiation oncology requires a re-evaluation of the methods of target volume delineation beyond anatomical localization. New molecular imaging techniques for tumour visualisation such as positron emission tomography (PET) provide insight into tumour characteristics and can be complementary to the anatomical data of computed tomography or magnetic resonance imaging. In this review, three issues are discussed: First, can PET identify a tumour more accurately? Second, can biological tumour characteristics be visualised? Third, can intratumoural heterogeneity of these characteristics be identified?, ((c) International Cancer Imaging Society.)

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.

In two women, aged 86 and 56 years, respectively, who suffered from back pain and loss of strength, and in a 55-year-old man who lost sensation and strength in his left leg, spinal-cord compression in connection with vertebral destruction was seen on radiological examination. When spinal-cord compression is the result of a local malignant tumour, the therapy often entails emergency radiotherapy. In the first two patients, histological examination revealed a solitary plasmocytoma and curative high-dose radiotherapy was applied. The third patient also had a lung tumour and received low-dose palliative radiotherapy to the vertebrae, as a metastasis was suspected. Later, however, histopathologic examination of the vertebral lesion revealed osteomyelitis due to Listeria monocytogenes and the lung tumour was diagnosed as a pT2N0M0 broncho-alveolar carcinoma which was surgically removed. When a patient is referred with a nontraumatic spinal-cord injury, it is important to complete the radiological and histological examinations before starting emergency radiotherapy in order to prevent an inadequate or even incorrect treatment.