• Occult breast carcinoma in breast reduction specimens in European women.

      Goyal, Amit (2011-08)
      Breast reduction is a common surgical procedure performed by plastic and oncoplastic breast surgeons. The authors report on the incidence and management of cancer and atypical hyperplasia in breast reduction specimens from one institution over a 10-year period. All patients who underwent breast reduction surgery at Northern General Hospital, Sheffield were identified from an electronic prospective database. The histopathology reports were analyzed. Case records of all patients with significant abnormalities were retrieved and examined to identify their management and follow-up. Between October 1999 and April 2010, 1,588 patients underwent breast reduction. Nine specimens showed atypical hyperplasia (0.57%). Five cancers were detected (0.31%). Four of the five patients had normal screening mammograms 1-3 years before the reduction operation. Of these cancers, four were invasive (three lobular, one ductal) (0.25%) and one was DCIS (0.06%). A lump was felt macroscopically by the pathologist in two of the four patients with invasive cancer. The patients with DCIS did not undergo further surgery, whereas those with invasive disease underwent mastectomy (three patients) and axillary nodal staging (four patients). None of the patients with normal post-reduction breast imaging had residual cancer on histology. The incidence of occult carcinoma in breast reduction specimens is low. Patients should be counseled with regards to the possible consequences preoperatively.
    • Oncological outcomes after laparoscopic and open radical nephroureterectomy: results from an international cohort.

      Walton, Tom (2011-08)
      OBJECTIVE: • To compare oncological outcomes in patients undergoing open radical nephroureterectomy (ONU) with those in patients undergoing laparoscopic radical nephroureterectomy (LNU). PATIENTS AND METHODS: • A total of 773 patients underwent radical nephroureterectomy at nine centres worldwide; 703 patients underwent ONU and 70 underwent LNU. • Demographic, perioperative and oncological outcome data were collected retrospectively. • Statistical analysis of data was performed using chi-squared, Mann-Whitney U- and log-rank tests, and Cox regression analyses. • The median (interquartile range) follow-up for the cohort was 34 (15-65) months. RESULTS: • The two groups were well matched for tumour stage, presence of lymphovascular invasion (LVI) and concomitant carcinoma in situ (CIS). • There were more high-grade tumours (77.1% vs. 56.3%; P < 0.001) but fewer lymph node positive patients (2.9% vs. 6.8%; P= 0.041) in the LNU group. • Estimated 5-year recurrence-free survival (RFS) was 73.7% and 63.4% for the ONU and LNU groups, respectively (P= 0.124) and estimated 5-year cancer-specific survival (CSS) was 75.4% and 75.2% for the ONU and LNU groups, respectively (P= 0.897). • On multivariable analyses, which included age, gender, race, previous endoscopic treatment for bladder cancer, technique for distal ureter management, tumour location, pathological stage, grade, lymph node status, LVI and concomitant CIS, the procedure type (LNU vs. ONU) was not predictive of RFS (Hazard ratio [HR] 0.80; P= 0.534) or CSS (HR 0.96; P= 0.907). CONCLUSION: • The present study is the second large, independent, multicentre cohort to show oncological equivalence between ONU and LNU for well selected patients with upper urinary tract urothelial cancer, and the first to suggest parity for the techniques in patients with unfavourable disease.
    • Poor tolerability of thalidomide in end-stage oesophageal cancer.

      Wilkes, Emilie; Selby, A; Cole, Andrew; Freeman, Jan; Rennie, M; Khan, Z (2011-09)
      Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.
    • The experience of patients with complex wounds and the use of NPWT in a home-care setting.

      Moffatt, Christine; Murray, Susan; Morgan, PA (2011-11)
      OBJECTIVE: To explore the experience of patients living with complex wounds and the impact of undergoing negative pressure wound therapy (NPWT) as part of their treatment. METHOD: Qualitative data were collected from eight patients, using semi-structured interviews. A purposive, stratified sampling approach was used to identify participants with a range of wound types, as well as age and gender. Participants were recruited from one primary care trust and were interviewed, following 10 days of treatment with NPWT. The matrix-based 'Framework' approach, from the National Centre for Social Research, was used to structure the analysis. RESULTS: Of the eight participants recruited, five were female and three male, with an age range of 46-77 years. Five overarching categories, with their constituent themes, were identified from the data. The first, developing a wound through crisis, has three themes: a failing body, missed diagnosis and failed professional intervention. The second category, decreased control, has four related themes: poor communication; failed wound healing; poor discharge planning and failure to recover. The third category, increased control, has four themes: understanding what is happening; symptom control; positive professional relationships and returning to health. The fourth category, using NPWT, has two themes: information and understanding of NPWT and expectations and experience of NPWT. The final category sets out participant recommendations about the device and has two themes: device issues and improving professional practice. CONCLUSION: This study investigated the experience of patients undergoing NPWT for complex wounds in the home setting and reveals a number of the psychosocial effects of using this therapy in this environment. Participants saw NPWT as an active intervention, associated with improved wound healing and symptom control. The participant experience described in this study, and the recommendations they make, provide a valuable resource to inform service improvement programmes and wound research.DECLARATION OF INTEREST: This study was supported by a research grant from Smith & Nephew Ltd.
    • A preliminary randomized controlled study to determine the application frequency of a new lymphoedema bandaging system.

      Moffatt, Christine (2012-03)
      BACKGROUND:  Bandaging plays an important role in the treatment of lymphoedema. OBJECTIVE: To investigate efficacy and safety of the 3M™ Coban™ 2 compression system (Coban 2 system) with different application frequencies in comparison to short-stretch bandaging. METHODS: A multicentre, randomized, prospective study was performed with 82 patients suffering from arm or leg lymphoedema stage II or late stage II. Patients were allocated to traditional short-stretch bandaging five times per week or to the Coban 2 system applied two, three or five times per week for 19 days. Limb volume and adverse events were recorded at each study visit. The primary endpoint was percentage volume reduction. RESULTS: The highest lymphoedema volume reduction was achieved with the Coban 2 system applied two times per week. A mean reduction of 18•7% (SD 14•5) in legs and 10•5% (SD 8•3) in arms was achieved. More frequent bandage changes of three and five times per week did not demonstrate additional benefits. Short-stretch bandaging five times per week showed a mean volume reduction of 10•9% (SD 5•2) and 8•2% (SD 3•1) for legs and arms, respectively. Bandage slippage was low for all treatment groups. A relevant change in overall mobility was achieved during the use of the Coban 2 system. The adverse reactions were in agreement with already known side-effects and did not differ remarkably between the treatment groups. CONCLUSION: The 3M™ Coban™ 2 compression system applied twice weekly demonstrated a high rate of volume reduction and a good safety profile. Oedema reduction was still effective with 4 days between bandage change, which allows a constant therapeutic effect in routine practice. This should give the patient a high degree of independence and mobility.
    • MRI in T staging of rectal cancer: How effective is it?

      Mulla, Mulbashir; Deb, Rahul; Singh, Rajeev (2012-05)
      BACKGROUND: Rectal cancer constitutes about one-third of all gastrointestinal (GI) tract tumors. Because of the high recurrence rates (30%) in rectal cancer, it is vitally important to accurately stage these tumours preoperatively so that appropriate surgical resection can be undertaken. MRI is the ideal technique for the preoperative staging of these tumours. AIM: To determine the accuracy of local T staging of rectal cancer with MRI, using histopathological staging as the gold. MATERIALS AND METHODS: Forty consecutive patients admitted with rectal cancer over a period of 18 months were included in this retrospective study. MRI scans were performed prior to surgery in all patients, on 1.5T scanners. Two radiologists, with a special interest in gastrointestinal imaging reported all images. Two dedicated histopathologists reported the histology slides. The accuracy of preoperative local MRI T staging was assessed by comparison with postoperative histopathological staging. RESULTS: There was agreement between MRI and histopathology (TNM) staging in 12 patients (30%). The sensitivity and specificity of MRI for T staging was 89% and 67% respectively. The circumferential resection margin (CRM) status was accurately staged in 94.1% of the patients. CONCLUSIONS: Preoperative staging with MRI is sensitive in identifying CRM involvement, which is the main factor affecting the outcome of surgery.
    • Effect of colon cancer and surgical resection on skeletal muscle mitochondrial enzyme activity in colon cancer patients: a pilot study.

      Lund, Jonathan (2013-03)
      BACKGROUND: Colon cancer (CC) patients commonly suffer declines in muscle mass and aerobic function. We hypothesised that CC would be associated with reduced muscle mass and mitochondrial enzyme activity and that curative resection would exacerbate these changes. METHODS: We followed age-matched healthy controls and CC patients without distant metastasis on radiological imaging before and 6 weeks after hemi-colectomy surgery. Body composition was analysed using dual energy X-ray absorptiometry. Mitochondrial enzyme activity and protein concentrations were analysed in vastus lateralis muscle biopsies. RESULTS: In pre-surgery, there were no differences in lean mass between CC patients and age-matched controls (46.1 + 32.5 vs. 46.1 + 37.3 kg). Post-resection lean mass was reduced in CC patients (43.8 + 30.3 kg, P < 0.01). When comparing markers of mitochondrial function, the following were observed: pyruvate dehydrogenase (PDH) activity was lower in CC patients pre-surgery (P < 0.001) but normalized post-resection and cytochrome c oxidase and pyruvate dehydrogenase E2 subunit protein expression were lower in CC patients pre-surgery and not restored to control values post-resection (P < 0.001). Nuclear factor kappa-B, an inflammatory marker, was higher in CC patients pre-surgery compared to controls (P < 0.01), returning to control levels post-resection. CONCLUSION: Muscle mass was affected by surgery rather than cancer per se. PDH activity was however lower in cancer patients, suggesting that muscle mass and mitochondrial enzyme activity are not inextricably linked. This reduction in mitochondrial enzyme activity may well contribute to the significant risks of major surgery to which CC patients are exposed.
    • Faecal occult blood testing (FOBT) and interval bowel cancers-results of a multicentre study

      George, Anil Thomas (2015-06)
      Introduction We aimed to assess the incidence and demographics of interval cancers (cancers diagnosed within 2 years of a negative FOBT screening) in the eligible population of the East Midlands region. Method The National Bowel Cancer Audit Programme data from three centres (Queens Medical Centre, Nottingham; Royal Derby Hospital and Sherwood Forest Hospitals) for all colorectal cancers in the screening age group (60-74 years)over a 2- year period (August 2011-August 2013) were linked for their FOBT screening status (BCSP database/Eastern Hub). Three cancer groups were identified: interval cancers, screen detected (positive FOBT) and those in the non-uptake group (eligible patients who declined screening). Tumours at and distal to the splenic flexure were classed as left sided tumours. Dukes C and D tumours were classed as advanced tumours. All three centres were in incident rounds of screening. Results Of the 521 colorectal cancers identified, 128 (25%) were interval cancers, 162(31%) were screen detected and 231 (44%) were from the non-uptake group. Gender, ethnicity and Deprivation index were comparable between the three groups. The mean age in the interval cancer group was greater (67 yrs) compared to the screen detected (66 yrs) (p = 0.005). The interval cancer group had a higher incidence of right sided cancers (38% vs. 25% and 29%; X2=6.59; p = 0.033) compared to the screen-detected and non-uptake groups. Cancers detected in the interval cancer group were of a more advanced stage (Dukes C/D) (70% vs. 34% and 54%; X2=37.2;p < 0.005) in comparison to screen-detected and non-uptake groups. The one year mortality in the interval cancer group (16%) was higher than the non-uptake group (12%) and the screen detected group (3%) (16%vs12% and 3%; X2=13.8;p < 0.005). Conclusion A quarter of colorectal cancers identified in our screening-eligible population were interval cancers. We highlight the probability that these cancers were 'missed' by the guaiacbased FOBT screening tests. The interval cancer group also had poorer outcomes when compared to the screen-detected group. We highlight the need for a test with a lower false negative rate for population based FOBT screening.
    • Are patients with cancers 'missed' on faecal occult blood (FOB) testing truly asymptomatic?-a multicentre analysis

      George, Anil Thomas (2015-06)
      Introduction We aimed to identify the symptomatology of patients who develop interval cancers (cancers diagnosed within 2 years of a negative FOBT screening) in the eligible population of the East Midlands region. Method Data from the National Bowel Cancer Audit Programme from three tertiary colorectal centres (Queens Medical Centre, Nottingham; Royal Derby Hospital and Sherwood Forest Hospitals ll) in the FOB testing age group (60-74 years) over 2 years (August 2011 to August 2013) were analysed and linked to the regional FOB hub to identify patients who had developed colorectal cancer after a negative FOBT in the screening interval (2 years) status. Tumours from and distal to the splenic flexure were classed as left sided tumours. Dukes C/D tumours were classed as advanced tumours. All three centres were in incident rounds of screening. Results The study covered a population of 2 million of which 200,000 were eligible for screening. 521 colorectal cancers were diagnosed in the above population (0.11%). Of these, 231 cancers (44%) were in patients who had declined screening,162 (31%) were picked up following on from a positive FOBT and 128 (25%) were picked up in patients who had a negative FOBT. Of these 128 patients (M: F; 84:44),median age 67 years (SD:3.8) the commonest presenting symptoms for these patients were change in bowel habits in 50(39%). Other presentations included bleeding per-rectum in 44 patients (34%), abdominal pain in 38 (30%) patients, anaemia in 36(28%) patients, loss of weight in14 (11%)patients, bowel obstruction in 13 (10%) patients, bowel perforation in 3(2%) patients. Only two patients were truly asymptomatic from the bowel cancer with this being identified in one patient during surgery for an ovarian cyst and during a trauma laparotomy in the other patient. In the 28% patients who had anaemia the blood picture included a Hb (mean)of 10.3gm;MCV of 82.4 and;MCH of 26.3. In 61% of anaemic patients, the cancer was located on the right side of the colon with an equal percentage being of advanced Duke's stage. The median interval between the negative FOB test and the diagnosis of cancer in these patients was 15 months (range 0.5-24 months). Conclusion Our findings suggest that the majority of patients with 'missed' interval cancers were symptomatic with 'red flag symptoms' inspite of the negative FOB test. We also raise the possibility of a natural bias of subjects volunteering for the FOB test in that some who opt for the test may not be 'truly' asymptomatic but may have bowel symptoms not yet discussed with their general practitioner. We highlight the need for improved awareness to reduce delays in symptomatic patients seeking medical advice against a background of a negative FOBT.
    • Demographics, management and survival of patients with malignant pleural mesothelioma in the National Lung Cancer Audit in England and Wales

      Beckett, Paul (2015-06)
      INTRODUCTION AND METHODS: Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. We have used data collected for the UK National Lung Cancer Audit to assess current practice and to highlight regional variation in the management of mesothelioma patients, as well as to describe survival patterns in subgroups. RESULTS: Our data on 8740 cases seen in hospitals in England and Wales is the largest cohort of MPM in the literature and represents approximately 80% of the total incident cases. 83% are male and median age is 73 years. Performance status is recorded in 81% and of these approximately 70% are PS 0-2. Stage is poorly recorded and unreliable in this dataset. The patient pathway is similar to lung cancer with approximately one-fifth having a non-elective referral to secondary care. A histo-cytological diagnosis is made in 87% and varies across organisations. Only 67% have anti-cancer treatment, and this also varies across organisations, but there has been an annual increase in the proportion receiving chemotherapy. Overall median survival was 9.5 months, with a 1YS of 41.4% and 3YS of 12.0%, but was strongly linked to performance status and histological subtype. Median survival also varied by cancer network from 209 days to 349 days, but appeared to increase from of 9.2 months in 2008 to 10.5 months in 2012. CONCLUSION: Our data provide a large scale, detailed assessment of MPM epidemiology, treatment choices and outcomes. Incidence is increasing in line bwith predictions and uptake of treatments has generally mirrored publication of key MPM treatment trials, in particular increasing use of chemotherapy but low uptake of radical surgery. However, there is significant variation in care patterns and outcomes that may reflect limited expertise in area with low incidence. Initiatives to improve outcomes should include improved recording of clinical stage.
    • The Role of Computed Tomography Scanning of the Thorax in the Initial Assessment of Gestational Trophoblastic Neoplasia.

      Price, JM (2015-11)
      OBJECTIVE: The aim of this study was to determine whether lesions found on computed tomography (CT) imaging of the thorax would affect FIGO (International Federation of Gynecology and Obstetrics) 2000 risk score and/or alter clinical management. METHODS: The Sheffield Trophoblastic Disease database was searched for all new patients registered for staging/scoring investigations between January 1, 2006, and June 30, 2010. The FIGO 2000 score was noted and then recalculated using information from CT scan reports. Where a change of risk score would have affected a patient's management, the case notes were further reviewed. RESULTS: 191 patients had undergone both modalities of imaging. Using standard FIGO scoring, 169 and 22 patients were noted to be at low and high risk, respectively. Using information from CT imaging, only a further 20 patients would have been reclassified as high risk. Fifteen of these "new" high-risk patients required salvage treatment with intravenous chemotherapy; all were cured. CONCLUSIONS: With no potential advantage in terms of patient outcome and significantly increased radiation dose, there is little justification for routine CT imaging of the thorax in the initial assessment of new patients with gestational trophoblastic neoplasia.
    • Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study

      Keeley, Vaughan (2015-12)
      OBJECTIVE: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. DESIGN: Prospective multicentre observational cohort study. SETTING: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). PARTICIPANTS: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. MAIN OUTCOME MEASURES: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. RESULTS: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. CONCLUSIONS: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.
    • Systematic review of pre-operative exercise in colorectal cancer patients.

      Boereboom, CL; Doleman, Brett; Lund, Jonathan; Williams, John P (2016-02)
      The aim of this systematic review was to evaluate the evidence for exercise interventions prior to surgery for colorectal cancer resection. The evidence for use of exercise to improve physical fitness and surgical outcomes is as yet unknown. A systematic search was performed of MEDLINE, EMBASE, CINAHL, AMED and BNI databases for studies involving pre-operative exercise in colorectal cancer patients. Eight studies were included in the review. There is evidence that pre-operative exercise improves functional fitness, and to a lesser extent objectively measurable cardio-respiratory fitness prior to colorectal cancer resection. There is no clear evidence at present that this improvement in fitness translates into reduced peri-operative risk or improved post-operative outcomes. Current studies are limited by risk of bias. This review highlights the common difficulty in transferring promising results in a research setting, into significant improvements in the clinical arena. Future research should focus on which type of exercise is most likely to maximise patient adherence and improvements in cardio-respiratory fitness. Ultimately, adequately powered, randomised controlled trials are needed to investigate whether pre-operative exercise improves post-operative morbidity and mortality.
    • Indolent CD8-positive lymphoid proliferation of acral sites: three further cases of a rare entity and an update on a unique patient.

      Persic, Mojca (2016-02)
      BACKGROUND: Primary cutaneous indolent CD8-positive lymphoid proliferation is an emerging entity characterized by slowly enlarging papules and nodules that are pathologically comprised of clonal nonepidermotropic medium-sized atypical CD8(+) T-cells. Although the majority of lesions are solitary and located on the ears,v bilateral symmetrical presentations have been described and lesions may arise at other peripheral or 'acral' sites. Patients follow a benign clinical course and systemic involvement has not yet been observed. Despite this, some medical practitioners classify such lesions as peripheral T-cell lymphoma, NOS, a category implying aggressive disease. OBJECTIVES: We present three cases seen in our institutions and provide an update on a previously reported unique patient who continues to develop recurrent and multifocal skin lesions. RESULTS: Systemic disease progression has not been observed, even in the presence of recurrent and multifocal cutaneous disease. CONCLUSIONS: Indolent CD8-positive lymphoid proliferation of acral sites is a distinctive and readily identifiable entity and should be included in the next consensus revision of cutaneous lymphoma classification. Although cases described thus far have followed an indolent clinical course, dermatologists should remain guarded about the prognosis and full staging and longitudinal observation are recommended until this condition is better understood
    • 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.

      Chakraborti, Prabir (2016-03)
      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(2)) 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 α 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.
    • Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.

      Chakraborti, Prabir (2016-04)
      IMPORTANCE: Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. OBJECTIVE: To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. DESIGN, SETTING, AND PARTICIPANTS: The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. INTERVENTIONS: Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. MAIN OUTCOMES AND MEASURES: Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression-free interval, total SREs, and overall survival (OS). RESULTS: Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). CONCLUSIONS AND RELEVANCE: Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN12808747.
    • Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

      Chakraborti, Prabir (2016-06)
      OBJECTIVES: To evaluate the cost-effectiveness of adding zoledronic acid (ZA) or strontium-89 (Sr89) to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC). PATIENTS AND METHODS: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2x2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the NHS and included expenditures for trial treatments, concomitant medications and use of related hospital and primary care services. QALYs were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument. Results are expressed as incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves. RESULTS: The per-patient cost for ZA was £12,667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group experienced on average 0.03 QALYs more than their counterparts in no ZA. The incremental cost-effectiveness ratio (ICER) for this comparison was £8,005. Sr89 was associated with a cost of £13,230, £1,365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16,884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively. CONCLUSIONS: The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources This article is protected by copyright. All rights reserved.
    • TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.

      Chakraborti, Prabir (2016-07)
      BACKGROUND: Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. METHODS: Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. RESULTS: PATIENTS: 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. CONCLUSION: Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. STUDY REGISTRATION: Current Controlled Trials ISRCTN12808747. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.
    • Personalised Care Plans in the Last Days of Life

      Bussooa, Karen; North, Elizabeth (2016-07)
      Personalised care plans prompt nursing staff to consider the priorities of care for patients nearing the end of life, in line with guidance from the Leadership Alliance for the Care of Dying People, when planning care. This article discusses the results of an acute hospital audit comparing the quality of care planning for patients in the last days of life using the trust care record documentation with the use of a personalised care plan for patients.