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Bartlett F.R.,Royal Marsden NHS Foundation Trust | Yarnold J.R.,Royal Marsden NHS Foundation Trust | Yarnold J.R.,Institute of Cancer Research | Donovan E.M.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | And 4 more authors.
Clinical Oncology | Year: 2013

Aims: To measure cardiac tissue doses in left-sided breast cancer patients receiving supine tangential field radiotherapy with multileaf collimation (MLC) cardiac shielding of the heart and to assess the effect on target volume coverage. Materials and methods: Sixty-seven consecutive patients who underwent adjuvant radiotherapy to the left breast (n=48) or chest wall (n=19) in 2009/2010 were analysed. The heart, left anterior descending coronary artery (LAD), whole breast and partial breast clinical target volumes (WBCTV and PBCTV) were outlined retrospectively (the latter only in patients who had undergone breast-conserving surgery [BCS]). The mean heart and LAD NTDmean and maximum LAD doses (LADmax) were calculated for all patients (NTDmean is a biologically weighted mean dose normalised to 2Gy fractions using a standard linear quadratic model). Coverage of WBCTV and PBCTV by the 95% isodose was assessed (BCS patients only). Results: The mean heart NTDmean (standard deviation) was 0.8 (0.3) Gy, the mean LAD NTDmean 6.7 (4.3) Gy and the mean LADmax 40.3 (10.1) Gy. Coverage of the WBCTV by 95% isodose was <90% in one in three patients and PBCTV coverage <95% (range 78-94%) in one in 10 BCS patients. Conclusion: The use of MLC cardiac shielding reduces doses to cardiac tissues at the expense of target tissue coverage. Formal target volume delineation in combination with an assessment of the likelihood of local relapse is recommended in order to aid decisions regarding field and MLC placement. © 2013 The Royal College of Radiologists.


Bartlett F.R.,Royal Marsden NHS Foundation Trust | Colgan R.M.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | Donovan E.M.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | McNair H.A.,Royal Marsden NHS Foundation Trust | And 8 more authors.
Radiotherapy and Oncology | Year: 2015

Purpose To compare mean heart and left anterior descending coronary artery (LAD) doses (NTDmean) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold (VBH) and free-breathing prone techniques. Materials and methods Following surgery for early breast cancer, patients with estimated breast volumes >750 cm3 underwent planning-CT scans in supine VBH and free-breathing prone positions. Radiotherapy treatment plans were prepared, and mean heart and LAD doses were calculated. Patients were randomised to receive one technique for fractions 1-7, before switching techniques for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging and alternate-day cone-beam CT (CBCT) imaging were performed. The primary endpoint was the difference in mean LAD NTDmean between techniques. Population systematic (Σ) and random errors (σ) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. Results 34 patients were recruited, with complete dosimetric data available for 28. Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 (p < 0.001) and 2.9 and 7.8 (p < 0.001). Clip-based CBCT errors for VBH and prone respectively were ≤3.0 mm and ≤6.5 mm (Σ) and ≤3.5 mm and ≤5.4 mm (σ). Conclusions In larger-breasted women, supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position. © 2014 Elsevier Ireland Ltd. All rights reserved.


Sartor O.,Tulane Cancer Center | Coleman R.,Weston Park Hospital | Nilsson S.,Karolinska University Hospital | Heinrich D.,Akershus University Hospital | And 18 more authors.
The Lancet Oncology | Year: 2014

Background: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). Interpretation: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding: Algeta and Bayer HealthCare Pharmaceuticals. © 2014 Elsevier Ltd.


Sherrill B.,RTI Health Solutions | Sherif B.,RTI Health Solutions | Amonkar M.M.,Collegeville | Maltzman J.,Collegeville | And 2 more authors.
Current Medical Research and Opinion | Year: 2011

Aim: Compare first-line lapatinib plus letrozole (L+Let) versus letrozole monotherapy (Let) in hormone-receptor-positive HER2+metastatic breast cancer, employing Q-TWiST (quality-adjusted time without symptoms and toxicity) analysis to account for differences in progression times, with offsets for the impact of adverse events during the treatment period. Methods: The area under survival curves for each treatment group was partitioned into distinct health states of varying utility: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period following disease progression until death or end of follow-up (REL). The utility-weighted sum of the mean health state durations was derived for each group. The threshold utility analysis evaluates how varying utility values across the states affects Q-TWiST differences between groups, although the method is limited by not varying utilities within each health state. Results: The primary analysis population was the HER2+subgroup (n=219). There was no significant difference between treatments in mean duration of grade 3/4 adverse events prior to progression (L+Let=1.95 weeks; Let=2.14 weeks; P=0.90). Using utility weights of 0.5 for TOX and REL, L+Let was favored for quality-adjusted survival by 8.8 weeks (P=0.09). The Q-TWiST difference between treatment groups ranged from 8 to 9.5 weeks, favoring combination therapy for all hypothetical utility levels, but none of the comparisons were statistically significant at P=0.05. Conclusions: No significant differences were found between L+Let versus Let in mean duration of severe adverse events. Quality-adjusted survival was favored for the combination treatment arm for all utility levels examined when toxicity was defined by grade 3/4 AEs, but differences between groups were not statistically significant. © 2011 Informa UK.


Strigari L.,Regina Elena Cancer Institute | Konijnenberg M.,Erasmus University Rotterdam | Chiesa C.,Instituto Nazionale Tumori | Bardies M.,University Paul Sabatier | And 4 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Molecular radiotherapy (MRT) has demonstrated unique therapeutic advantages in the treatment of an increasing number of cancers. As with other treatment modalities, there is related toxicity to a number of organs at risk. Despite the large number of clinical trials over the past several decades, considerable uncertainties still remain regarding the optimization of this therapeutic approach and one of the vital issues to be answered is whether an absorbed radiation dose–response exists that could be used to guide personalized treatment. There are only limited and sporadic data investigating MRT dosimetry. The determination of dose–effect relationships for MRT has yet to be the explicit aim of a clinical trial. The aim of this article was to collate and discuss the available evidence for an absorbed radiation dose–effect relationships in MRT through a review of published data. Based on a PubMed search, 92 papers were found. Out of 79 studies investigating dosimetry, an absorbed dose–effect correlation was found in 48. The application of radiobiological modelling to clinical data is of increasing importance and the limited published data on absorbed dose–effect relationships based on these models are also reviewed. Based on National Cancer Institute guideline definition, the studies had a moderate or low rate of clinical relevance due to the limited number of studies investigating overall survival and absorbed dose. Nevertheless, the evidence strongly implies a correlation between the absorbed doses delivered and the response and toxicity, indicating that dosimetry-based personalized treatments would improve outcome and increase survival. © 2014, Springer-Verlag Berlin Heidelberg.


PubMed | Lund University, Gurutzeta Cruces University Hospital and Royal Marsden NHS Foundation Trust and Institute of Cancer Research
Type: Journal Article | Journal: Medical physics | Year: 2016

To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC).Eighteen DTC patients were administered 1.11 GBq of The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in the S-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients.Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.


Sherrill B.,RTI Health Solutions | Amonkar M.M.,Glaxosmithkline | Sherif B.,RTI Health Solutions | Maltzman J.,Glaxosmithkline | And 2 more authors.
Oncologist | Year: 2010

Background. A phase III trial compared lapatinib plus letrozole (L + Let) with letrozole plus placebo (Let) as first-line therapy for hormone receptor (HR)+ metastatic breast cancer (MBC) patients. The primary endpoint of progression-free survival (PFS) in patients whose tumors were human epidermal growth factor receptor (HER)-2+ was significantly longer for L + Let than for Let (8.2 months versus 3 months; p=.019). This analysis focuses on quality of life (QOL) in the HER-2+ population. Methods. QOL was assessed at screening, every 12 weeks, and at withdrawal using the Functional Assessment of Cancer Therapy-Breast (FACT-B). Changes from baseline were analyzed and the proportions of patients achieving minimally important differences in QOL scores were compared. Additional exploratory analyses evaluated how QOL changes reflected tumor progression status. Results. Among the 1,286 patients randomized, 219 had HER-2+ tumors. BaselineQOLscores were comparable in the two arms. Mean changes in QOL scores were generally stable over time for patients who stayed on study. The average change from baseline on the FACT-B total score in both arms was positive at all scheduled visits through week 48. There was no significant difference between the two treatment arms in the percentage of QOL responders. Conclusion. The addition of lapatinib to letrozole led to a significantly longer PFS interval while maintaining QOL during treatment, when compared with letrozole alone, thus confirming the clinical benefit of the combination therapy in the HR+ HER-2+ MBC patient population. This all oral regimen provides an effective option in this patient population, delaying the need for chemotherapy and its accompanying side effects. © AlphaMed Press.


Omlin A.,Kantonsspital St Gallen | Sartor O.,Tulane University | Rothermundt C.,Kantonsspital St Gallen | Cathomas R.,Kantonsspital Graubunden | And 4 more authors.
Clinical Genitourinary Cancer | Year: 2015

Introduction We hypothesized that the adverse event (AE) profile of cabazitaxel with regard to alopecia, nail changes, neuropathy, and dysgeusia differs from docetaxel. Materials and Methods Prospectively collected data on treatment-emergent AEs (frequency and grade [G]) from clinical trial databases of docetaxel every 3 weeks (q3w) (in TAX327 and VENICE) and cabazitaxel q3w (in TROPIC) were analyzed. Results The frequency of new or worsening AEs (all G and G3-4) for 1301 patients was significantly less for alopecia, nail changes, neuropathy, and dysgeusia for cabazitaxel compared with docetaxel. Conclusion Treatment with cabazitaxel might cause less alopecia, nail changes, neuropathy, and dysgeusia compared with docetaxel. © 2015 Elsevier Inc. All rights reserved.


McNair H.A.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | Wedlake L.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | Lips I.M.,University Utrecht | Andreyev J.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | And 2 more authors.
Practical Radiation Oncology | Year: 2014

While the importance of a consistent rectal volume during radiation therapy planning and treatment for patients receiving radiation therapy to the prostate is recognized, there is no clear guidance as to the most effective method. This review examines the evidence for the efficacy of rectal preparations. Eighteen papers were found where the primary aim was to investigate a rectal emptying intervention and included 5 different strategies. These included evacuation techniques, dietary interventions, laxatives, and enemas and were either investigated alone or in combination. There is no robust evidence to recommend one rectal emptying strategy over another. Further investigation in adequately powered clinical trials is advised. © 2014 American Society for Radiation Oncology.


Riches S.F.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | Payne G.S.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | Morgan V.A.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | Dearnaley D.,Royal Marsden NHS Foundation Trust and Institute of Cancer Research | And 6 more authors.
European Radiology | Year: 2015

Objectives: The objectives are determine the optimal combination of MR parameters for discriminating tumour within the prostate using linear discriminant analysis (LDA) and to compare model accuracy with that of an experienced radiologist. Methods: Multiparameter MRIs in 24 patients before prostatectomy were acquired. Tumour outlines from whole-mount histology, T2-defined peripheral zone (PZ), and central gland (CG) were superimposed onto slice-matched parametric maps. T2, Apparent Diffusion Coefficient, initial area under the gadolinium curve, vascular parameters (Ktrans,Kep,Ve), and (choline+polyamines+creatine)/citrate were compared between tumour and non-tumour tissues. Receiver operating characteristic (ROC) curves determined sensitivity and specificity at spectroscopic voxel resolution and per lesion, and LDA determined the optimal multiparametric model for identifying tumours. Accuracy was compared with an expert observer. Results: Tumours were significantly different from PZ and CG for all parameters (all p < 0.001). Area under the ROC curve for discriminating tumour from non-tumour was significantly greater (p < 0.001) for the multiparametric model than for individual parameters; at 90 % specificity, sensitivity was 41 % (MRSI voxel resolution) and 59 % per lesion. At this specificity, an expert observer achieved 28 % and 49 % sensitivity, respectively. Conclusion: The model was more accurate when parameters from all techniques were included and performed better than an expert observer evaluating these data. Key Points: • The combined model increases diagnostic accuracy in prostate cancer compared with individual parameters • The optimal combined model includes parameters from diffusion, spectroscopy, perfusion, and anatominal MRI • The computed model improves tumour detection compared to an expert viewing parametric maps © 2014, European Society of Radiology.

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