Now showing items 21-40 of 11955

    • The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens

      Canton, J.; Blees, H.; Henry, C. M.; Buck, M. D.; Schulz, O.; Rogers, N. C.; Childs, E.; Zelenay, Santiago; Rhys, H.; Domart, M. C.; et al. (2020)
      Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8+ T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.
    • Developing and evaluating a pathway for screening and treatment of depression in patients with head and neck cancer

      Waltho, A.; Thomson, David J; Pattison, Richard; Woolley, Joanne; Hawthorn, T.; Derbyshire Community Health Services Foundation Trust, Cavendish Hospital, Manchester Road, Buxton SK17 6TE, (2020)
    • Use of immunomodulating drugs and risk of cutaneous melanoma: a nationwide nested case-control study

      Berge, L. A. M.; Andreassen, B. K.; Stenehjem, J. S.; Heir, T.; Karlstad, Ø.; Juzeniene, A.; Ghiasvand, R.; Larsen, I. K.; Green, Adèle C; Veierød, M. B.; et al. (2020)
      Purpose: Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level. Patients and methods: In the Cancer Registry of Norway, we identified all cases aged 18-85 with a first primary cutaneous melanoma diagnosed in 2007-2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004-2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use. Results: Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk. Conclusion: We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.
    • Optimal timing for COVID-19 vaccination in oncology patients receiving chemotherapy?

      Sudan, A.; Iype, Rohan; Kelly, C.; Iqbal, M. S.; Northern Centre for Cancer Care, The Newcastle Hospital Foundation Trust, High Heaton, Newcastle upon Tyne, UK. (2020)
    • Patient and public involvement refines the design of ProtOeus: a proposed phase II trial of proton beam therapy in oesophageal cancer

      Nicholas, O. J.; Joseph, O.; Keane, A.; Cleary, K.; Campbell, S. H.; Gwynne, S. H.; Crosby, T.; Radhakrishna, Ganesh; Hawkins, M. A.; South West Wales Cancer Centre, Singleton Hospital, Sketty Lane, Swansea, SA2 8QA (2020)
      Background: Neoadjuvant chemoradiotherapy for oesophageal cancer significantly improves overall survival but is associated with severe post-operative complications. Proton beam therapy may reduce these toxicities by sparing normal tissues compared with standard radiotherapy. ProtOeus is a proposed randomised phase II study of neoadjuvant chemoradiotherapy in oesophageal cancer that compares proton beam therapy to standard radiotherapy techniques. As proton beam therapy services are often centralised in academic centres in major cities, proton beam therapy trials raise distinct challenges including patient acceptance of travelling for proton beam therapy, coordination of treatments with local centres and ensuring equity of access for patients. Methods: Focus groups were held early in the trial development process to establish patients' views on the trial proposal. Topics discussed include perception of proton beam therapy, patient acceptability of the trial pathway and design, patient-facing materials, and common clinical scenarios. Focus groups were led by the investigators and facilitated by patient involvement teams from the institutions who are involved in this research. Responses for each topic were analysed, and fed back to the trial's development group. Results: Three focus groups were held in separate locations in the UK (Manchester, Cardiff, Wigan). Proton beam therapy was perceived as superior to standard radiotherapy making the trial attractive. Patients felt strongly that travel costs should be reimbursed to ensure equity of access to proton beam therapy. They were very supportive of a shorter treatment schedule and felt that toxicity reduction was the most important endpoint. Discussion and conclusions: Incorporating patient views early in the trial development process resulted in significant trial design refinements including travel/accommodation provisions, choice of primary endpoint, randomisation ratio and fractionation schedule. Focus groups are a reproducible and efficient method of incorporating the patient and public voice into research.
    • Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial

      Morgan, Robert David; McNeish, I. A.; Cook, A. D.; James, E. C.; Lord, R.; Dark, G.; Glasspool, R. M.; Krell, J.; Parkinson, C.; Poole, C. J.; et al. (2020)
      Background: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. Methods: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with, NCT01654146. Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. Interpretation: The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response.
    • A phase II study of biodegradable stents plus palliative radiotherapy in oesophageal cancer

      Maishman, T.; Sheikh, Hamid; Boger, P.; Kelly, J.; Cozens, K.; Bateman, A.; Davies, S.; Fay, M.; Sharland, D.; Jackson, A.; et al. (2021)
      Aims: Self-expanding metal stents provide rapid improvement of dysphagia in oesophageal cancer but are associated with complications. The aim of the present study was to test the effectiveness of an alternative treatment of combining biodegradable stents with radiotherapy. Materials and methods: A Simon two-stage single-arm prospective phase II trial design was used to determine the efficacy of biodegradable stents plus radiotherapy in patients with dysphagia caused by oesophagus cancer who were unsuitable for radical treatment. Fourteen patients were recruited and data from 12 were included in the final analyses. Results: Five of 12 patients met the primary end point: one stent-related patient death; four further interventions for dysphagia within 16 weeks of stenting (41.7%, 95% confidence interval 15.2-72.3%). The median time to a 10-point deterioration of quality of life was 2.7 weeks. Nine patients died within 52 weeks of registration. The median time to death from any cause was 15.0 weeks (95% confidence interval 9.6-not reached). Conclusion: The high re-intervention observed, which met the pre-defined early stopping criteria, meant that the suggested alternative treatment was not sufficiently effective to be considered for a larger scale trial design. Further work is needed to define the place of biodegradable stents in the management of malignant oesophageal strictures.
    • Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma

      Morschhauser, F.; Dyer, M. J. S.; Walter, H. S.; Danilov, A. V.; Ysebaert, L.; Hodson, D. J.; Fegan, C.; Rule, S. A.; Radford, John A; Cartron, G.; et al. (2020)
    • Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer

      Karunamuni, R. A.; Huynh-Le, M. P.; Fan, C. C.; Thompson, W.; Eeles, R. A.; Kote-Jarai, Z.; Muir, K.; Lophatananon, A.; Schleutker, J.; Pashayan, N.; et al. (2021)
      Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). Materials and method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
    • The impact of changes in service delivery in patients with colorectal cancer during the initial phase of the COVID-19 pandemic

      Kamposioras, Konstantinos; Saunders, Mark P; Lim, Kok Haw Jonathan; Marti, Kalena; Anderson, Daniel; Cutting, Mark; McCool, Danielle; Connell, Jacqueline; Simpson, Lilly; Hasan, Jurjees; et al. (2020)
      Background: The Coronavirus disease 2019 (COVID-19) pandemic has imposed significant changes in cancer service delivery resulting in increased anxiety and distress in both patients and clinicians. We aimed to investigate how these changes have been perceived by patients diagnosed with colorectal cancer and identify determinants of increased anxiety. Patients and methods: An anonymized 32-item survey in the specialized lower gastrointestinal cancer outpatient clinics at a tertiary cancer center in North West England between May 18 and July 1, 2020. Self-reported anxiety was based on the General Anxiety Disorder-7 screening tool. Results: Of 143 participants who completed the survey (response rate, 67%), 115 (82%) were male, and the median age group was 61 to 70 years. A total of 112 (78%) participants had telephone consultation (83% met needs), and 57 (40%) had radiologic scan results discussed over the phone (96% met needs). In total, 23 (18%) participants were considered to have anxiety (General Anxiety Disorder-7 score ≥ 5), with 7 (5.5%) scoring for moderate or severe anxiety. Those concerned about getting COVID-19 infection, and worried COVID-19 would have effect on their mental health, and affect their experience of cancer care, were most likely to have anxiety (P < .05, multivariate analysis). The majority did not feel they needed support during this phase of the pandemic. Participants felt that friends and family had been very supportive, but less so the primary care services (P < .05). Conclusions: The findings of this survey suggest that some of the service changes implemented may have already improved the overall experience of cancer care among patients with colorectal cancer at our institute. Reassuringly, the incidence of participants with moderate to severe anxiety levels during the peak of COVID-19 in the United Kingdom was much lower than anticipated. Importantly, patients were much more concerned about their cancer treatment than COVID-19, emphasizing the need to continue to provide comprehensive cancer care even with a "second wave" of COVID-19.
    • ESMO20 YO for YO: highlights on oncogene-addicted NSCLC

      Lim, Kok Haw Jonathan; Gomes, Fabio; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Department of Immunology and Inflammation, Imperial College London, London, UK. (2020)
    • Disease course of Neurofibromatosis Type 2; a 30-year follow-up study of 353 patients seen at a single institution

      Forde, C.; King, A. T.; Rutherford, S. A.; Hammerbeck-Ward, C.; Lloyd, S. K.; Freeman, S. R.; Pathmanaban, O. N.; Stapleton, E.; Thomas, O. M.; Laitt, R. D.; et al. (2020)
      Background: Limited data exists on the disease course of Neurofibromatosis Type 2 (NF2) to guide clinical trial design. Methods: A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990-2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred and inheritance type. Interventions for NF2-related tumours were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. Results: Three-hundred-and-fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65 respectively per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P=0.03 and P=0.02 respectively) but those presenting between 16-39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P=0.004). Conclusion: Understanding disease course improves prognostication, allowing for better informed decisions about care.
    • Evaluation of the safety and effectiveness of prostate-specific antigen (PSA) monitoring in primary care after discharge from hospital-based follow-up following prostate cancer treatment

      Johnson, Helen; Taylor, Sally; Peat, Sara; Booker, Jane; Yorke, Janelle; The Christie NHS Foundation Trust, Manchester, (2020)
      Objective: To examine follow-up procedures after men are discharged into primary care following prostate cancer and highlight any areas for service improvement. Methods: Patient record data from two Greater Manchester boroughs were retrieved retrospectively to investigate discharge instructions and monitoring adherence. Questionnaires were sent to patients exploring their understanding of the follow-up process. Results: A total of 300 records were accessed. Prostate-specific antigen (PSA) re-referral level was provided to GPs in 39% of cases. Forty- six percent of men were not tested frequently enough, and 6% had no PSA testing recorded post-discharge. A total of 222 patient questionnaires were returned. Sixty-seven percent felt GPs should be responsible for PSA monitoring, and 60% felt confident that their GP was doing so effectively. Conversely, 12% felt their PSA monitoring had been neglected. Conclusion: The findings highlight the complex nature of the follow-up and monitoring processes for prostate cancer patients. There is an urgent need for consensus in terms of monitoring frequency and referral pathways. Many patients do not engage in accurate monitoring post-treatment which has implications for early diagnosis of recurrence. Findings will be used to create an evidence-based, uniform Greater Manchester PSA monitoring service which is safe, acceptable and effective for all
    • Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance

      Hafeez, S.; Webster, A.; Hansen, V. N.; McNair, H. A.; Warren-Oseni, K.; Patel, E.; Choudhury, Ananya; Creswell, J.; Foroudi, F.; Henry, A.; et al. (2020)
      Introduction: Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused 'plan of the day' radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. Methods and analysis: Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes.
    • Intensity-modulated radiotherapy for rectal cancer in the UK in 2020

      Hanna, C. R.; Slevin, F.; Appelt, A.; Beavon, M.; Adams, R.; Arthur, Claire; Beasley, M.; Duffton, A.; Gilbert, A.; Gollins, S.; et al. (2021)
      Aims: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance. Materials and methods: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out. Results: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres. Conclusion: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance.
    • Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (ProCAID)

      Crabb, S. J.; Griffiths, G.; Marwood, E.; Dunkley, D.; Downs, N.; Martin, K.; Light, M.; Northey, J.; Wilding, S.; Whitehead, A.; et al. (2020)
      Purpose: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. Patients and methods: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. Results: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. Conclusion: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.
    • Permanent hair loss associated with taxane chemotherapy use in breast cancer: A retrospective survey at two tertiary UK cancer centres

      Chan, J.; Adderley, Helen; Alameddine, M.; Armstrong, Anne C; Arundell, D.; Fox, Rosalyn; Harries, M.; Lim, Kok Haw Jonathan; Salih, Zena; Tetlow, Christine; et al. (2020)
      Purpose: Taxane chemotherapy is commonly used in the management of breast cancer. Hair loss (alopecia) is an expected side effect which may have a significant effect on quality of life. Alopecia is normally temporary but permanent chemotherapy-induced alopecia (pCIA) is increasingly recognised especially following docetaxel chemotherapy. However, the prevalence following docetaxel is not well understood and there is no published literature for paclitaxel chemotherapy. The aim of this study is to investigate the prevalence and patterns of pCIA resulting from both docetaxel and paclitaxel chemotherapy at two tertiary UK cancer centres. Methods: In collaboration between Clatterbridge Cancer Centre and The Christie NHS Foundation Trusts, a retrospective survey was conducted for breast cancer patients who had received taxane chemotherapy in the neoadjuvant and adjuvant settings. Patients who had concluded chemotherapy at least a year previously were contacted by post and invited to participate by completing a questionnaire and returning it to their treatment centre. Data collected included the incidence and pattern of pCIA using the Savin pictorial hair loss scale, and the methods used by patients to manage it. Fisher's exact test was used to compare pCIA between the docetaxel and paclitaxel cohorts. Results: 383 patients responded to the survey (a 63.3% overall response rate). These comprised 245 patients receiving docetaxel and 138 patients treated with paclitaxel. pCIA was reported by 23.3% of patients receiving docetaxel and 10.1% paclitaxel (p < 0.01). Overall 16.7% of patients in both groups reported the ongoing use of products or appliances such as wigs to camouflage their pCIA. In the docetaxel group, pCIA appeared to be more frequent in post-menopausal women than peri- or pre-menopausal women (37.8%, 12.3% and 19.6% respectively [Chi-square test p < 0.01]). Also in the docetaxel group, there appeared to be a trend for more severe scalp alopecia when the patient also received an aromatase inhibitor (AI) or tamoxifen and this difference was most marked in those who had received both an AI and tamoxifen as components of their treatment regime (p = 0.04). The use of scalp cooling was only recorded in the Christie paclitaxel group (n = 12). Of these 12 patients, 83.3% reported no hair loss. While overall rates of permanent eyebrow, eyelash and nostril hair loss were low, this pattern of hair loss appeared more frequent in the paclitaxel than the docetaxel group 4.3% vs. 1.8% (p = 0.29). Conclusions: Both docetaxel and paclitaxel may cause permanent scalp hair loss, but it is significantly more prevalent with docetaxel compared with paclitaxel.
    • Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study

      Chalkidou, A.; Macmillan, T.; Grzeda, M. T.; Peacock, J.; Summers, J.; Eddy, S.; Coker, B.; Patrick, H.; Powell, H.; Berry, L.; et al. (2021)
      Background: Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far. Methods: In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24-60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed. Findings: Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62-76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6-23). Overall survival was 92·3% (95% CI 90·5-93·9) at 1 year and 79·2% (76·0-82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported. Interpretation: In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. 'The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease.
    • An unusual case of oedematous prostate volumetric changes observed over the course of radiotherapy on the MR linear accelerator

      Clough, Abigael; Bridge, P.; Hales, Rosie; McDaid, Lisa; Choudhury, Ananya; Eccles, Cynthia L; The Christie NHSFT, Manchester, United Kingdom. (2020)
      Introduction: The integration of magnetic resonance (MR) imaging into radiotherapy through new technology, including the MR -linear accelerator (MRL), has allowed further advancements into image guided radiotherapy (IGRT). Better soft tissue visualisation has led to some unusual findings. Case and outcomes: A patient with T1c N0 M0 prostate adenocarcinoma received 60Gy in 20# radiotherapy on the MRL. Radiotherapy planning (RTP) scans were completed on both CT and MR (using T2 and T1 weighted three-dimensional turbo spin echo sequences, reconstructed transaxially (TRA). The MR scans revealed atypical oedema in the right peripheral zone, visualised on T2-weighted (T2w) MR Images as an accumulation of high signal intensity fluid. Daily MRL treatment includes a (T2w 3D Tra) sequence with which oedematous changes could be monitored. The images demonstrated an increase in oedematous volume over fractions 1-10 causing the prostate contour variations from the initial planning scans. Despite the prostate volume variations PTV coverage was never breached and dose constraints were always met for both PTV and surrounding organs at risk (OAR's), excluding the need for oncologist input. A single Therapeutic Radiographer (RTT) experienced in MRL delivery, contoured the prostate and oedematous volumes on the radiotherapy plan (RTP) MR and all on-treatment MR images to assess change over the radiotherapy course. The initial volumes were 53.4 cm3 and 8.3 cm3 for the prostate plus oedema and oedema alone respectively. The most significant change was seen for both the prostate and oedema on fraction nine (68.0 cm3 and 10.1 cm3, respectively). Reductions were noted after this with final (fraction 20) volumes of 55.2 cm3 and 0.58 cm3 respectively. Discussion: The ability to visualise prostatic oedema was new to the radiotherapy treatment team due to better soft tissue visualisation than standard radiotherapy. The results from contouring the prostate and oedema volumes confirmed radiographer observations and demonstrated how oedema impacted the overall prostate volume by quantifying the oedematous variations over time. The changes in oedema volume are presumed to be in response to radiotherapy. Conclusion: Further adaptive radiotherapy work-flow developments, utilising an "Adapt to Shape" model will allow real-time re-contouring of the prostate to ensure tumour control is not compromised. Further work investigating the frequency and impact of oedemotous changes to external beam prostate patients will help to inform practice.