Royal Marsden National Health Service Foundation Trust

Sutton, United Kingdom

Royal Marsden National Health Service Foundation Trust

Sutton, United Kingdom
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Sutherland S.,Royal Marsden National Health Service Foundation Trust | Ashley S.,Royal Marsden National Health Service Foundation Trust | Walsh G.,Royal Marsden National Health Service Foundation Trust | Smith I.E.,National Health Research Institute | Johnston S.R.D.,National Health Research Institute
Cancer | Year: 2010

BACKGROUND: Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered. METHODS: Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS. RESULTS: The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation. CONCLUSIONS: Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook. © 2010 American Cancer Society.

Chinot O.L.,Aix - Marseille University | Wick W.,German Cancer Research Center | Mason W.,Princess Margaret Hospital | Henriksson R.,Regional Cancer Center | And 12 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. METHODS: We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. RESULTS: A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P = 0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P = 0.049) and 33.9% and 30.1% at 2 years (P = 0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). CONCLUSIONS: The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. Copyright © 2014 Massachusetts Medical Society.

Chong I.,Royal Marsden National Health Service Foundation Trust | Hawkins M.,Royal Marsden National Health Service Foundation Trust | Hansen V.,Royal Marsden National Health Service Foundation Trust | Thomas K.,Royal Marsden National Health Service Foundation Trust | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: There has been no previously published data related to the quantification of rectal motion using cone-beam computed tomography (CBCT) during standard conformal long-course chemoradiotherapy. The purpose of the present study was to quantify the interfractional changes in rectal movement and dimensions and rectal and bladder volume using CBCT and to quantify the bony anatomy displacements to calculate the margins required to account for systematic (Σ) and random (σ) setup errors. Methods and Materials: CBCT images were acquired from 16 patients on the first 3 days of treatment and weekly thereafter. The rectum and bladder were outlined on all CBCT images. The interfraction movement was measured using fixed bony landmarks as references to define the rectal location (upper, mid, and low), The maximal rectal diameter at the three rectal locations was also measured. The bony anatomy displacements were quantified, allowing the calculation of systematic (Σ) and random (σ) setup errors. Results: A total of 123 CBCT data sets were analyzed. Analysis of variance for standard deviation from planning scans showed that rectal anterior and lateral wall movement differed significantly by rectal location. Anterior and lateral rectal wall movements were larger in the mid and upper rectum compared with the low rectum. The posterior rectal wall movement did not change significantly with the rectal location. The rectal diameter changed more in the mid and upper than in the low rectum. No consistent relationship was found between the rectal and bladder volume and time, nor was a significant relationship found between the rectal volume and bladder volume. Conclusions: In the present study, the anterior and lateral rectal movement and rectal diameter were found to change most in the upper rectum, followed by the mid rectum, with the smallest changes seen in the low rectum. Asymmetric margins are warranted to ensure phase 2 coverage. © 2011 Elsevier Inc.

Carreira S.,Institute of Cancer Research | Romanel A.,University of Trento | Goodall J.,Institute of Cancer Research | Grist E.,Institute of Cancer Research | And 23 more authors.
Science Translational Medicine | Year: 2014

It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR)mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. © 2014, American Association for the Advancement of Science. All rights reserved.

Attard G.,National Health Research Institute | Attard G.,Royal Marsden National Health Service Foundation Trust | Reid A.H.M.,National Health Research Institute | Reid A.H.M.,Royal Marsden National Health Service Foundation Trust | And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Abiraterone acetate is a small-molecule cytochrome P450 17A1 (CYP17A1) inhibitor that is active in castration-resistant prostate cancer. Objective: Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis. Design and Methods: We treated 42 castrate, castration-resistant prostate cancer patients with continuous, daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0.5 mg daily. Results: Treatment with single-agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of CYP17A1. This resulted in side effects, including hypertension, hypokalemia, and fluid overload, in 38 of 42 patients that were generally treated effectively with eplerenone. Importantly, serum and urinary androgens were suppressed by more than 90% from baseline. Urinary metabolites of 17-hydroxypregnenolone and 17-hydroxyprogesterone downstream of 17α-hydroxylase remained unchanged. However, 3α5α-17- hydroxypregnanolone, which can be converted via the backdoor pathway toward 5α-dihydrotestosterone, increased significantly and correlated with levels of the major 5α-dihydrotestosterone metabolite androsterone. In contrast, urinary metabolites of 11-deoxycortisol and active glucocorticoids declined significantly. Addition of dexamethasone to abiraterone acetate significantly suppressed ACTH and endogenous steroids, including 3α5α-17- hydroxypregnanolone. Conclusion: CYP17A1 inhibition with abiraterone acetate is characterized by significant suppression of androgenandcortisol synthesis. The latter is associated with a rise inACTHthat causes raised mineralocorticoids, leading to side effects and incomplete 17α-hydroxylase inhibition. Concomitant inhibition of 17,20-lyase results in diversion of 17-hydroxyprogesterone metabolites toward androgen synthesis via the backdoor pathway. Addition of dexamethasone reverses toxicity and could further suppress androgens by preventing a rise in substrates of backdoor androgen synthesis. Copyright © 2012 by The Endocrine Society.

Juneja P.,Institute of Cancer Research | Harris E.J.,Institute of Cancer Research | Kirby A.M.,Royal Marsden National Health Service Foundation Trust | Evans P.M.,Institute of Cancer Research
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To validate and compare the accuracy of breast tissue segmentation methods applied to computed tomography (CT) scans used for radiation therapy planning and to study the effect of tissue distribution on the segmentation accuracy for the purpose of developing models for use in adaptive breast radiation therapy. Methods and Materials: Twenty-four patients receiving postlumpectomy radiation therapy for breast cancer underwent CT imaging in prone and supine positions. The whole-breast clinical target volume was outlined. Clinical target volumes were segmented into fibroglandular and fatty tissue using the following algorithms: physical density thresholding; interactive thresholding; fuzzy c-means with 3 classes (FCM3) and 4 classes (FCM4); and k-means. The segmentation algorithms were evaluated in 2 stages: first, an approach based on the assumption that the breast composition should be the same in both prone and supine position; and second, comparison of segmentation with tissue outlines from 3 experts using the Dice similarity coefficient (DSC). Breast datasets were grouped into nonsparse and sparse fibroglandular tissue distributions according to expert assessment and used to assess the accuracy of the segmentation methods and the agreement between experts. Results: Prone and supine breast composition analysis showed differences between the methods. Validation against expert outlines found significant differences (P<.001) between FCM3 and FCM4. Fuzzy c-means with 3 classes generated segmentation results (mean DSC = 0.70) closest to the experts' outlines. There was good agreement (mean DSC = 0.85) among experts for breast tissue outlining. Segmentation accuracy and expert agreement was significantly higher (P<.005) in the nonsparse group than in the sparse group. Conclusions: The FCM3 gave the most accurate segmentation of breast tissues on CT data and could therefore be used in adaptive radiation therapy-based on tissue modeling. Breast tissue segmentation methods should be used with caution in patients with sparse fibroglandular tissue distribution. © 2012 Elsevier Inc.

Lee Y.K.,Royal Marsden National Health Service Foundation Trust | Brooks C.J.,Royal Marsden National Health Service Foundation Trust | Bedford J.L.,Royal Marsden National Health Service Foundation Trust | Warrington A.P.,Royal Marsden National Health Service Foundation Trust | Saran F.H.,Royal Marsden National Health Service Foundation Trust
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To develop and compare a volumetric modulated arc therapy (VMAT) technique with conventional radiotherapy for craniospinal irradiation with respect to improved dose conformity and homogeneity in the planning target volume (PTV) and to reduced dose to organs at risk (OAR). Methods and Materials: Conventional craniospinal axis radiotherapy plans of 5 patients were acquired. The median (range) length of the PTV was 58.9 (48.1-83.7) cm. The 6-MV VMAT plans were inversely planned with one isocenter near the base of the brain and the minimum number of isocenters required for the specified lengths of spine. The plans were optimized with high weighting for PTV coverage and low weighting for OAR sparing. Conformity and heterogeneity indices, dose-volume histograms, mean doses, and non-PTV integral doses from the two plans (prescription dose 23.4 Gy in 13 fractions) were compared. Results: The median (range) conformity index of VMAT was 1.22 (1.09-1.45), compared with 1.69 (1.44-2.67) for conventional plans (p = 0.04). The median (range) heterogeneity index was also lower for VMAT compared with conventional plans: 1.04 (1.03-1.07) vs. 1.12 (1.09-1.19), respectively (p = 0.04). A significant reduction of mean and maximum doses was observed in the heart, thyroid, esophagus, optic nerves, and eyes with VMAT when compared with conventional plans. A decrease in body V 10Gy was observed, but for 4 of 5 patients non-PTV integral dose was increased with VMAT when compared with the conventional plans. Conclusions: A VMAT technique to treat the craniospinal axis significantly reduces OAR dose, potentially leading to lower late organ toxicity. However, this is achieved at the expense of increased low-dose volumes, which is inherent to the technique, carrying a potentially increased risk of secondary malignancies. © 2012 Elsevier Inc.

Neoptolemos J.P.,University of Liverpool | Stocken D.D.,University of Birmingham | Bassi C.,University of Verona | Ghaneh P.,University of Liverpool | And 24 more authors.
JAMA - Journal of the American Medical Association | Year: 2010

Context: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. Objective: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. Design, Setting, and Patients: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. Interventions: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m2, intravenous bolus injection, followed by fluorouracil, 425 mg/m2 intravenous bolus injection given 1-5 days every 28 days) (n=551) or gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks) (n=537) for 6 months. Main Outcome Measures: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. Results: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (χ1 2=0.7; P=.39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P<.001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. Conclusion: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. Trial Registration: Identifier: NCT00058201. ©2010 American Medical Association. All rights reserved.

PubMed | Royal Marsden National Health Service Foundation Trust, University of Houston, Stanford University, University of Florida Health Cancer Center Orlando Health and 3 more.
Type: Journal Article | Journal: Cancer | Year: 2016

The National Cancer Institutes Common Terminology Criteria for Adverse Events (CTCAE) is the universal framework for toxicity reporting in oncology trials. The objective of this study was to develop a CTCAE-compatible modified barium swallow (MBS) grade for the purpose of grading pharyngeal dysphagia as a toxicity endpoint in cooperative-group organ-preservation trials for head and neck cancer (HNC). It was hypothesized that a 5-point, CTCAE-compatible MBS grade (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST]) based on the interaction of pharyngeal residue and laryngeal penetration/aspiration ratings would be feasible and psychometrically sound.A modified Delphi exercise was conducted for content validation, expert consensus, and operationalization of DIGEST criteria. Two blinded raters scored 100 MBSs conducted before or after surgical or nonsurgical organ preservation. Intrarater and interrater reliability was tested with weighted values. Criterion validity against oropharyngeal swallow efficiency (OPSE), the Modified Barium Swallow Impairment Profile (MBSImP), the MD Anderson Dysphagia Inventory (MDADI), and the Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) was assessed with a 1-way analysis of variance and post hoc pairwise comparisons between DIGEST grades.Intrarater reliability was excellent (weighted =0.82-0.84) with substantial to almost perfect agreement between raters (weighted =0.67-0.81). DIGEST significantly discriminated levels of pharyngeal pathophysiology (MBSImP: r=0.77; P<.0001), swallow efficiency (OPSE: r=-0.56; P<.0001), perceived dysphagia (MDADI: r=-0.41; P<.0001), and oral intake (PSS-HN diet: r=-0.49; P<.0001).With the development of DIGEST, the MBS rating has been adapted to the CTCAE nomenclature of ordinal toxicity grading used in oncology trials. DIGEST offers a psychometrically sound measure for HNC clinical trials and investigations of toxicity profiles, dose responses, and predictive modeling. Cancer 2017;62-70. 2016 American Cancer Society.

Douillard J.-Y.,Institute Of Cancerologie Of Louest Ico Rene Gauducheau | Oliner K.S.,Amgen Inc. | Siena S.,Ospedale Niguarda Ca Granda | Tabernero J.,Autonomous University of Barcelona | And 18 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy. METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%. RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P = 0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P = 0.04). A total of 108 patients (17%) with non-mutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified. CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. Copyright © 2013 Massachusetts Medical Society.

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