• 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

      Woodings, P (2019-06)
      BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.
    • 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.
    • Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

      Das, P
      BACKGROUND: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial]
    • Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

      Chakraborti, Prabir (2017-06)
      Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). Results A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). Conclusions Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544
    • Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

      Chakraborti, Prabir (2018-02)
      Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP vs SOC+DocP. Method: Recruitment to SOC+DocP and SOC+AAP overlapped Nov-2011─Mar-2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2yrs and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly x6 + prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg + prednisolone 5mg daily. AAP duration depended on stage & intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards & flexible parametric models, adjusted for stratification factors. This was not a formally-powered comparison. A hazard ratio (HR)<1 favours SOC+AAP, HR > 1 favours SOC+DocP. Results: 566 consenting patients were contemporaneously randomised: 189 SOC+DocP, 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66yr & median PSA 56ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1·16 (95%CI 0·82-1·65); failure-free survival HR = 0·51 (95%CI 0·39-0·67); progression-free survival HR = 0·65 (95%CI 0·48-0·88); metastasis-free survival HR = 0·77 (95%CI 0·57-1·03); prostate cancer-specific survival HR = 1·02 (0·70-1·49); and symptomatic skeletal events HR = 0·83 (95%CI 0·55-1·25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, & 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2yrs on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer (HNPC) showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events, suggesting that Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.
    • 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.
    • Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.

      Chakraborti, Prabir (2020-04)
      BACKGROUND: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. METHODS: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4•5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. FINDINGS: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0•45, 95% CI 0•30-0•68; p=0•0001) at a median follow-up of 30•3 months (IQR 18•0-47•5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. INTERPRETATION: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. FUNDING: Cancer Research UK.
    • 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.
    • Audit of uptake and user satisfaction of Attend Anywhere video consultations in Haematology outpatients QHB

      Iqbal, Mariyam; Khan, Irfan; Hambleton, Harry; Aldalaq, Ahmad; Ahmad, Humayun; Razzak, Aurangzeb; Beal, Donna
      Introduction: Telemedicine clinics have historically been unpopular due to a range of clinical barriers. In March 2020 WHO declared COVID-19 as a global pandemic. This was a paradigm shift in the world of clinical medicine and initiated a rapid transition into virtual clinics as a strategy to minimise face to face (FtF) visits and limit viral spread. At Queen's Hospital Burton, Haematology patients are among the most vulnerable given the immunosuppressive effects of their conditions and treatments. Our outpatient work involves assessment of patients receiving chemotherapy which can be associated with fatal complications. It was felt that telephone consultations may be suboptimal for these assessments, and with the unclear duration of the pandemic, there has been an initiative to recruit more patients to video clinics. The Attend Anywhere' (AA) video consultation system was implemented in June. This drastically reduced the need for FtF visits to reduce infection risks. Objective(s): The primary objective of this audit was to evaluate the uptake of AA over time. We also used the data to assess whether particular patient groups were more likely to engage in video consultations. A concurrent survey was organised in order to assess patient satisfaction with AA. Method(s): A quantitative analysis of data from a consultant-led clinic was obtained from June to December 2020. The clinic letters were examined for patient demographics and to assess the type of consultation undertaken. A separate mixed-method survey of 29 patients was conducted as a part of our audit. Result(s): The results revealed a trend towards video consultations over telephone consultations during the period of time analysed, although the volume of patients undertaking telephone consultations remained higher overall. Despite the proportion of AA consultations being higher in the lower age groups, it remained popular in older age groups. The patient survey showed a high rate of patient satisfaction. A lot of the patients considered AA to be an excellent alternative to FtF and cited other significant benefits in saving time, reducing effort and minimising risk. Video consultations also felt more personal than over the phone and patients felt all their concerns were addressed with high standards of patient care. Conclusion(s): The audit showed that AA consultations are popular with patients in all demographics. They are felt to be safer than telephone consultations. As many appointments are still conducted via telephone, there is further work to be done to encourage more patients onto AA. A number of barriers to AA were noted. There were initially difficulties with staff accessing the software. There were a number of cases where patients either had no computer access, or struggled with the software. Improving communication and information booklets helped to overcome this. The older ages may have had higher representation if they had easier access to a computer, or if the software had been more straightforward. It is felt that a dedicated mobile application may provide a more user friendly system for patients. Whilst the added value of physical examination is missing in AA consultations, especially in new clinic patients, this has been a novel solution to challenges the pandemic has brought. It has helped to ensure continuity and safety in patient care.
    • Barriers to delivering advanced cancer nursing: A workload analysis of specialist nurse practice linked to the English National Lung Cancer Audit.

      Beckett, Paul (2018-10)
      PURPOSE: Health services across the world utilise advanced practice in cancer care. In the UK, lung cancer nurse specialists (LCNS) are recognised as key components of quality care in national guidelines, yet access to LCNS contact is unequal and some responsibilities are reportedly left undone. We assess whether any variation in working practices of LCNS is attributable to factors of the lung cancer service at the hospital trust. METHOD: Nationwide workload analysis of LCNS working practices in England, linked at trust level to patient data from the National Lung Cancer Audit. Chi-squared tests were performed to assess whether patient contact, workload, involvement in multidisciplinary teams (MDT), and provision of key interventions were related to 1) the trust's lung cancer service size, 2) LCNS caseload, 3) anti-cancer treatment facilities and 4) lung cancer patient survival. RESULTS: Unpaid overtime was substantial for over 60% of nurses and not associated with particular service factors assessed; lack of administrative support was associated with large caseloads and chemotherapy facilities. LCNS at trusts with no specialty were more likely to challenge all MDT members (80%) compared with those at surgical (53%) or chemotherapy (58%) trusts. The most frequent specialist nursing intervention to not be routinely offered was proactive case management. CONCLUSION: Working practices of LCNS vary according to service factors, most frequently associated with trust anti-cancer treatment facilities. High workload pressures and limited ability to provide key interventions should be addressed across all services to ensure patients have access to recommended standards of care.
    • Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and pathogenesis and guidelines for pathological diagnosis and management.

      Deb, Rahul (2019-12)
      AIMS: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon complication associated largely with textured implants. It is important that the symptoms associated with BIA-ALCL are recognised and that robust pathways are in place to establish the diagnosis. The aim of this paper is to review what is known of the incidence of the disease, current thoughts on pathogenesis, patterns of presentation and pathological features to provide standard guidelines for its diagnosis. METHODS AND RESULTS: Systematic review of the literature via PubMed covering cases series, modes of presentation, cytological, histological and immunohistochemical features and disease outcome. Since 1997, 518 cases throughout 25 countries have been registered on the American Society of Plastic Surgeons PROFILE registry, with an estimated risk for women with an implant of one to three per million per year. It most frequently presents as a late-onset accumulation of seroma fluid, sometimes as a mass lesion. The neoplastic cells are highly atypical, consistently strongly positive for CD30, with 43-90% also positive for EMA, and all are ALK-negative. Behaviour is best predicted using a staging system for solid tumours. CONCLUSION: BIA-ALCL is a rare but important complication of breast implants. While characterised by CD30-positive neoplastic cells this must be interpreted with care, and we provide pathological guidelines for the robust diagnosis of this lesion as well as the most appropriate staging system and management strategies. Finally, in order to generate more accurate data on incidence, we recommend mechanisms for the routine central reporting of all cases.
    • Carcinoma of Unknown Primary (CUP) in a patient presenting with lower back pain: An Important Clinical Lesson

      Hind, Jamie; Sidhu, Gur Aziz; Powell, Chris; Lacon, Andrew; Ashwood, Neil (2020-09)
      Carcinoma of unknown primary (CUP) is associated with high rates of morbidity and mortality. We report a case of a 33-year-old female, diagnosed with CUP, after presenting with gradual onset worsening lower back pain. Immunohistochemistry, blood tests, further investigations, and Multidisciplinary team meetings failed to identify the primary malignancy. This is not an uncommon pathway for patients with CUP. This report highlights how CUP can affect the quality of life of patients and how management for CUP should be focused on enhancing Quality of Life (QOL). It also addresses the difficulty of identifying which group of patients may benefit from further investigations to identify the primary and thus receive target treatment therapy.
    • Cellulitis in chronic oedema of the lower leg: an international cross-sectional study

      Keeley, Vaughan (2021-01)
      Background: Cellulitis and chronic oedema are common conditions with considerable morbidity. The number of studies designed to assess the epidemiology of cellulitis in chronic oedema are scarce. Objectives: To investigate the prevalence and risk factors of cellulitis in chronic leg oedema, including lymphoedema. Methods: A cross-sectional study, including 40 sites in nine countries, 2014-2017. Adults with clinically proven unilateral or bilateral chronic oedema (oedema >3 months) of the lower leg were included. The main outcome measures were frequency and risk factors for cellulitis within the last 12 months. Results: Out of 7477 patients, 15⋅78% had cellulitis within the last 12 months, with a life-time prevalence of 37⋅47%. The following risk factors for cellulitis were identified by multivariable analysis: wounds [odds ratio (OR) 2⋅37, 95% confidence interval (CI) 2⋅03-2⋅78], morbid obesity (OR 1⋅51, CI 95% 1⋅27-1⋅80), obesity (OR 1⋅21, CI 95% 1⋅03-1⋅41), midline swelling (OR 1⋅32, CI 95% 1⋅04-1⋅66), male sex (OR 1⋅32, CI 95% 1⋅15-1⋅52) and diabetes (OR 1⋅27, CI 95% 1⋅08-1⋅49). Controlled swelling was associated with a reduced risk (OR 0⋅59, CI 95% 0⋅51-0⋅67). In a subgroup analysis, the risk increased with the stage of oedema [International Society of Lymphology (ISL), stage II OR 2⋅04, CI 95% 1⋅23-3⋅38, and stage III OR 4⋅88, CI 95% 2⋅77-8⋅56]. Conclusions: Cellulitis in chronic leg oedema is a global problem. Several risk factors for cellulitis were identified, of which some are potentially preventable. Our findings suggest that oedema control, is one of these. We also identified that advanced stages of oedema, with hard/fibrotic tissue, might be an important clinical indicator to identify patients at particular risk.
    • Chronic oedema: a prevalent health care problem for UK health services

      Keeley, Vaughan; Moffatt, Christine; Rich, Anna (2016-12)
      Chronic oedema (CO) is a major clinical problem worldwide, which has many important secondary consequences for health, activity and participation. Effective treatment planning and organisation of services is dependent on an understanding of the condition and its epidemiology. This cross-sectional study was designed to estimate the point prevalence of CO within the health services of one UK urban population and to determine the proportions that have concurrent leg ulceration. Patients with CO in all anatomic sites were ascertained by health care professionals in one acute and one community hospital, all relevant outpatient and community nursing services, general practices and all nursing/residential homes in one urban catchment area (Derby City). The presence and distribution of oedema was confirmed through a brief clinical examination. A battery of demographic and clinical details was recorded for each case. Within the study population of Derby City residents, 971 patients were identified with CO [estimated crude prevalence 3·93 per 1000, 95% confidence interval (CI) 3·69–4·19]. The prevalence was the highest among those aged 85 or above (28·75 per 1000) and was higher among women (5·37 per 1000) than men (2·48 per 1000). The prevalence among hospital inpatients was 28·5%. Only five (3%) patients in the community population had oedema related to cancer or cancer treatment. Of the 304 patients identified with oedema from the Derby hospitals or community health services, 121 (40%) had a concurrent leg ulcer. Prevalence statistics and current demographic trends indicate that CO is a major and growing health care problem.
    • 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.
    • Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

      Walker, GA; Keni, Manjusha (2018-01)
      AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.
    • 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.
    • 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.
    • 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.
    • 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.