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  • Prognostic significance of positive circumferential resection margin post neoadjuvant chemotherapy in patients with esophageal or gastro-esophageal junction adenocarcinoma

    Patrao, Ana; Papaxoinis, Georgios; Kordatou, Zoe; Weaver, Jamie M; Owen-Holt, Vikki; Alkhaffaf, B; Galloway, S; Mansoor, Was; University of Manchester Division of Cancer Sciences, The Christie NHS Foundation Trust, Manchester, UK (2019)
    BACKGROUND: The aim of the present study was to assess the prognosis of patients with esophageal or gastroesophageal junction (E/GEJ) adenocarcinoma extending beyond the muscularis propria layer (?ypT3) and positive circumferential resection margin (CRM), post neoadjuvant chemotherapy. METHODS: 177 patients were retrospectively studied. The majority (94.9%) received ECX (epirubicin, cisplatin, capecitabine), and all had clear proximal/distal resection margins. CRM was defined as positive (CRM+) when it was directly infiltrated (infiltrated CRM) or when tumor cells were detected within 1 mm from CRM (close CRM) and as negative (CRM-) when tumor cells were found in a distance > 1 mm from CRM. RESULTS: CRM+ was found in 83 patients (46.9%). Of them, infiltrated CRM was recorded in 36 (20.3%) and close CRM in 47 (26.6%). Adjuvant chemotherapy was administered to 132 patients (74.6%). Lymphovascular invasion and primary site in the lower esophagus were independently associated with higher risk of CRM+. Patients with infiltrated CRM, compared to those with close CRM and those CRM-, had the shortest median time-to-relapse (11.4 vs. 15.6 vs. 22.1 months, respectively, p?=?0.005) and overall survival (18.7 vs. 23.1 vs. 38.8 months, respectively, p = 0.001). However, CRM status was not an independent predictor of poor outcome. Symptomatic isolated locoregional recurrences were rare in both CRM+ and CRM-patients (4/56 [7.1%] vs. 5/52 [9.6%], p?=?0.736), as well as in infiltrated vs. non-infiltrated CRM (CRM- and close CRM) (0/26 [0%] vs. 9/82 [11.0%], p?=?0.110). CONCLUSION: Although CRM status is associated with poor outcome, it does not represent an independent prognostic factor. The status of CRM did not significantly influence the pattern of cancer relapse
  • Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma

    Rini, I; Plimack, R; Stus, V; Gafanov, R; Hawkins, Robert E; Nosov, D; Pouliot, F; Alekseev, B; Soulieres, D; Melichar, B; Vynnychenko, I; Kryzhanivska, A; Bondarenko, I; Azevedo, SJ; Borchiellini, D; Szczylik, C; Markus, M; McDermott, S; Bedke, J; Tartas, S; Chang, H; Tamada, S; Shou, Q; Perini, F; Chen, M; Atkins, B; Powles, T; Cleveland Clinic Taussig Cancer Institute, Cleveland (2019)
    BACKGROUND: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. METHODS: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. RESULTS: After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group. CONCLUSIONS: Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 number, NCT02853331.).
  • A systematic review of the role of penile rehabilitation in prostate cancer patients receiving radiotherapy and androgen deprivation therapy

    Doherty, Wesley; Bridge, P; Radiotherapy Department, Christie Hospital NHS Trust, Manchester, UK (2019)
    INTRODUCTION/BACKGROUND: Treatment-induced erectile dysfunction (ED) is a common side effect of radiotherapy and androgen deprivation therapy (ADT) that impacts on patient quality of life. Penile rehabilitation interventions including pharmacologic and physical therapies aim to reduce the impact of ED. Despite The National Institute for Health and Care Excellence guidelines recommending access to ED services, penile rehabilitation is not widely discussed or implemented. This systematic review aimed to appraise the evidence base for penile rehabilitation and identify evidence-based recommendations for practice. METHODS: A systematic review of the evidence base was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Scopus and Medline (EBSCO) databases were searched for articles relevant to penile rehabilitation interventions for prostate radiotherapy patients. Study quality was graded using the Oxford Levels of Evidence and the Scottish Intercollegiate Guidelines Network. RESULTS: This study identified 19 articles on penile rehabilitation in prostate radiotherapy patients, consisting of eight randomized controlled trials, three systematic reviews, and eight case studies. Findings confirmed the value of early use of phosphodiesterase type 5 inhibitors. DISCUSSION: Despite the range of available physical and pharmaceutical interventions, relevant research focussed solely on the use of phosphodiesterase type 5 inhibitors. Themes from the reviewed articles indicated that timing of intervention was important with early on-going dosage most useful. There was also an identified need for ongoing prophylactic use during ADT. Evidence, in general, was of low quality and based on quantitative data only. CONCLUSION: Additional research into the wider range of penile rehabilitation interventions is urgently required to ensure patients have access to those therapies that are most appropriate for them. A paradigm shift toward qualitative research in the field of penile rehabilitation for prostate cancer patients treated with radiotherapy and ADT may be of value in future studies.
  • Genome-wide association study of germline variants and breast cancer-specific mortality

    Escala-Garcia, M; Guo, Q; Dork, T; Canisius, S; Keeman, R; Dennis, J; Beesley, J; Lecarpentier, J; Bolla, K; Wang, Q; Abraham, J; Andrulis, L; Anton-Culver, H; Arndt, V; Auer, L; Beckmann, W; Behrens, S; Benitez, J; Bermisheva, M; Bernstein, L; Blomqvist, C; Boeckx, B; Bojesen, E; Bonanni, B; Borresen-Dale, L; Brauch, H; Brenner, H; Brentnall, A; Brinton, L; Broberg, P; Brock, W; Brucker, Y; Burwinkel, B; Caldas, C; Caldes, T; Campa, D; Canzian, F; Carracedo, A; Carter, D; Castelao, E; Chang-Claude, J; Chanock, J; Chenevix-Trench, G; Cheng, D; Chin, F; Clarke, L; Cordina-Duverger, E; Couch, J; Cox, G; Cox, A; Cross, S; Czene, K; Daly, B; Devilee, P; Dunn, A; Dunning, M; Durcan, L; Dwek, M; Earl, M; Ekici, B; Eliassen, H; Ellberg, C; Engel, C; Eriksson, M; Evans, G; Figueroa, J; Flesch-Janys, D; Flyger, H; Gabrielson, M; Gago-Dominguez, M; Galle, E; Gapstur, M; Garcia-Closas, M; Garcia-Saenz, A; Gaudet, M; George, A; Georgoulias, V; Giles, G; Glendon, G; Goldgar, E; Gonzalez-Neira, A; Alnaes, G; Grip, M; Guenel, P; Haeberle, L; Hahnen, E; Haiman, A; Hakansson, N; Hall, P; Hamann, U; Hankinson, S; Harkness, F; Harrington, A; Hart, N; Hartikainen, JM; Hein, A; Hillemanns, P; Hiller, L; Holleczek, B; Hollestelle, A; Hooning, J; Hoover, N; Hopper, L; Howell, Anthony; Huang, G; Humphreys, K; Hunter, J; Janni, W; John, M; Jones, E; Jukkola-Vuorinen, A; Jung, A; Kaaks, R; Kabisch, M; Kaczmarek, K; Kerin, J; Khan, S; Khusnutdinova, E; Kiiski, I; Kitahara, M; Knight, A; Ko, D; Koppert, B; Kosma, M; Kraft, P; Kristensen, N; Kruger, U; Kuhl, T; Lambrechts, D; Le, L; Lee, E; Lejbkowicz, F; Li, L; Lindblom, A; Lindstrom, S; Linet, M; Lissowska, J; Lo, Y; Loibl, S; Lubinski, J; Lux, P; MacInnis, J; Maierthaler, M; Maishman, T; Makalic, E; Mannermaa, A; Manoochehri, M; Manoukian, S; Margolin, S; Martinez, E; Mavroudis, D; McLean, C; Meindl, A; Middha, P; Miller, N; Milne, L; Moreno, F; Mulligan, M; Mulot, C; Nassir, R; Neuhausen, L; Newman, T; Nielsen, F; Nordestgaard, G; Norman, A; Olsson, H; Orr, N; Pankratz, S; Park-Simon, W; Perez, A; Perez-Barrios, C; Peterlongo, P; Petridis, C; Pinchev, M; Prajzendanc, K; Prentice, R; Presneau, N; Prokofieva, D; Pylkas, K; Rack, B; Radice, P; Ramachandran, D; Rennert, G; Rennert, S; Rhenius, V; Romero, A; Roylance, R; Saloustros, E; Sawyer, J; Schmidt, DF; Schmutzler, K; Schneeweiss, A; Schoemaker, J; Schumacher, F; Schwentner, L; Scott, J; Scott, C; Seynaeve, C; Shah, M; Simard, J; Smeets, A; Sohn, C; Southey, C; Swerdlow, J; Talhouk, A; Tamimi, M; Tapper, J; Teixeira, R; Tengstrom, M; Terry, B; Thone, K; Tollenaar, M; Tomlinson, I; Torres, D; Truong, T; Turman, C; Turnbull, C; Ulmer, U; Untch, M; Vachon, C; van Asperen, J; van den Ouweland, W; van Veen, M; Wendt, C; Whittemore, S; Willett, W; Winqvist, R; Wolk, A; Yang, R; Zhang, Y; Easton, F; Fasching, A; Nevanlinna, H; Eccles, M; Pharoah, P; Schmidt, K; Radiotherapy Department, Christie Hospital NHS Trust, Manchester, UK (2019)
    BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P?<?5?×?10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP?=?7%, P?=?1.28?×?10-7, hazard ratio [HR]?=?0.88, 95% confidence interval [CI]?=?0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP?=?11%, P?=?1.38?×?10-7, HR?=?1.27, 95% CI?=?1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP?<?15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
  • Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE)

    Bachelot, T; Ciruelos, E; Schneeweiss, A; Puglisi, F; Peretz-Yablonski, T; Bondarenko, I; Paluch-Shimon, S; Wardley, Andrew M; Merot, L; du, Y; Easton, V; Lindegger, N; Miles, D; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (2019)
    BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab (8?mg/kg loading dose, then 6?mg/kg every 3 weeks [q3w]) and pertuzumab (840?mg loading dose, then 420?mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; seven discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab, and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% vs 16%) but less febrile neutropenia (1% vs 11%) and mucositis (14% vs 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 (95% CI 18.9-22.7) months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.
  • COSMOS-E: guidance on conducting systematic reviews and meta-analyses of observational studies of etiology

    Dekkers, M; Vandenbroucke, P; Cevallos, M; Renehan, Andrew G; Altman, G; Egger, M; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Division of Molecular Pathology, Amsterdam, The Netherlands (2019)
    BACKGROUND: To our knowledge, no publication providing overarching guidance on the conduct of systematic reviews of observational studies of etiology exists. METHODS AND FINDINGS: Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) provides guidance on all steps in systematic reviews of observational studies of etiology, from shaping the research question, defining exposure and outcomes, to assessing the risk of bias and statistical analysis. The writing group included researchers experienced in meta-analyses and observational studies of etiology. Standard peer-review was performed. While the structure of systematic reviews of observational studies on etiology may be similar to that for systematic reviews of randomised controlled trials, there are specific tasks within each component that differ. Examples include assessment for confounding, selection bias, and information bias. In systematic reviews of observational studies of etiology, combining studies in meta-analysis may lead to more precise estimates, but such greater precision does not automatically remedy potential bias. Thorough exploration of sources of heterogeneity is key when assessing the validity of estimates and causality. CONCLUSION: As many reviews of observational studies on etiology are being performed, this document may provide researchers with guidance on how to conduct and analyse such reviews.
  • Identification of patients with pancreatic adenocarcinoma due to inheritable mutation: challenges of daily clinical practice

    Fulton, J; Lamarca, Angela; Nuttall, Christina; McCallum, Lynne; Pihlak, Rille; O'Reilly, D; Lalloo, F; McNamara, Mairead G; Hubner, Richard A; Clancy, T; Valle, Juan W; Cleveland Clinic Taussig Cancer Institute, Cleveland (2019)
    BACKGROUND: Identification of germ-line mutations in pancreatic ductal adenocarcinoma (PDAC) could impact on patient/family. AIM: To assess the referral pathways for genetic consultations in PDAC. METHODS: Electronic records of PDAC patients were reviewed retrospectively. Patients eligible for genetic consultation referral were identified following the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) criteria. RESULTS: Four-hundred patients were eligible. Of 113 patients (28.3%) meeting EUROPAC criteria, 8.8% were referred for genetic opinion. Germ-line mutations were identified in 0.75% of the whole population. CONCLUSION: Earlier referrals and increased awareness may be able to overcome the low rate of successful genetic appointments. KEYWORDS: BRCA; Genetic consultation; Genetic counselling; Germline; Pancreatic adenocarcinoma
  • Radiotherapy toxicity

    De Ruysscher, D; Niedermann, G; Burnet, Neil G; Siva, S; Lee, M; Hegi-Johnson, F; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M204BX, United Kingdom (2019)
    Radiotherapy is used in >50% of patients with cancer, both for curative and palliative purposes. Radiotherapy uses ionizing radiation to target and kill tumour tissue, but normal tissue can also be damaged, leading to toxicity. Modern and precise radiotherapy techniques, such as intensity-modulated radiotherapy, may prevent toxicity, but some patients still experience adverse effects. The physiopathology of toxicity is dependent on many parameters, such as the location of irradiation or the functional status of organs at risk. Knowledge of the mechanisms leads to a more rational approach for controlling radiotherapy toxicity, which may result in improved symptom control and quality of life for patients. This improved quality of life is particularly important in paediatric patients, who may live for many years with the long-term effects of radiotherapy. Notably, signs and symptoms occurring after radiotherapy may not be due to the treatment but to an exacerbation of existing conditions or to the development of new diseases. Although differential diagnosis may be difficult, it has important consequences for patients.
  • Biosimilars: what the oncologist should know

    Thill, M; Thatcher, Nick; Hanes, V; Lyman, H; Department of Medical Oncology, Gustave Roussy, Villejuif, France (2019)
    As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex therapies with a goal of providing more affordable treatment options. Many of these molecules, known as biosimilars, are now approved worldwide and several more are expected to be introduced in the near future. As more biosimilars become available, it is important for clinicians to become familiar with this new category of products and understand how biosimilars are developed, how their development differs from that of originator biologics and how they differ from generics. This review aims to provide the practicing clinician with the knowledge needed to understand biosimilars, along with some guidance on their use in treating oncologic diseases.
  • Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up

    Escudier, B; Porta, C; Schmidinger, M; Rioux-Leclercq, N; Bex, A; Khoo, V; Grunwald, V; Gillessen, Silke; Horwich, A; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK (2019)
  • Attitudes and knowledge of clinicians and dieticians towards cancer nutrition in a tertiary referral oncology centre

    Khan, M; Vickers, Alexander J; Kordatou, Zoe; Abraham, M; Mansoor, Was; Meta-analysis Group, MRC Clinical Trials Unit at UCL, London, UK (2018)
  • Integrating personalised medicine into the routine cancer diagnostic pathway in Manchester, UK

    Henry, J; Radford, John A; Department of Internal Medicine and Intensive Care Unit, Catharina Hospital Eindhoven, Eindhoven, The Netherlands (2018)
  • Real-time adaptive planning method for radiotherapy treatment delivery for prostate cancer patients, based on a library of plans accounting for possible anatomy configuration changes

    Antico, M; Prinsen, P; Cellini, F; Fracassi, A; Isola, A; Cobben, David; Fontanarosa, D; Department of Radiation Oncology, University Hospital of Zurich, University of Zurich, Switzerland (2019)
    BACKGROUND AND PURPOSE: In prostate cancer treatment with external beam radiation therapy (EBRT), prostate motion and internal changes in tissue distribution can lead to a decrease in plan quality. In most currently used planning methods, the uncertainties due to prostate motion are compensated by irradiating a larger treatment volume. However, this could cause underdosage of the treatment volume and overdosage of the organs at risk (OARs). To reduce this problem, in this proof of principle study we developed and evaluated a novel adaptive planning method. The strategy proposed corrects the dose delivered by each beam according to the actual position of the target in order to produce a final dose distribution dosimetrically as similar as possible to the prescribed one. MATERIAL AND METHODS: Our adaptive planning method was tested on a phantom case and on a clinical case. For the first, a pilot study was performed on an in-silico pelvic phantom. A "library" of intensity modulated RT (IMRT) plans corresponding to possible positions of the prostate during a treatment fraction was generated at planning stage. Then a 3D random walk model was used to simulate possible displacements of the prostate during the treatment fraction. At treatment stage, at the end of each beam, based on the current position of the target, the beam from the library of plans, which could reproduce the best approximation of the prescribed dose distribution, was selected and delivered. In the clinical case, the same approach was used on two prostate cancer patients: for the first a tissue deformation was simulated in-silico and for the second a cone beam CT (CBCT) taken during the treatment was used to simulate an intra-fraction change. Then, dosimetric comparisons with the standard treatment plan and, for the second patient, also with an isocenter shift correction, were performed. RESULTS: For the phantom case, the plan generated using the adaptive planning method was able to meet all the dosimetric requirements and to correct for a misdosage of 13% of the dose prescription on the prostate. For the first clinical case, the standard planning method caused underdosage of the seminal vesicles, respectively by 5% and 4% of the prescribed dose, when the position changes for the target were correctly taken into account. The proposed adaptive planning method corrected any possible missed target coverage, reducing at the same time the dose on the OARs. For the second clinical case, both with the standard planning strategy and with the isocenter shift correction target coverage was significantly worsened (in particular uniformity) and some organs exceeded some toxicity objectives. While with our approach, the most uniform coverage for the target was produced and systematically the lowest toxicity values for the organs at risk were achieved. CONCLUSIONS: In our proof of principle study, the adaptive planning method performed better than the standard planning and the isocenter shift methods for prostate EBRT. It improved the coverage of the treatment volumes and lowered the dose to the OARs. This planning method is particularly promising for hypofractionated IMRT treatments in which a higher precision and control on dose deposition are needed. Further studies will be performed to test more extensively the proposed adaptive planning method and to evaluate it at a full clinical level.
  • Prostate radiotherapy for metastatic hormone-sensitive prostate cancer: a STOPCAP systematic review and meta-analysis

    Burdett, S; Boeve, M; Ingleby, C; Fisher, J; Rydzewska, H; Vale, L; van, G; Clarke, Noel W; Hulshof, C; James, D; Parker, C; Parmar, K; Sweeney, J; Sydes, R; Tombal, B; Verhagen, C; Tierney, F; School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland, Australia (2019)
    BACKGROUND: Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC). OBJECTIVE: To systematically review trials of prostate radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: Using a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators. INTERVENTION: We included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis. RESULTS AND LIMITATIONS: We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81-1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84-1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67-0.82, p=0.94×10-8) and FFS (HR=0.76, 95% CI 0.69-0.84, p=0.64×10-7), equivalent to ?10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden-a pattern consistent across trials and outcome measures, including survival (<5, ?5; interaction HR=1.47, 95% CI 1.11-1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases. CONCLUSIONS: Prostate radiotherapy should be considered for men with mHSPC with a low metastatic burden. PATIENT SUMMARY: Prostate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.
  • Differences in identification of patients' deterioration may hamper the success of clinical escalation protocols

    de Bie, R; Subbe, P; Bezemer, R; Cooksley, Timothy J; Kellett, G; Holland, M; Bouwman, A; Bindels, H; Korsten, M; Schuster Laboratory, School of Physics and Astronomy, The University of Manchester, Oxford Road, Manchester (2019)
    BACKGROUND: Timely and consistent recognition of a "clinical crisis", a life threatening condition that demands immediate intervention, is essential to reduce "failure to rescue" rates in general wards.AimTo determine how different clinical caregivers define a "clinical crisis" and how they respond to it. DESIGN: An international survey. METHODS: Clinicians working on general wards, intensive care units, or emergency departments in the Netherlands, the United Kingdom, and Denmark were asked to review ten scenarios based on common real-life cases. Then they were asked to grade the urgency and severity of the scenario, their degree of concern, their estimate for the risk for death and indicate their preferred action for escalation. The primary outcome was the scenarios with a National Early Warning Score (NEWS) ?7 considered to be a "clinical crisis". Secondary outcomes included how often a rapid response system (RRS) was activated, and if this was influenced by the participant's professional role or experience. The data from all participants in all three countries was pooled for analysis. RESULTS: A total of 150 clinicians participated in the survey. The highest percentage of clinicians that considered one of the three scenarios with a NEWS ?7 as a "clinical crisis" was 52%, while a RRS was activated by?<?50% of participants. Professional roles and job experience only had a minor influence on the recognition of a "clinical crisis" and how it should be responded to. CONCLUSION: This international survey indicates that clinicians differ on what they consider to be a "clinical crisis" and on how it should be managed. Even in cases with a markedly abnormal physiology (i.e. NEWS ?7) many clinicians do not consider immediate activation of a RRS is required.
  • MRI commissioning of 1.5T MR-linac systems - a multi-institutional study

    Tijssen, N; Philippens, P; Paulson, S; Glitzner, M; Chugh, B; Wetscherek, A; Dubec, Michael; Wang, J; van der Heide, A; The Christie Hospital NHS Foundation Trust, Manchester (2019)
    BACKGROUND: Magnetic Resonance linear accelerator (MR-linac) systems represent a new type of technology that allows for online MR-guidance for high precision radiotherapy (RT). Currently, the first MR-linac installations are being introduced clinically. Since the imaging performance of these integrated MR-linac systems is critical for their application, a thorough commissioning of the MRI performance is essential. However, guidelines on the commissioning of MR-guided RT systems are not yet defined and data on the performance of MR-linacs are not yet available. MATERIALS & METHODS: Here we describe a comprehensive commissioning protocol, which contains standard MRI performance measurements as well as dedicated hybrid tests that specifically assess the interactions between the Linac and the MRI system. The commissioning results of four MR-linac systems are presented in a multi-center study. RESULTS: Although the four systems showed similar performance in all the standard MRI performance tests, some differences were observed relating to the hybrid character of the systems. Field homogeneity measurements identified differences in the gantry shim configuration, which was later confirmed by the vendor. CONCLUSION: Our results highlight the importance of dedicated hybrid commissioning tests and the ability to compare the machines between institutes at this very early stage of clinical introduction. Until formal guidelines and tolerances are defined the tests described in this study may be used as a practical guideline. Moreover, the multi-center results provide initial bench mark data for future MR-linac installations.
  • Predictors of weight gain in a cohort of premenopausal early breast cancer patients receiving chemotherapy

    Gandhi, A; Copson, E; Eccles, D; Durcan, L; Howell, A; Morris, J; Howell, Sacha J; McDiarmid, S; Sellers, K; Gareth, D; Harvie, M; Medical Oncology Department, Centre Leon Berard, Lyon, France (2019)
    AIM: In breast cancer patients, post chemotherapy weight gain is linked with increased risk of cancer recurrence. We prospectively studied a cohort of premenopausal women receiving contemporary chemotherapy following a diagnosis of breast cancer to examine factors predicting weight increase. METHODS: Between May 2005 and January 2008, 523 patients from the Prospective Outcomes in Sporadic versus Hereditary (POSH) breast cancer study entered this sub-study comparing weight prior to chemotherapy and weight and waist/hip measurements 12-months following chemotherapy. RESULTS: Data from 380 patients were available. Mean (standard deviation [SD]) pre-treatment body mass index (BMI) was 26.3 (5.6) kg/m2; 30% women gained?>?5% body weight during the study period. Lower BMI at diagnosis predicted greater subsequent post treatment weight gain (4.3% relative weight gain for those in the 1st quartile of BMI compared to 0.8% for those in the 4th quartile; r?=?-0.22; p?<?0.001). No link to chemotherapy regimens, cigarette smoking, previous parity or chemotherapy induced amenorrhoea was noted. A total of 44% of women had central obesity (post-treatment waist measurement of ?88?cm). CONCLUSIONS: Almost a third of premenopausal patients receiving adjuvant chemotherapy for breast cancer will gain clinically significant weight and over 40% will have central obesity 12-months following diagnosis. A greater weight gain is predicted by lower pretreatment BMI.
  • Improving molecular radiotherapy dosimetry using anthropomorphic calibration

    Price, E; Robinson, P; Cullen, M; Tipping, Jill; Calvert, Nicholas; Hamilton, David; Oldfield, C; Page, Emma; Pietras, B; Smith, A; Division of Cancer Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester (2019)
    The optimised delivery of Molecular Radiotherapy requires individualised calculation of absorbed dose to both targeted lesions and neighbouring healthy tissue. To achieve this, accurate quantification of the activity distribution in the patient by external detection is vital. METHODS: This work extends specific anatomy-related calibration to true organ shapes. A set of patient-specific 3D printed organ inserts based on a diagnostic CT scan was produced, comprising the liver, spleen and both kidneys. The inserts were used to calculate patient-specific calibration factors for 177Lu. These calibration factors were compared with previously reported calibration factors for corresponding organ models based on the Cristy and Eckerman phantom series and for a comparably sized sphere. Monte Carlo calculations of the patient-specific radiation dose were performed for comparison with current clinical dosimetry methods for these data. RESULTS: Patient-specific calibration factors are shown to be dependent on the volume, shape and position of the organ containing activity with a corresponding impact on the calculation of the dose to the patient. The impact of organ morphology on calculated dose is reduced when the dominant contributor to dose is beta particles. This is due to the small range of beta particles in tissue. Overestimations of recovered activity and hence dose of up to 135% are observed. CONCLUSION: For accurate quantification to be performed calibration factors accounting for organ size, shape and position must be used. Such quantification is vital if accurate, patient-specific dosimetry is to be achieved.
  • Optimal management of brain metastases in oncogenic-driven non-small cell lung cancer (NSCLC)

    Andratschke, N; Kraft, J; Nieder, C; Tay, Rebecca; Califano, Rafaelle; Soffietti, R; Guckenberger, M; Department of Gynecology and Gynecological Oncology, Agaplesion Markus Hospital, Frankfurt am Main, Germany (2019)
    Brain metastases are common events in the natural course of many advanced solid cancers like breast, lung and renal cancer or melanoma with a cumulative risk of 10-30% in adults [1-3]. Non-small cell lung cancer (NSCLC) is associated with an increased risk for the development of brain metastases and the prognosis until recently has been poor except for some patients' subgroups and depending on the disease-specific GPA prognostic factors [4]. For patients receiving only best supportive care, average survival is about 3 months and it is assumed that through additional whole brain radiotherapy average survival may be improved up to 6-9 months in selected patients [5]. In recent years, complex treatment strategies for different solid tumors have been developed and this has impacted on the general management of brain metastases. Most of the studies on brain metastases have included different histological subtypes and therefore have made tumor- specific recommendations difficult. In this review, we discuss the current evidence on management of brain metastases and incorporate specific recent data on oncogenic-driven NSCLC in order to suggest recommendations on the optimal management of brain metastases in this subgroup of NSCLC where formal level I evidence is lacking.
  • Clinical presentation, diagnosis, and staging of cholangiocarcinoma

    Forner, A; Vidili, G; Rengo, M; Bujanda, L; Ponz-Sarvise, M; Lamarca, Angela; Department of Radiotherapy, University Medical Center Utrecht, the Netherlands (2019)
    Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.

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