Staff Publication

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial (2016)

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Type of publication:
Journal article

Author(s):
James N.D., Sydes M.R., Clarke N.W., Mason M.D., Dearnaley D.P., Spears M.R., Ritchie A.W.S., Parker C.C., Russell J.M., Attard G., De Bono J., Cross W., Jones R.J., Thalmann G., Amos C., Matheson D., Millman R., Alzouebi M., Beesley S., Birtle A.J., Brock S., Cathomas R., Chakraborti P., Chowdhury S., Cook A., Elliott T., Gale J., Gibbs S., Graham J.D., Hetherington J., Hughes R., Laing R., McKinna F., McLaren D.B., O'Sullivan J.M., Parikh O., Peedell C., Protheroe A., Robinson A.J., *Srihari N., Srinivasan R., Staffurth J., Sundar S., Tolan S., Tsang D., Wagstaff J., Parmar M.K.B.

Citation:
The Lancet, March 2016, vol./is. 387/10024(1163-1177)

Abstract:
Background
Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.
Methods
Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m<sup>2</sup>) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2.5% one-sided alpha for hazard ratio (HR) 0.75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).
Findings
2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0.94, 95% CI 0.79-1.11; p=0.450), 81 months (41 to not reached) for SOC + Doc (0.78, 0.66-0.93; p=0.006), and 76 months (39 to not reached) for SOC + ZA + Doc (0.82, 0.69-0.97; p=0.022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.
Interpretation
Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
Funding
Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Link to more details or full-text: http://www.sciencedirect.com/science/article/pii/S0140673615010375

Breast reconstruction changes coping mechanisms in breast cancer survivorship (2016)

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Type of publication:
Conference abstract

Author(s):
*Lake B., *Fuller H.R., *Rastall S., *Usman T.

Citation:
Cancer Research, February 2016, vol./is. 76/4 SUPPL. 1(no pagination)

Abstract:
Introduction
Cancer survivorship is the process of living through and beyond cancer; a key part is how a patient copes with their diagnosis. Breast cancer is the most common malignancy of women worldwide and is known to be a severe stressor. Research has determined that the coping strategies used by women with breast cancer are vital to adjustment to their disease. Immediate breast reconstruction at the time of mastectomy with preservation of the breast form has been shown to be a positive influence on breast cancer patients however there are currently no studies to show whether breast reconstruction changes mechanisms of coping for such patients. The aim of this study, therefore, was to conduct a prospective cohort study to determine whether immediate breast reconstruction following mastectomy changes the way women with breast cancer cope with their diagnosis, compared to those who have mastectomy alone.
Method
A standardised questionnaire, the Brief Cope Scale was sent to two cohorts of patients who had a mastectomy and immediate reconstruction or mastectomy alone over an 11 year period 2003 to 2014 in Shropshire, England. It is a 28-point item with a four point Likert scale, which measures 14 different coping mechanisms: self-distraction, active coping, denial, substance use, use of emotional support, use of instrumental support, behavioral disengagement, venting, positive reframing, planning humour, acceptance, religion and self-blame. The inclusion criteria for this study was all woman who had mastectomy with immediate breast reconstruction in Shropshire between 2003 and 2014 for either Ductal carcinoma in situ (DCIS) or breast cancer which was node negative (cohort 1). The principle exclusion criteria were: men, node positive cancer, prophylactic mastectomy and breast reconstruction. Each index patient was matched for year of diagnosis, adjuvant therapy and age to woman who had mastectomy alone for DCIS or breast cancer which was node negative (cohort 2). An anonymous questionnaire was sent out to all patients identified who were still living, with a reminder letter at six weeks.
Results
Questionnaires were sent to a total of 234 patients; 117 patients in each cohort. Preliminary results indicate a response rate of 46%, with 60 responses from reconstruction cohort and 48 from mastectomy. The mean age was 50, with range 29 to 70 for reconstruction cohort, and the mean age of mastectomy cohort was 52, with range 32 to 70. Common coping styles for the reconstruction cohort were acceptance, active coping and use of emotional support. Common coping styles for mastectomy cohort were acceptance, use of emotional support and positive reframing. Significantly more patients from the reconstruction cohort coped by active coping (T value 1.88 at P value 0.02). Significantly less patients coped by active venting in reconstructive cohort compared to mastectomy cohort; (T value 1.91 at P value 0.03).
Conclusion
Breast reconstruction alters coping mechanisms in breast cancer patients allowing less venting coping style and more active coping. Understanding how breast surgery changes coping mechanisms allows clinicians to understand cancer survivorship in breast cancer patients and helps to provide needed support.

Does the number of tissue fragments removed from the cervix with excisional treatment for CIN pathology affect the completeness of excision and cytology recurrence at follow-up? An observational cohort study (2016)

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Type of publication:
Journal article

Author(s):
*Papoutsis D., *Panikkar J., *Gornall A., *Blundell S.

Citation:
Journal of Obstetrics and Gynaecology, February 2016, vol./is. 36/2(251-256)

Abstract:
The objective of our study was to determine whether removing multiple pieces of cervical tissue during large loop excision of the transformation zone (LLETZ) reduced the margin positivity of excision and cytology recurrence rates at follow-up. We conducted an observational cohort study and identified 462 women having had a single LLETZ treatment for cervical intraepithelial neoplasia (CIN) over a two-year period. Women with previous cervical treatment, cervical cancer on the excised tissue or missing follow-up data were excluded. Multiple regression analysis showed that removal of cervical tissue in multiple pieces did not offer any benefit in removing more disease and less recurrence rates. When multiple pieces were taken there was a four-fold increased risk for inconclusive excision margins as reported by the histopathologist. Removal of multiple pieces led to significantly more tissue being removed which may expose the patient to an increased risk of preterm delivery in a future pregnancy.

A dedicated undergraduate gynaecology teaching clinic: The Keele experience (2016)

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Type of publication:
Journal article

Author(s):
Katali H.M., *Parry-Smith W.R., Eliot R.L., Omahony F.

Citation:
Journal of Obstetrics and Gynaecology, February 2016, vol./is. 36/2(227-229)

Abstract:
Much discussion in the literature centres on how best to teach medical students the intricacies of gynaecological assessment and the subsequent formulation of a management plan. At Keele University skills are initially developed in a simulated setting and then transferred to the workplace where students continue to develop their skills. A dedicated undergraduate gynaecology teaching clinic has been developed and comprises of 2-3 students and a tutor. All 38 students rotating through the department between January and June 2013 were invited to complete an anonymous questionnaire to evaluate this clinic and 36 (95%) of them responded. Respondents felt significantly more comfortable taking a gynaecology history, ensuring privacy during examination and formulating a management plan post-clinic (all p < 0.001), with female students feeling significantly more comfortable than their male counterparts (p = 0.04). The use of this clinic shows great promise to help students learn an unfamiliar and challenging skill.

Magnetic resonance imaging for the diagnosis of vestibular schwannoma - Increasing cost-effectiveness and the diagnostic yield (2016)

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Type of publication:
Conference abstract

Author(s):
Kumar S., Olaitan A., Danino J., Scott A.

Citation:
Otorhinolaryngologist, 2016, vol./is. 9/1(9-13)

Abstract:
Introduction: We aimed to assess whether MRI scans for screening of vestibular schwannoma (VS) are a cost effective tool and how best to maximise their positive yield. Materials and Methods: We undertook a retrospective analysis of 1000 scans to assess the diagnostic yield and the sensitivity and specificity of four published protocols Results: Of 756 patients included 8 patients were positively identified with a VS. If only patients who had either a 15dB or 20dB hearing loss at any single frequency underwent screening the number of negative scans would have been reduced by over 50%. No patients with unilateral tinnitus alone and normal hearing (8.6%) were diagnosed with VS. Discussion: To reduce the burden of MRI scans all departments should scan in accordance with a published protocol.

Outcomes of two trials of oxygen-saturation targets in preterm infants (2016)

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Type of publication:
Journal article

Author(s):
Tarnow-Mordi W., Stenson B., Kirby A., Juszczak E., Donoghoe M., *Deshpande S., Morley C., King A., Doyle L.W., Fleck B.W., Davis P.G., Halliday H.L., Hague W., Cairns P., Darlow B.A., Fielder A.R., Gebski V., Marlow N., Simmer K., Tin W., Ghadge A., Williams C., Keech A., Wardle S.P., Kecskes Z., Kluckow M., Gole G., Evans N., Malcolm G., Luig M., Wright I., Stack J., Tan K., Pritchard M., Gray P.H., Morris S., Headley B., Dargaville P., Simes R.J., Brocklehurst P.

Citation:
New England Journal of Medicine, February 2016, vol./is. 374/8(749-760)

Abstract:
BACKGROUND The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P = 0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P = 0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P = 0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P = 0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P = 0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P = 0.001). CONCLUSIONS Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Link to more details or full-text: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&AN=00006024-201602250-00011&LSLINK=80&D=ovft

Partial breast radiotherapy for women with early breast cancer: First results of local recurrence data for IMPORT LOW (CRUK/06/003) (2016)

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Type of publication:
Conference abstract

Author(s):
Coles C., *Agrawal R., Ah-See M.L., Algurafi H., Alhasso A., Brunt A.M., Chan C., Griffin C., Harnett A., Hopwood P., Kirby A., Sawyer E., Syndikus I., Titley J., Tsang Y., Wheatley D., Wilcox M., Yarnold J., Bliss J.M.

Citation:
European Journal of Cancer, April 2016, vol./is. 57/(S4)

Abstract:
Background: IMPORT LOW is a randomised, multi-centre phase III trial testing partial breast radiotherapy (RT) using intensity modulated RT in women with low risk early stage breast cancer, for whom late complications of RT are the dominant hazard rather than local recurrence (LR). Materials and Methods: Women age >50 who had breast conservation surgery, for invasive adenocarcinoma (excluding classical lobular carcinoma) pT1-2 (<3 cm) N0-1, any grade, with minimum microscopic margins of ge;2 mm, were eligible. Patients were randomised (1:1:1) to 40Gy/15F to whole breast (control); 36Gy/15F to whole breast and 40Gy/15Fr to partial breast (test 1); or 40Gy/15F to partial breast (test 2). The primary endpoint is local tumour control in the ipsilateral breast. 1935 patients were required to exclude 2.5% inferiority for each test group (80% power, one-sided alpha 2.5%) assuming 2.5% local recurrence (LR) rate at 5 years in the control group. Key secondary endpoints were late adverse effects measured using a combination of clinical, photographic and patient self-assessments. Analysis was by intention to treat. Results: 2018 patients were recruited from 05/2007 to 09/2010 from 30 UK RT centres (675 control, 674 test 1, 669 test 2). Baseline characteristics were balanced with median age 63 (IQR 58-68); 43%, 47% and 10% were tumour grade 1, 2 and 3; 3% were pN+. Median follow-up is 68.3 (IQR 60.3-73.4) months. The 5-year rate of LR was 1.1% (95% CI 0.5, 2.3), 0.2% (95% CI 0.02, 1.2) and 0.5% (95% CI 0.2-1.4) in the control, test 1 and test 2 groups respectively. Absolute treatment differences in LR with control compared with test 1 is -0.83% (95% CI -1.04, 0.18) and -0.69% (-0.99, 0.44) compared with test 2. For each of the test groups non-inferiority, assessed against the pre-specified 2.5% threshold was demonstrated. Conclusions: At 5 years, partial breast RT was shown to be non-inferior to whole breast RT in women with low risk early breast cancer. LR rates were very low in all treatment groups and moderate and marked normal tissue events were also low across all groups. Follow-up is ongoing and 10 year LR rates will be reported. (Figure Presented).

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial (2016)

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Type of publication:
Journal article

Author(s):
James, Nicholas D, Spears, Melissa R, Clarke, Noel W, Dearnaley, David P, Mason, Malcolm D, Parker, Christopher C, Ritchie, Alastair W S, Russell, J Martin, Schiavone, Francesca, Attard, Gerhardt, de Bono, Johann S, Birtle, Alison, Engeler, Daniel S, Elliott, Tony, Matheson, David, O'Sullivan, Joe, Pudney, Delia, *Srihari, Narayanan, Wallace, Jan, Barber, Jim, Syndikus, Isabel, Parmar, Mahesh K B, Sydes, Matthew R, STAMPEDE Investigators

Citation:
JAMA oncology, Mar 2016, vol. 2, no. 3, p. 348-357

Abstract:
The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT. To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients. Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011. Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry. Failure-free survival (FFS) and overall survival. A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]). Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease. clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.

A "systems medicine" approach to the study of non-alcoholic fatty liver disease (2016)

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Type of publication:
Journal article

Author(s):
Petta, Salvatore; Valenti, Luca; Bugianesi, Elisabetta; Targher, Giovanni; *Bellentani, Stefano ; Bonino, Ferruccio; Special Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver (AISF), Special Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver AISF (2016)

Citation:
Digestive and Liver Disease, Mar 2016, vol. 48, no. 3, p. 333-342

Abstract:
The prevalence of fatty liver (steatosis) in the general population is rapidly increasing worldwide. The progress of knowledge in the physiopathology of fatty liver is based on the systems biology approach to studying the complex interactions among different physiological systems. Similarly, translational and clinical research should address the complex interplay between these systems impacting on fatty liver. The clinical needs drive the applications of systems medicine to re-define clinical phenotypes, assessing the multiple nature of disease susceptibility and progression (e.g. the definition of risk, prognosis, diagnosis criteria, and new endpoints of clinical trials). Based on this premise and in light of recent findings, the complex mechanisms involved in the pathology of fatty liver and their impact on the short- and long-term clinical outcomes of cardiovascular, metabolic liver diseases associated with steatosis are presented in this review using a new "systems medicine" approach. A new data set is proposed for studying the impairments of different physiological systems that have an impact on fatty liver in different subsets of subjects and patients. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.