Search

Background Breast cancer treatment with radiotherapy can induce late radiation toxicity, characterized by pain, fibrosis, edema, impaired arm mobility, and poor cosmetic outcome. Hyperbaric oxygen therapy (HBOT) has been proposed as treatment for late radiation toxicity; however, high-level evidence of effectiveness is lacking. As HBOT is standard treatment and reimbursed by insurers, performing classic randomized controlled trials is difficult. The “Hyperbaric OxygeN therapy on brEast cancer patients with late radiation toxicity” (HONEY) trial aims to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the trial within cohorts (TwiCs) design. Methods The HONEY trial will be conducted within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation (UMBRELLA). Within UMBRELLA, breast cancer patients referred for radiotherapy to the University Medical Centre Utrecht are eligible for inclusion. Patients consent to collection of clinical data and patient-reported outcomes and provide broad consent for randomization into future intervention studies. Patients who meet the HONEY in- and exclusion criteria (participation ≥ 12 months in UMBRELLA, moderate/severe breast or chest wall pain, completed primary breast cancer treatment except hormonal treatment, no prior treatment with HBOT, no contraindications for HBOT, no clinical signs of metastatic or recurrent disease) will be randomized to HBOT or control group on a 2:1 ratio (n = 120). Patients in the control group will not be informed about participation in the trial. Patients in the intervention arm will undergo 30–40 HBOT treatment sessions in a high pressure chamber (2.4 atmospheres absolute) where they inhale 100% oxygen through a mask. Cohort outcome measures (i.e., physical outcomes, quality of life, fatigue, and cosmetic satisfaction) of the HBOT group will be compared to the control group at 3 months follow-up. Discussion This pragmatic trial within the UMBELLA cohort was designed to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the TwiCs design. Use of the TwiCs design is expected to address issues encountered in classic randomized controlled trials, such as contamination (i.e., HBOT in the control group) and disappointment bias, and generate information about acceptability of HBOT. Trial registration ClinicalTrials.gov. NCT04193722. Registered on 10 December 2019.

Clinical hyperthermia (i.e., heating of tumor tissue to 40–43 °C) is used in clinical oncology to enhance the therapeutic effect of chemotherapy and radiotherapy. Most recurrent breast cancer and melanoma lesions reach up to a few cm deep and can be effectively treated with currently available superficial hyperthermia devices using infrared or microwave radiation. Effective heating of more challenging and complex semi-superficial or semi-deep tumor lesions, including intact breast or lesions near silicone implants, requires dedicated treatment protocols. Herein, new treatment protocols are presented, which combine simultaneous and consecutive use of different wIRA, microwave, and radiofrequency hyperthermia devices. Examples are included, showing the clinical setup, applicator choice, and invasive and noninvasive thermometry.

Additional file 1. Data management plan.

To improve shared decision making, clinical- and patient-reported outcomes between immediate implant-based and autologous breast reconstruction followed by postmastectomy radiotherapy (PMRT) were compared.All women with in situ and/or invasive breast cancer who underwent skin sparing mastectomy with immediate breast reconstruction (IBR) (autologous- or implant based, one- or two staged) followed by PMRT in the Utrecht region between 2012 and 2016 were selected from the Netherlands Cancer Registry, of which 112 (59%) agreed to participate. The primary outcome was reconstruction failure after the start of radiotherapy, and secondary outcomes were patient-reported outcomes measured with BREAST-Q.109 patients underwent skin-sparing mastectomy, of which 29 (27%) underwent immediate autologous reconstruction and 80 (73%) received immediate implant-based reconstruction. After PMRT, reconstruction failure occurred in 17 patients (21%) with implant-based reconstruction, while no failure was seen in the autologous group (p = 0.04). Mean patient-reported 'Satisfaction with Breasts' (50.9 vs. 63.7, p = 0.001) and 'Sexual Well-being' (46.0 vs. 55.5, p = 0.037) were lower after implant-based reconstruction compared to autologous reconstruction. Thirteen patients with autologous flaps underwent surgical cosmetic corrections compared to ten patients in the implant group (45 vs. 13%, p = 0.001). IBR and PMRT in this study resulted in a high rate of severe capsular contraction in implant-based reconstruction (16.9%) and fibrosis in autologous reconstruction (13.8%).Patients treated with PMRT and one or two stage immediate implant-based reconstruction were at greater risk of developing reconstruction failure and were less satisfied when compared to one or two stage immediate autologous reconstruction. Since fairly high complication rates in both reconstruction methods after PMRT are observed, it raises the question whether immediate breast reconstruction should be considered at all when PMRT is indicated. Patients considering or potential candidates for IBR should be informed about the consequences of PMRT and especially when opting for autologous reconstruction one should possibly perform reconstruction in a secondary setting.

Background: Physical activity has been shown to reduce side-effects of breast cancer and its treatment. As physical activity levels of patients with breast cancer are largely unknown, we investigated these levels and compared them to women from the general population. Methods: In this prospective cohort study, physical activity levels of women with breast cancer participating in the UMBRELLA cohort were assessed at radiotherapy intake and thereafter every 6 months up to 3 years with the SQUASH questionnaire, which was also used in a random sample of the Dutch population. We compared physical activity levels (no activity, low, moderate or high levels of sports, leisure time or total activity) between patients and the Dutch female population using multinomial logistic regression. Standardized Prevalence Ratios (SPR) were calculated to compare adherence to Dutch physical activity guidelines. Results: Women with breast cancer (nbaseline = 1655, n6 months = 1414, n12 months = 1186, n18 months = 957, n24 months = 744, n30 months = 555, and n36 months = 377) were less likely to spend time in physical activity compared to the general population (n = 11,710) until 3 years post-diagnosis, especially after 6 months (ORhigh-vs.-no activity = 0.34, 95% CI: 0.28–0.41). From 12 months onwards, patients were more likely to perform sports compared to the general population, especially patients who underwent systemic therapy. Guideline adherence was significantly lower in patients at baseline and 6 months (SPRbaseline = 89, 95% CI: 82–97; SPR6 months = 88, 95% CI: 81–96), and comparable to the general population at 12–36 months, especially in older women. Conclusions: Physical activity levels in women with breast cancer during and after treatment were lower compared to the Dutch female population. Three years post-treatment, they were still less physically active, although they spend more time in sport activities. As about half of the patients did not perform any sports, physical activity needs to be stimulated during and after treatment.

Introduction: The randomized controlled trial (RCT) is the gold standard for evaluation of effectiveness of new interventions. In oncology, however, RCTs are often complicated by logistic challenges, slow recruitment, limited generalisability, and strong patient's and doctor's preferences for new interventions. At the University Medical Center Utrecht (the Netherlands), we implemented an innovative alternative to the classic RCT: the cohort multiple randomized controlled trial (cmRCT). The cmRCT serves as a multi-trial facility and has the potential to improve recruitment and generalisability. Methods: We initiated the 'Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation (UMBRELLA)' at the department of radiation oncology. UMBRELLA is a large prospective cohort of breast cancer patients, for whom we capture clinical data (patient and tumor characteristics, treatment, imaging, toxicity, recurrence and survival). Patients provide Patient Reported Outcome Measures (PROMs) on quality of life, pain, fatigue, anxiety and depression, physical activity and cosmetics. For each intervention to be tested, a subcohort of eligible patients is identified within UMBRELLA. From this subcohort, a random sample of patients is selected and offered the intervention (which they can accept or refuse). Patients from the subcohort, who are not randomly selected, receive standard care, serve as controls, and are not informed about the trial. Outcomes of patients offered the intervention are compared to those of patients receiving standard care. This process can be repeated (simultaneously) for multiple experimental interventions. Results: Since October 2013, some 1000 patients have been enrolled in UMBRELLA. In order to make the design suitable for the clinical oncology practice, we developed a tailored informed consent procedure. First, we ask patients to enroll in the cohort and to provide PROMs. In addition, patients give broad consent to be either randomly selected to receive experimental interventions or to serve as control without further notice. In a second stage, at the initiation of a trial within the cohort, informed consent to receive the experimental intervention is sought in those randomly selected to receive the intervention. After completion of the trial, aggregated results are shared with all patients. Participation in UMBRELLA is 90%, and 90% of enrolled patients give broad consent for randomization. PROMs return rates vary from 70-90%. In September 2015, the first trial will be initiated, which aims to evaluate the impact of exercise programs on quality of life of inactive survivors. Preliminary inclusion and participation rates of this trial will be presented in December. Conclusion: High participation rates, high PROM return rates and high levels of broad informed consent for randomisation within UMBRELLA indicate that this innovative design is feasible in the oncology practice, acceptable for patients and likely to provide generalisable results. Results of trials within UMBRELLA need to confirm whether cmRCT is indeed an acceptable alternative for classic pragmatic RCTs. Citation Format: Verkooijen HM, Young Afat D, van den Bongard D, van Vulpen M, May AM, van Gils C. The cohort multiple randomized controlled trial is a feasible and patient-acceptable design for pragmatic evaluation of multiple interventions, with potential for improved recruitment and generalisability: The UMBRELLA experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-18-02.

PURPOSE/OBJECTIVE Innovations in loco-regional breast cancer treatment, such as oncoplastic surgery and neoadjuvant chemotherapy, have been suggested to increase the risk of breast and chest wall edema, which may impair quality of life (QoL) during and after treatment. The objective of this study is to evaluate prevalence and risk factors of breast and chest wall edema and its effect on quality of life. METHODS We conducted this study within a prospective observational cohort of breast cancer patients indicated to undergo radiation treatment after being treated with surgery (Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation, UMBRELLA). At the time of inclusion all participants consented to the collection of clinical data and 'patient reported outcomes' (PROMs) at regular intervals during and after treatment. Presence of breast and chest wall edema was registered by radiation oncologists according to CTCAE V4.0 scoring system, at weekly follow-up visits during radiation treatment, and at standard follow-up intervals after radiation treatment. When present, edema was defined as 'acute' (i.e. breast and chest wall edema within 0-90 days after the start of radiation treatment), 'late' (i.e. >90 days) or both. Information on potential risk factors, such as patient and tumor characteristics, and treatment (e.g. surgical procedure, RT target volumes, (neo)adjuvant chemotherapy) was collected from electronic patient files and questionnaires. We performed univariate and multivariable logistic regression analysis to identify determinants that were (independently) associated with breast and chest wall edema. PROMs on quality of life and pain (i.e. EORTC QLQ-C30/BR23) were collected regularly (i.e. baseline, 3, 6 and 12 months) and compared between patients with and without edema. RESULTS We included 427 patients with at least 3 months follow-up (median follow-up 48 weeks). Sixteen percent (70/427) had acute edema, 23% (73/314) had late edema and 8% (25/314) had both acute and late edema. The proportion of women with acute edema was significantly higher in patients treated with oncoplastic surgery (31% vs. 15%, p=0.03) or mastectomy (31% vs. 14% p CONCLUSION Breast and chest wall edema is associated with reduced quality of life during the first year of treatment. Oncoplastic surgery and mastectomy increase the risk for acute edema, while oncoplastic surgery, mastectomy, axillary treatment (i.e. ALND, radiation therapy) and the presence of acute edema are associated with late edema. Early treatment of acute edema may reduce the risk for late edema, prolonged pain and impaired quality of life. Citation Format: Young-Afat DA, Verkooijen HM, Gregorowitsch ML, van Gils CH, van der Pol CC, Witkamp AJ, Burgmans I, Jonasse Y, van Vulpen M, van den Bongard DJ. Breast and chest wall edema during and following radiotherapy in breast cancer patients: Prevalence, risk factors and quality of life. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-23.

INTRODUCTION Patients with ductal carcinoma in situ (DCIS) have excellent overall survival rates. Yet, previous studies suggested that quality of life (QoL) between patients with DCIS and patients with early-invasive breast cancer (early-IBC) are similar after treatment. We compared anxiety, depression and quality of life of patients with DCIS and patients with early-IBC during treatment, at the initiation of postsurgical radiotherapy. METHODS We conducted this study within a prospective observational cohort of breast cancer patients indicated to receive adjuvant radiation treatment at the department of Radiation Oncology at the University Medical Center Utrecht, the Netherlands ('the UMBRELLA cohort'). At the time of inclusion all cohort participants consented to the collection of clinical and patient reported outcomes (PROMs) at regular intervals. Patient reported outcomes on QoL (i.e. EORTC QLQ-C30) and anxiety and depression (i.e. HADS) were collected at the start of postsurgical radiotherapy. All patients who were diagnosed between October 2013 and January 2015 with DCIS or early-IBC (i.e. pT1 and pT2 without lymph node involvement) were included in this analysis. To analyze differences in mean levels of PROMs (i.e. anxiety and depression, QoL) between patients with DCIS and early-IBC, two sample t-tests were used. Differences in proportions of patients with high anxiety or high depressive scores (i.e. scores ≥11) were analyzed with the Pearson-Chi square test. We compared PROMS of DCIS and early-IBC patients with those of patients with advanced-invasive breast cancer from the UMBRELLA cohort using analyses of variance (ANOVA). RESULTS Forty-six patients were diagnosed with DCIS and 227 with early-IBC. DCIS and early-IBC patients did not show statistically significant differences in levels of anxiety (mean DCIS 4.5, early-IBC 5.2, p=0.18), depression (mean DCIS 2.6, early-IBC 3.0, p=0.73) or QoL (mean DCIS 78.3, early-IBC 74.7 p=0.70). Seven percent of women with DCIS women reported severe anxious symptoms, compared to 8% in women with early-IBC (p=0.22). Severe symptoms of depression were seen in 2% of DCIS patients and 4% of early-IBC (p=0.30). Patients with advanced invasive breast cancer (n=118) reported significantly higher anxiety (mean 6.3, p CONCLUSION Despite excellent survival probabilities and less invasive treatment, women with DCIS report similar levels of anxiety, depression and quality of life during treatment as compared to women with early-invasive breast cancer. Citation Format: Young-Afat DA, Gregorowitsch ML, Pignol J-P, van Gils CH, van Vulpen M, van den Bongard DJ, Verkooijen HM. Quality of life, anxiety and depression during treatment of ductal carcinoma in situ and invasive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-12.

PURPOSE: In oncology, RCTs are often beset by slow recruitment, limited generalizability, and strong preferences for interventions by patients and physicians. The cohort multiple randomized controlled trial (cmRCT) is an innovative design with the potential to overcome those challenges. In cmRCT, a prospective cohort serves as an infrastructure for multiple RCTs. We implemented cmRCT in a clinical breast cancer setting by creating UMBRELLA-a large prospective cohort of breast cancer and DCIS patients/survivors. METHODS: For all participants, clinical data and patient-reported outcomes (PROs, i.e., quality of life, fatigue, anxiety and depression, physical activity, work ability, and cosmetic satisfaction) are being collected at regular time-intervals for a period of 10 years. These data are being used both for observational and randomized studies. For each intervention to be tested against standard care, a subcohort of eligible patients is identified within UMBRELLA. From this subcohort, a random sample of patients is offered the intervention. Their outcomes are compared to the outcomes of patients receiving standard care. RESULTS: So far, between October 2013 and July 2016, we have recruited 1308 participants. In this period, 1308/1486 (88%) patients who were invited for participation in UMBRELLA consented to cohort participation. Of these patients, 1138 (87%) gave broad consent for randomization to future interventions. Return rate for PROs at baseline were 80%, and varied from 67 to 74% during follow-up. Several observational studies-and the first randomized intervention study-are currently ongoing. CONCLUSIONS: Results from UMBRELLA show that this novel study design is feasible and acceptable to patients in a clinical breast cancer setting. We invite researchers who are interested in conducting randomized or observational studies within the UMBRELLA cohort to contact the UMBRELLA scientific advisory board.

Background The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) was based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. Methods and materials Patients 60 years, T ≤ 3 cm, pN0(sn) (sentinel node procedure before RT), ductal carcinoma, unifocal on mammogram and MRI, undergo preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks); 6 weeks hereafter a wide local excision is performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). Results From May 2010- 2013, 58 patients (pts) were included. For 52 pts follow up information is available up to at least 3 months after treatment; mean age 67.2 years (59-80); mean tumor size 1.4 cm (0.4-3.2); differentiation grade: grade 1 (n = 22), grade 2 (n = 28), unknown n = 8; mainly ER+PR + neu- (n = 50). 34 pts received hormonal therapy, none chemotherapy. Toxicity Acute RT toxicity grade 0 (23) grade 1(8). Postoperative complications were noted in 9/52 pts (17%): 2/52 had direct post-operative bleeding needing re-surgery; 1/52 developed a hematoma two months after surgery, needing re-surgery; 6/52 (11.5%) had a postoperative wound infection and received oral antibiotics. Of these 6; 1 wound abscess needing re-surgery; 1 small fistula closing within ten months. In the first year 9/52 pts developed localized oedema at the RT side fading away within 9 months. 4/53 pts developed hematoma post surgery. Fibrosis and cosmetic outcome Fibrosis score at 1 year (n = 35): grade 0 (9), grade 1 (21), grade 2 (4) grade 3 (1). Cosmetic outcome was scored at 1 year (n = 28): excellent/good (25; 89%), fair (3;11%). At 2 years follow up: 10/11 patients excellent/good and 1/11 patient fair. Fibrosis was noted in a limited volume. One ipsi-lateral breast tumor recurrence was diagnosed after 12 months at skin entry of the biopsy tract. Discussion The short term results of this PAPBI trial are promising in terms of acute treatment-related toxicities, complications and cosmetic outcome. Our complication rate of 17% (11% wound infection, 8% hematoma) is comparable with others*. Excellent or good cosmetic outcome was found in 90%, improving over time. Longer follow-up and increasing patient inclusion are needed to evaluate treatment efficacy, cosmetic results and toxicity on the longer term. *Mukesh et al (Eur J Surg Oncol 2012; 648 pts Cambridge IMRT trial), 18% infection, 8% hematoma. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-05.

E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics (PK) of the drug. A population PK analysis revealed that the human plasma concentration - time data were best described by a three-compartment model with non-linear distribution. We have studied the in vitro interaction of 14C-radiolabeled E7070 with red blood cells (RBC) and its binding to plasma proteins in the concentration range where non-linearity in disposition was observed in humans to get more insight into the behavior of the drug. After the addition of E7070 to whole blood at 37°C, the drug is taken up or binds to RBC in a concentration-dependent manner. The addition of sodium azide, however, did not result in a decrease of drug uptake by RBC, indicating passive diffusion processes. A non-linear increase in drug uptake was observed at incubation concentrations above 4 μg/ml E7070 in whole blood. This non-linearity was confirmed by lower partition coefficients between RBC and plasma at higher incubation concentrations (from 2.37 at 4 μg/ml to 0.31 at 200 μg/ml). The plasma protein binding of E7070 was high (98-99%) and linear in the concentration range studied (20-200 μg/ml). In conclusion, E7070 in whole blood is preferentially bound to RBC and exhibits high plasma protein binding. The non-linear distribution of E7070 in humans can be caused, in part at least, by saturable binding of E7070 to RBC. © 2003 Lippincott Williams & Wilkins.

Purpose. The purpose of this study was to develop a population pharmacokinetic model for Cremophor EL used as a formulation vehicle for paclitaxel. Methods. Plasma concentration-time data from 70 patients (85 courses) treated with paclitaxel dissolved in Cremophor EL were used. The nonlinear mixed-effect modelling (NONMEM) program was used for the population pharmacokinetic analysis. The influence of patient characteristics on the pharmacokinetics of Cremophor EL was determined. The stability of the final model was evaluated using bootstrapping. Results. The data were optimally fitted to a three-compartment model with Michaelis-Menten elimination from the central compartment. The following pharmacokinetic parameters were estimated: volume of the central compartment (V1=2.59 l), volumes of two peripheral compartments (V2=1.81 l, V3=1.61 l), intercompartmental clearance between central and peripheral compartments (Q12=1.44 l/h, Q13=0.155 l/h), maximal elimination rate (Vmax=0.193 ml/h), and concentration at half Vmax (Km=0.122 ml/l). Interindividual variability of the pharmacokinetic parameters was quantified for V1 (25%), V2 (36%) and Vmax (31%). Residual variability consisted of a combined additional (0.095 ml/l) and proportional error (7%). Gender, body surface area and performance status according to the World Health Organization were significantly correlated with V1, V2 and Vmax, respectively (P

Purpose: In regional radiotherapy (RT) for breast-cancer patients, direct visualization of individual lymph nodes (LNs) may reduce target volumes and Result in lower toxicity (i.e. reduced radiation pneumonitis, arm edema, arm morbidity), relative to standard CT-based delineations. To this end, newly designed magnetic resonance imaging (MRI) sequences were optimized and assessed qualitatively and quantitatively. Methods: In ten healthy female volunteers, a scanning protocol was developed and optimized. Coronal images were acquired in supine RT position positioned on a wedge board on a 1.5 T Ingenia (Philips) wide-bore MRI. In four volunteers the optimized MRI protocol was applied, including a 3-dimensional (3D) T1-weighted (T1w) fast-field-echo (FFE). T2w sequences, including 3D FFE, 3D and 2D fast spin echo (FSE), and diffusion-weighted single-shot echo-planar imaging (DWI) were also performed. Several fatsuppression techniques were used. Qualitative evaluation parameters included LN contrast, motion susceptibility, visibility of anatomical structures, and fat suppression. The number of visible axillary and supraclavicular LNs was also determined. Results: T1 FFE, insensitive to motion, lacked contrast of LNs, which often blended in with soft tissue and blood. T2 FFE showed high contrast, but some LNs were obscured due to motion. Both 2D and 3D FSE were motion-insensitive having high contrast, although some blood remained visible. 2D FSE showed more anatomical details, while in 3D FSE, some blurring occurred. DWI showed high LN contrast, but suffered from geometric distortions and low resolution. Fat suppression by mDixon was the most reliable in regions with magnetic-field inhomogeneities. The FSE sequences showed the highest sensitivity for LN detection. Conclusion: MRI of regional LNs was achieved in volunteers. The FSE techniques were robust and the most sensitive. Our optimized MRI sequences can facilitate direct delineation of individual LNs. This can Result in smaller target volumes and reduced toxicity in regional RT compared to standard CT planning.

Purpose: Magnetic resonance imaging (MRI) enables direct characterization of intra-fraction motion ofbreast tumors, due to high softtissue contrast and geometric accuracy. The purpose is to analyzethis motion in early-stage breast-cancer patients using pre-operative supine cine-MRI. Methods: MRI was performed in 12 female early-stage breast-cancer patients on a 1.5-T Ingenia (Philips)wide-bore scanner in supine radiotherapy (RT) position, prior to breast-conserving surgery. Twotwodimensional (2D) T2-weighted balanced fast-field echo (cine-MRI) sequences were added tothe RT protocol, oriented through the tumor. They were alternately acquired in the transverse andsagittal planes, every 0.3 s during 1 min. A radiation oncologist delineated gross target volumes(GTVs) on 3D contrast-enhanced MRI. Clinical target volumes (CTV = GTV + 15 mm isotropic)were generated and transferred onto the fifth time-slice of the time-series, to which subsequents lices were registered using a non-rigid Bspline algorithm; delineations were transformed accordingly. To evaluate intra-fraction CTV motion, deformation fields between the transformed delineations were derived to acquire the distance ensuring 95% surface coverage during scanning(P95%), for all in-plane directions: anteriorposterior (AP), left-right (LR), and caudal-cranial(CC). Information on LR was derived from transverse scans, CC from sagittal scans, AP fromboth sets. Results: Time-series with registration errors - induced by motion artifacts - were excluded bymore » visual inspection. For our analysis, 11 transverse, and 8 sagittal time-series were taken into account. Themedian P95% calculated in AP (19 series), CC (8), and LR (11) was 1.8 mm (range: 0.9–4.8), 1.7mm (0.8–3.6), and 1.0 mm (0.6–3.5), respectively. Conclusion: Intra-fraction motion analysis of breast tumors was achieved using cine-MRI. These first results show that in supine RT position, motion amplitudes are limited. This information can be used for adaptive RT planning, and to develop preoperative partial-breast RT strategies, such asablative RT for early-stage breast-cancer patients.« less

NAMI-A is a novel ruthenium-containing experimental anticancer agent. We have developed and validated a rapid and sensitive analytical method to determine NAMI-A in human plasma, plasma ultrafiltrate and urine using atomic absorption spectrometry with Zeeman correction. The sample pretreatment procedure is straightforward, involving only dilution with an appropriate hydrochloric acid buffer-solution. Because the response signal of the spectrometer depended on the composition of the sample matrix, in particular on the amount of human plasma in the sample, all unknown samples were diluted to match the matrix composition in which the standard line was prepared (plasma-buffer 1:10 v/v). This procedure enabled the measurement of samples of different biological matrices in a single run. The validated range of determination was 1.1-220 μM NAMI-A for plasma and urine, and 0.22-44 μM for plasma ultrafiltrate. The lower limit of detection was 0.85 μM in plasma and urine and 0.17 μM in plasma ultrafiltrate. The lower limit of quantitation was 1.1 and 0.22 μM, respectively. The performance of the method, in terms of precision and accuracy, was according to the generally accepted criteria for validation of analytical methodologies. The applicability of the method was demonstrated in a patient who was treated in a pharmacokinetic phase I trial with intravenous NAMI-A. © Springer-Verlag 2001.

Background and aim of the study: A.The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) is based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. B. By assessing tumor response to radiotherapy, an additional goal of the study is to develop a gene expression profile that predicts breast cancer radiosensitivity. This gene signature of breast radiosensitivity would further design optimal treatment strategies for individual breast cancer patients treated with BCT. Inclusion citeria: Patients 60 years or older with a cT< = 3cm, ductal carcinoma (no in situ component), unifocal on mammogram and MRI, pN0(sn) (sentinel node procedure before RT), will be treated by preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks). Six weeks after pre-operative RT, a wide local excision will be performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). To study radiosensit ivity, gene expression profiling from RNA and DNA isolated from biopsies (mRNA gene expression profiles, the miRNA expression profiles and the DNA copy number changes) taken of the tumor before radiotherapy and at time of surgery will be correlated with response to radiotherapy, defined as pathologic response at the time of the lumpectomy. Response of the tumor will be evaluated by MRI scan and PET (before radiotherapy and before surgery) and classical pathology. Endpoint : The main objective is to investigate the impact of a short fractionated schedule given preoperatively on cosmesis and breast fibrosis. Therefore, it is anticipated that the percentage of moderate or severe fibrosis will decrease from 27% as found in the boost arm of the EORTC boost-no boost trial to 15% (Collette et al EJC 2008). The total sample size of 120 patients will provide in excess of 80% power to detect the difference between the null hypotheses (a rate of fibrosis of 27%) and the alternative hypothesis (a rate of fibrosis of 15%) with an exact binomial test at 0.05 2-sided significance level. In addition, the 2-sided 95% confidence interval for the proportion of patients without local recurrence will extend 0.035 from the observed proportion for an expected proportion of 96%. An additional objective is to build a classifier (genomic or proteomic or any kind of molecular signature) to identify responders and non-responders. A total of 120 patients will be included in the study. The main analysis will include 60 patients in the training set and 60 in the validation set. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-03.

Cremophor EL is a polyethoxylated castor oil that is used for the formulation of a variety of hydrophobic drugs. Recently, it has been demonstrated that the pharmacokinetic (PK) behaviour of Cremophor EL influences the disposition of paclitaxel [1]. Consequently, assessment of the clinical PK of Cremophor EL during paclitaxel administration is of major importance. The purpose of the present study was to develop a population PK model of Cremophor EL as a solubilizing agent for paclitaxel. Plasma concentration-time data (85 courses) of Cremophor EL concentrations were collected from 71 patients with solid tumours treated with paclitaxel dissolved in Cremophor EL. Cremophor EL was intravenously infused during 3, 24 and 96 h (doses ranging from 8.3–20.8 ml m−2). Population PK analysis of plasma concentration-time data was performed using the nonlinear mixed effect modeling software program NONMEM. Thirteen covariates were investigated for their influence on the PK parameters of Cremophor EL. The stability of the final model was evaluated by bootstrapping. The median parameter estimates obtained from 1000 bootstrap replicates were compared with those obtained from the original data set. The data were fitted to a 3-compartment model with Michaelis-Menten elimination from the central compartment. The following PK parameters were estimated: volume of the central compartment V1=2.59 l), volume of the first peripheral compartment (V2=1.81 l), volume of the second peripheral compartment (V3=1.61 l), intercompartmental clearance between the central compartment and the first peripheral compartment (Q12=1.44 l h−1) and the second peripheral compartment (Q13=0.16 l h−1), maximal elimination rate (Vmax=0.19 ml h−1), and the plasma concentration at half of the Vmax (Km=0.12 ml l−1). Interindividual variability (IIV) was estimated using an exponential error model, and was quantified for V1 (25%), V2 (36%), and Vmax (31%). Residual variability was small with a combined additional and proportional error of 0.095 ml l−1 and 7%, respectively. Significant relationships (P

Routine removal of the internal mammary chain (IMC) sentinel node in breast cancer patients remains a subject of discussion. The aim of this study was to determine the impact of routinely performed IMC sentinel node biopsy on the systemic and locoregional treatments plan. All patients with biopsy proven breast cancer who underwent a sentinel node procedure between 2002 and 2011 were included in a prospective database. In cases of IMC drainage, successful exploration of the IMC (i.e., sentinel node removed) and surgical complications were registered. If the removed sentinel node contained malignant cells we determined if this altered the treatment plan when practising the current guidelines. In total, 119 of the 493 included patients showed IMC drainage on lymphoscintigraphy. Exploration of the IMC was performed in 107 (89 %) patients; in 86/107 (80 %) exploration was successful. In 14/107 patients (13 %) the IMC sentinel node was tumor positive. Macro and micro metastases were found in eight and six patients, respectively. In the group of patients who underwent surgical exploration of the IMC, systemic treatment was changed in none, radiotherapy treatment in 13/107 patients (11 %). Routine sentinel node biopsy of the IMC does not alter the systemic treatment. Radiotherapy treatment is altered in a small proportion of the patients; however, solid scientific evidence for this adjustment is lacking. © The Author(s) 2012.