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Porta C.,University of Pavia | Gore M.E.,Royal Marsden Hospital NHS Trust | Rini B.I.,Cleveland Clinic | Escudier B.,Gustave Roussy | And 5 more authors.
European Urology | Year: 2016

Background Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr. Objective To analyze long-term safety with sunitinib in mRCC patients. Design, setting, and participants Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g. cytokine refractory or treatment-naïve). Outcome measurements and statistical analysis Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment. Results and limitations Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients. Conclusions Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative. Patient summary More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk. © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Taylor F.G.M.,University of Surrey | Quirke P.,University of Leeds | Heald R.J.,North Hampshire Hospital | Moran B.,North Hampshire Hospital | And 6 more authors.
Annals of Surgery | Year: 2011

Objective: To assess local recurrence, disease-free survival, and overall survival in magnetic resonance imaging (MRI)-predicted good prognosis tumors treated by surgery alone. Background: The MERCURY study reported that high-resolution MRI can accurately stage rectal cancer. The routine policy in most centers involved in the MERCURY study was primary surgery alone in MRI-predicted stage II or less and in MRI "good prognosis" stage III with selective avoidance of neoadjuvant therapy. PATIENTS and Methods: Data were collected prospectively on all patients included in the MERCURY study who were staged as MRI-defined "good" prognosis tumors. "Good" prognosis included MRI-predicted safe circumferential resection margins, with MRI-predicted T2/T3a/T3b (less than 5 mm spread from muscularis propria), regardless of MRI N stage. None received preoperative or postoperative radiotherapy. Overall survival, disease-free survival, and local recurrence were calculated. Results: Of 374 patients followed up in the MERCURY study, 122 (33%) were defined as "good prognosis" stage III or less on MRI. Overall and disease-free survival for all patients with MRI "good prognosis" stage I, II and III disease at 5 years was 68% and 85%, respectively. The local recurrence rate for this series of patients predicted to have a good prognosis tumor on MRI was 3%. Conclusions: The preoperative identification of good prognosis tumors using MRI will allow stratification of PATIENTS and better targeting of preoperative therapy. This study confirms the ability of MRI to select patients who are likely to have a good outcome with primary surgery alone. © 2011 Lippincott Williams & Wilkins.


Schlumberger M.,University Paris - Sud | Tahara M.,National Cancer Center Hospital East | Wirth L.J.,Massachusetts General Hospital | Robinson B.,University of Sydney | And 15 more authors.
New England Journal of Medicine | Year: 2015

Results The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.Conclusions Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.) Copyright © 2015 Massachusetts Medical Society.Background Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor á, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).Methods In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.


Koffman J.,King's College London | Higginson I.J.,King's College London | Hall S.,King's College London | Riley J.,Royal Marsden Hospital NHS Trust | And 2 more authors.
Palliative Medicine | Year: 2012

Background: Bereaved relatives are considered to be a vulnerable group and there is debate as to whether it is ethical to engage them in research at a time that can be difficult for them.Aim: We conducted a cross-sectional study using cognitive interviewing with the aim of exploring the acceptability of a mortality follow-back survey among bereaved relatives of recently deceased cancer patients to inform the development of a large-scale survey about end-of-life care.Results: Thirty-three next-of-kin of recently deceased cancer patients were invited to participate in a face-to-face interview, or to complete a postal questionnaire. At the end, they were asked about their views of engaging in the study. Nine bereaved relatives participated in a face-to-face interview and 11 completed the postal questionnaire. Eleven relatives reported it was helpful to take part in the study; of these, six did not consider it distressing, and five stated whilst it had been distressing it had been helpful. Thoughts about bringing back memories, altruism and therapeutic value emerged.Conclusions: We have new evidence that although engaging in follow-back surveys can evoke distress, many participants report it to be a positive experience. We therefore believe that this approach is acceptable when conducted sensitively. © 2011 The Author(s).


Bystricky B.,Royal Marsden Hospital NHS Trust | Okines A.F.C.,Royal Marsden Hospital NHS Trust | Cunningham D.,Royal Marsden Hospital NHS Trust | Cunningham D.,Royal Marsden Hospital
Drugs | Year: 2011

Oesophageal cancer is the eighth most common cancer diagnosed worldwide, with almost half a million new cases diagnosed each year. Despite improvements in surgical and radiotherapy techniques and refinements of chemotherapeutic regimens, long-term survival, even from localized oesophageal cancer, remains poor. Surgical resection alone remains the standard approach for very early stage disease (stage I), but whilst surgery remains fundamental to the treatment of stage IIIII resectable adenocarcinoma, multimodality therapy with chemotherapy or chemoradiation (CRT) is internationally accepted as the standard of care. Data from two large, randomized phase III trials support the use of perioperative combination chemotherapy in lower oesophageal and oesophagogastric junction adenocarcinomas, but the contribution of the adjuvant therapy is uncertain. There are conflicting data from randomized studies of a purely neoadjuvant approach; however, recent meta-analyses have demonstrated that chemotherapy or CRT given prior to radical surgery improves survival in patients with adenocarcinoma of the oesophagus. Neoadjuvant CRT but not chemotherapy alone is also beneficial for patients with squamous cell carcinoma. Definitive CRT has emerged as a useful option for the treatment of resectable squamous cell carcinoma of the oesophagus, avoiding potential surgical morbidity and mortality for most patients, with salvage surgery reserved for those with persistent disease.In this review, we focus on the pharmacotherapy of resectable oesophageal and oesophagogastric junction cancers and how clinical trials and meta-analyses inform current clinical practice. © 2011 Adis Data Information BV. All rights reserved.


Walters Z.S.,Molecular Therapeutics | Villarejo-Balcells B.,Molecular Therapeutics | Olmos D.,Molecular Therapeutics | Olmos D.,Royal Marsden Hospital NHS Trust | And 9 more authors.
Oncogene | Year: 2014

Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and characteristically show features of developing skeletal muscle. The alveolar subtype is frequently associated with a PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated myogenic phenotype of RMS cells. Histone methylation of lysine residues controls developmental processes in both normal and malignant cell contexts. Here we show that JARID2, which encodes a protein known to recruit various complexes with histone-methylating activity to their target genes, is significantly overexpressed in RMS with PAX3-FOXO1 compared with the fusion gene-negative RMS (t-test; P<0.0001). Multivariate analyses showed that higher JARID2 levels are also associated with metastases at diagnosis, independent of fusion gene status and RMS subtype (n=120; P=0.039). JARID2 levels were altered by silencing or overexpressing PAX3-FOXO1 in RMS cell lines with and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein. Silencing JARID2 resulted in reduced cell proliferation coupled with myogenic differentiation, including increased expression of Myogenin (MYOG) and Myosin Light Chain (MYL1) in RMS cell lines representative of both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a decrease in JARID2 levels and this phenotype could be rescued by overexpressing JARID2. Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent on EED, a core component of the polycomb repressive complex 2 (PRC2). Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients. © 2014 Macmillan Publishers Limited.


Rini B.I.,Cleveland Clinic | Cohen D.P.,Pfizer | Lu D.R.,Pfizer | Chen I.,Pfizer | And 5 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib. We evaluated the association of sunitinib-induced HTN with antitumor efficacy and HTN-associated adverse events in patients with metastatic renal cell carcinoma. Methods This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d administered on a 4-week-on 2-week-off schedule (schedule 4/2). Blood pressure (BP) was measured in the clinic on days 1 and 28 of each 6-week cycle. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods; hazard ratios (HRs) for survival were also estimated by a Cox proportional hazards models using HTN as a time-dependent covariate. Efficacy outcomes were compared between patients with and without HTN (maximum systolic BP [SBP] ≥140 mm Hg or diastolic BP [DBP] ≥90 mm Hg). Adverse events were also compared between patients with and without HTN (mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg). All P values were two-sided. Results Patients with metastatic renal cell carcinoma and sunitinib-induced HTN defined by maximum SBP had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P <. 001 for all). Similar results were obtained when comparing patients with vs without sunitinib-induced HTN defined by maximum DBP. In a Cox proportional hazards model using HTN as a time-dependent covariate, PFS (HR of disease progression or death =. 603, 95% CI =. 451 to. 805; P <. 001) and OS (HR of death =. 332, 95% CI =. 252 to. 436; P <. 001) were improved in patients with treatment-induced HTN defined by maximum SBP; OS (HR of death =. 585, 95% CI =. 463 to. 740; P <. 001) was improved in patients with treatment-induced HTN defined by maximum DBP, but PFS was not. Few any-cause cardiovascular, cerebrovascular, ocular, and renal adverse events were observed. Rates of adverse events were similar between patients with and without HTN defined by mean SBP; however, hypertensive patients had somewhat more renal adverse events (5% vs 3%; P =. 013). Conclusions In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN-associated adverse events, supporting its viability as an efficacy biomarker. © The Author 2011.


Gore M.E.,Royal Marsden Hospital NHS Trust
British Journal of Cancer | Year: 2015

Background:We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.Methods:Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.Results:A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%).Conclusion:Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.British Journal of Cancer advance online publication, 18 June 2015; doi:10.1038/bjc.2015.196 www.bjcancer.com. © 2015 Cancer Research UK


Pearson H.,Royal Marsden Hospital NHS Trust
Paediatric nursing | Year: 2010

Caring for a child at the end of life stage is one of the greatest challenges a nurse can encounter in practice. The way professionals help support, maintain and give comfort to the child and his or her family helps shape the experience the young patient is about to face. Whatever the stage of your nursing career it is likely you will provide end of life care to a child or young person and their family. This article is designed to help enable professionals to cope emotionally and provide the best quality of care in an emotionally charged situation. The information contained may be used as a guidance tool through is challenging and difficult time.


Hewish M.,Institute of Cancer Research | Hewish M.,Royal Marsden Hospital NHS Trust | Martin S.A.,Institute of Cancer Research | Elliott R.,Institute of Cancer Research | And 3 more authors.
British Journal of Cancer | Year: 2013

Background:DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour.Methods:To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1-deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene.Results:We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants.Conclusion:We propose that cytarabine-based chemotherapy regimens may represent a tumour-selective treatment strategy for mismatch repair-deficient cancers. © 2013 Cancer Research UK.

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