• Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program

      Heidenreich, A; Gillessen, Silke; Heinrich, D; Keizman, D; O'Sullivan J; Carles, J; Wirth, M; Miller, K; Reeves, J; Seger, M; Nilsson, S; Saad, F; Department of Urology, University Hospital Cologne, Cologne, Germany (2019)
      Radium-223, a targeted alpha therapy, is used to treat symptomatic patients with castration-resistant prostate cancer (CRPC) and bone metastases. Data for radium-223 in asymptomatic CRPC patients with bone metastases are lacking. METHODS: This was a prospective, single-arm phase 3b study. Patients with metastatic CRPC (malignant lymphadenopathy not exceeding 6?cm was allowed, visceral disease was excluded) received radium-223, 55?kBq/kg intravenously, every 4?weeks for up to 6?cycles. Co-primary endpoints were safety and overall survival. Post hoc analyses were performed according to baseline asymptomatic or symptomatic disease status. Asymptomatic status was defined as no pain and no opioid use at baseline. RESULTS: Seven hundred eight patients received ?1 radium-223 injection: 548 (77%) were symptomatic to various degrees, and 135 (19%) were asymptomatic. Asymptomatic patients had more favorable baseline disease characteristics than symptomatic. A lower proportion of asymptomatic versus symptomatic patients had received prior abiraterone (25% vs 35%) and prior docetaxel (52% vs 62%). A higher proportion of asymptomatic (71%) versus symptomatic (55%) patients completed radium-223 treatment. Overall survival (hazard ratio [HR] 0.486), time to disease progression (HR 0.722) and time to first symptomatic skeletal event (HR 0.328) were better in asymptomatic than symptomatic patients. Alkaline phosphatase (ALP) response rates were similar (46% vs 47%), and ALP normalization (44% vs 25%) and prostate-specific antigen response rates (21% vs 13%) were higher in asymptomatic than symptomatic patients. A lower proportion of asymptomatic patients reported treatment-emergent adverse events (TEAEs, 61% vs 79%), grade 3-4 TEAEs (29% vs 40%) and drug-related TEAEs (28% vs 44%). There were two treatment-related deaths, both in patients with baseline symptomatic disease. CONCLUSIONS: Using radium-223 earlier in the disease course, when patients are asymptomatic or minimally symptomatic, may enable patients to complete treatment and optimize treatment outcome compared to symptomatic patients, and therefore may allow sequencing with other life-prolonging therapies. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov , number NCT01618370 on June 13, 2012 and the European Union Clinical Trials Register, EudraCT number 2012-000075-16 on April 4, 2012.
    • Expression of Notch 3 and Jagged 1 is associated with merkel cell polyomavirus status and prognosis in merkel cell carcinoma

      Wardhani, LO; Matsushita, M; Kuwamoto, S; Nonaka, Daisuke; Nagata, K; Kato, M; Kitamura, Y; Hayashi, K; Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, Japan (2019)
      AIM: Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine skin cancer and most MCCs are related to infection with Merkel cell polyomavirus (MCPyV). Notch signaling modulates cell fate in various tissues including the skin during development and homeostasis, and its aberrant activity relates to onset and progression of various malignancies. Therefore, association of NOTCH1/ NOTCH2/NOTCH3/jagged 1 (JAG1) expression with MCPyV status and prognosis in MCC was investigated. MATERIALS AND METHODS: A total of 19 MCPyV-positive and 19 MCPyV-negative MCC samples from patients were stained immunohistochemically with antibodies against NOTCH1, NOTCH2, NOTCH3, and JAG1 and analyzed. RESULTS: Expression of NOTCH1 and NOTCH2 was not associated with MCPyV status or prognosis. However, higher JAG1 expression was found in MCPyV-negative than in MCPyV-positive MCC (p<0.001), and NOTCH3 expression was higher in MCPyV-positive MCC (p=0.062). Kaplan-Meier and multivariate analyses showed that patients with MCC with higher NOTCH3 expression had better overall survival than otherwise (p=0.001 and p=0.033, respectively). CONCLUSION: Expression of NOTCH3, as a tumor suppressor, is an independent predictor of MCC outcome.
    • The management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice paper

      Cwynarski, K; Marzolini, M; Barrington, S; Follows, G; Illidge, Timothy M; Stern, S; Davies, A; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK (2019)
    • Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial

      Horwitz, S; O'Connor, O; Pro, B; Illidge, Timothy M; Fanale, M; Advani, R; Bartlett, N; Christensen, J; Morschhauser, F; Domingo-Domenech, E; Rossi, G; Kim, W; Feldman, T; Lennard, A; Belada, D; Illes, A; Tobinai, K; Tsukasaki, K; Yeh, S; Shustov, A; Huttmann, A; Savage, K; Yuen, S; Iyer, S; Zinzani, P; Hua, Z; Little, M; Rao, S; Woolery, J; Manley, T; Trumper, L; Memorial Sloan Kettering Cancer Center, New York, NY, USA (2019)
      Erratum in Department of Error. [Lancet. 2019] BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1.8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1.4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48.2 months (95% CI 35.2-not evaluable) in the A+CHP group and 20.8 months (12.7-47.6) in the CHOP group (hazard ratio 0.71 [95% CI 0.54-0.93], p=0.0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.
    • An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system

      Larkin, J; Brown, M; Arance, A; Hauschild, A; Queirolo, P; Vecchio, M; Ascierto, P; Krajsová, I; Schachter, J; Neyns, B; Garbe, C; Sileni, VC; Mandalà, M; Gogas, H; Espinosa, E; Hospers, G; Lorigan, Paul C; Nyakas, M; Guminski, A; Liszkay, G; Rutkowski, P; Miller, W; Donica, M; Makrutzki, M; Blank, C; Royal Marsden NHS FT, London (2019)
      BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ?1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further.
    • The advanced prostate cancer consensus on a regional level - what can we learn?

      Omlin, A; Gillessen, Silke; Department of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, University of Bern, Bern, Switzerland (2019)
    • Dose-dense cisplatin with gemcitabine for relapsed platinum-resistant ovarian cancer.

      Morgan, Robert David; Clamp, Andrew R; Zhou, Cong; Saunders, Geoff; Mescallado, Nerissa; Welch, Richard; Mitchell, Claire L; Hasan, Jurjees; Jayson, Gordon C; The Christie NHS Foundation Trust, Manchester, UK (2019)
      INTRODUCTION: Standard of care treatment for women who develop relapsed ovarian cancer includes sequential platinum- and/or paclitaxel-based chemotherapy, with reducing disease-free intervals. Once platinum resistance develops, treatment options become limited and dose-dense regimens may be offered. We report the efficacy and safety of dose-dense cisplatin with gemcitabine chemotherapy for relapsed platinum-resistant ovarian cancer. METHODS: A retrospective analysis of all patients with relapsed, platinum-resistant ovarian, primary peritoneal or fallopian tube cancer treated with cisplatin 35 mg/m2 of body surface area by intravenous infusion with gemcitabine 1000 mg/m2 of body surface area by intravenous infusion on days 1 and 8 of every 21-day treatment cycle between 1 January 2009 and 1 June 2017. RESULTS: Ninety-four eligible patients had received a median of three (range one-eight) prior lines of cytotoxic therapy for relapsed ovarian cancer. Sixty patients (64%) had received ? 1 prior dose-dense chemotherapy regimen. Dose-dense cisplatin with gemcitabine was associated with a median progression-free survival (PFS) of 4.4 months (95% CI 3.6 to 5.3) and overall survival of 7.6 months (95% CI 5.6 to 9.6). The median PFS for dose-dense cisplatin with gemcitabine as first- (n = 34), second- (n = 42), and third-line or later (n = 18) dose-dense therapy was 4.2 (95% CI 3.2 to 5.2), 5.0 (95% CI 3.5 to 6.5), and 4.2 (95% CI 3.3 to 5.1) months respectively. The RECIST objective response rate for first-, second-, and third-line dose-dense cisplatin with gemcitabine was 23%, 14 %, and 7 % respectively. The most common grade 3 - 4 adverse events were thrombocytopenia (20%), anemia (18%), and neutropenia (14%). DISCUSSION: Dose-dense cisplatin with gemcitabine provides modest efficacy whether it is used as a first- or subsequent line of dose-dense chemotherapy to treat relapsed platinum-resistant ovarian cancer and the toxicity is manageable with supportive measures.
    • Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

      Matejcic, M; Saunders, E; Dadaev, T; Brook, M; Wang, K; Sheng, X; Olama, A; Schumacher, F; Ingles, S; Govindasami, K; Benlloch, S; Berndt, S; Albanes, D; Koutros, S; Muir, K; Stevens, V; Gapstur, S; Tangen, C; Batra, J; Clements, J; Gronberg, H; Pashayan, N; Schleutker, J; Wolk, A; West, Catharine ML; Mucci, L; Kraft, P; Cancel-Tassin, G; Sorensen, K; Maehle, L; Grindedal, E; Strom, S; Neal, D; Hamdy, F; Donovan, J; Travis, R; Hamilton, R; Rosenstein, B; Lu, Y; Giles, G; Kibel, A; Vega, A; Bensen, J; Kogevinas, M; Penney, K; Park, J; Stanford, J; Cybulski, C; Nordestgaard, B; Brenner, H; Maier, C; Kim, J; Teixeira, M; Neuhausen, S; De, R; Razack, A; Newcomb, L; Lessel, D; Kaneva, R; Usmani, N; Claessens, F; Townsend, Paul A; Gago-Dominguez, M; Roobol, M; Menegaux, F; Khaw, K; Cannon-Albright, L; Pandha, H; Thibodeau, S; Schaid, D; Wiklund, F; Chanock, S; Easton, D; Eeles, R; Kote-Jarai, Z; Conti, D; Haiman, C; Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA (2019)
      The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Erratum for Germline variation at 8q24 and prostate cancer risk in men of European ancestry. [Nat Commun. 2018]
    • Prophylactic cranial irradiation for limited-stage small-cell lung cancer patients: secondary findings from the prospective randomized phase 3 CONVERT trial.

      Levy, A; Le Pechoux, C; Mistry, Hitesh; Martel-Lafay, I; Bezjak, A; Lerouge, D; Padovani, L; Taylor, Paul; Faivre-Finn, Corinne; Department of Radiation Oncology, Institut d'Oncologie Thoracique (IOT), Gustave Roussy, Villejuif (2019)
      INTRODUCTION: The impact of the dose and fractionation of thoracic radiotherapy on the risk of developing brain metastasis (BM) has not been evaluated prospectively in limited stage SCLC patients receiving prophylactic cerebral irradiation (PCI). METHODS: Data from patients treated with PCI from the CONVERT trial were analyzed. RESULTS: Four hundred forty-nine of 547 patients (82%) received PCI after completion of chemoradiotherapy. Baseline brain imaging consisted of computed tomographic scans in 356 of 449 patients (79%) and magnetic resonance imaging in 83 of 449 (18%) patients. PCI was delivered to 220 of 273 participants (81%) in the twice-daily (BD) group and 229 of 270 in the once-daily (OD) group (85%; p = 0.49). Total median PCI dose was 25 Gy in both the BD and OD groups (p = 0.74). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, gross tumor volume (GTV) was associated with an increased risk of BM (p = 0.007) or other radiological progression events (p = 0.006), whereas in a multivariate analysis both thoracic GTV (tGTV) and ECOG performance score were associated with either progression type. The median overall survival (OS) of patients treated with PCI was 29 months. In the univariate analysis of OS, PCI timing from end of chemotherapy, weight loss of more than 10%, and tGTV were prognostic factors associated with OS. In the multivariate analysis, only tGTV was associated with OS. Delay between end of chemotherapy and PCI was not associated with OS. CONCLUSIONS: Patients receiving OD or BD thoracic radiotherapy have the same risk of developing BM. Larger tumors are associated with a higher risk of BM.
    • Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial.

      Fuchs, C; Shitara, K; Di, B; Lonardi, S; Al-Batran, S; Van, C; Ilson, D; Alsina, M; Chau, I; Lacy, J; Ducreux, M; Mendez, G; Alavez, A; Takahari, D; Mansoor, Was; Enzinger, P; Gorbounova, V; Wainberg, Z; Hegewisch-Becker, S; Ferry, D; Lin, J; Carlesi, R; Das, M; Shah, M; Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT, USA (2019)
      BACKGROUND: VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. METHODS: For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1-5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. FINDINGS: Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607-0·935, p=0·0106; median progression-free survival 5·7 months [5·5-6·5] vs 5·4 months [4·5-5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768-1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801-1·156, p=0·6757; median overall survival 11·2 months [9·9-11·9] in the ramucirumab group vs 10·7 months [9·5-11·9] in the placebo group). The most common grade 3-4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). INTERPRETATION: Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population.
    • Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine +/- nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2).

      Strauss, V; Shaw, R; Virdee, P; Hurt, C; Ward, E; Tranter, B; Patel, N; Bridgewater, J; Parsons, P; Radhakrishna, Ganesh; O'Neill, E; Sebag-Montefiore, D; Hawkins, M; Corrie, P; Maughan, T; Mukherjee, S; Centre for Statistics in Medicine, University of Oxford, Oxford, UK (2019)
      BACKGROUND: Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). METHODS: Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C?+?D) or standard-dose (arms A?+?B) radiotherapy with (arms A?+?C) or without (arms B?+?D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19-9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. DISCUSSION: SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen. TRIAL REGISTRATION: Eudract No: 2013-004968-56; ClinicalTrials.gov : NCT02024009.
    • General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): a position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

      Jessop, H; Farge, D; Saccardi, R; Alexander, T; Rovira, M; Sharrack, B; Greco, R; Wulffraat, N; Moore, J; Kazmi, M; Badoglio, M; Adams, G; Verhoeven, B; Murray, John; Snowden, J; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK (2019)
      Over the last 20 years, haematopoietic stem cell transplantation (HSCT) has been used to treat patients with severe autoimmune and inflammatory diseases whose response to standard treatment options has been limited, resulting in a poor long-term prognosis in terms of survival or disability. The vast majority of patients have received autologous HSCT where an increasing evidence-base supports its use in a wide range of autoimmune diseases, particularly relapsing remitting MS, systemic sclerosis and Crohn's disease. Compared with standard treatments for autoimmune diseases, HSCT is associated with greater short-term risks, including a risk of treatment-related mortality and long-term complications. There is a need for a careful appraisal of potential benefits and risks by disease and transplant specialists working closely together with patients and carers to determine individual suitability for HSCT. HSCT should be conducted in accredited transplant centres with robust arrangements for long-term follow-up with both disease and transplant specialists. The aim of this open-access position statement is to provide plainly worded guidance for patients and non-specialist clinicians considering HSCT for an autoimmune disease, especially when treatment abroad is being considered. Recent technical publications in the field have been referenced to support the statement and provide more detail for clinicians advising patients.
    • Impact of patient choice and hospital competition on patient outcomes after prostate cancer surgery: a national population-based study.

      Aggarwal, A; Sujenthiran, A; Lewis, D; Walker, K; Cathcart, P; Clarke, Noel W; Sullivan, R; van der Meulen, J; Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom (2019)
      BACKGROUND: Policies that encourage patient choice and hospital competition have been introduced across several countries with the purpose of improving the quality of health care services. The objective of the current national cohort study was to analyze the correlation between choice and competition on outcomes after cancer surgery using prostate cancer as a case study. METHODS: The analyses included all men who underwent prostate cancer surgery in the United Kingdom between 2008 and 2011 (n = 12,925). Multilevel logistic regression was used to assess the effect of a radical prostatectomy center being located in a competitive environment (based on the number of centers within a threshold distance) and being a successful competitor (based on the ability to attract patients from other hospitals) on 3 patient-level outcomes: postoperative length of hospital stay >3 days, 30-day emergency readmissions, and 2-year urinary complications. RESULTS: With adjustment for patient characteristics, men who underwent surgery in centers located in a stronger competitive environment were less likely to have a 30-day emergency readmission, irrespective of the type or volume of procedures performed at each center (odds ratio, 0.46; 95% confidence interval, 0.36-0.60; P = .005). Men who received treatment at centers that were successful competitors were less likely to have a length of hospital stay >3 days (odds ratio, 0.49; 95% confidence interval, 0.25-0.94; P = .02). CONCLUSIONS: The current results suggest for the first time that hospital competition improves short-term outcomes after prostate cancer surgery. Further evaluation of the potential role of patient choice and hospital competition is required to inform health service design in contrast to the role of top-down-driven approaches, which have focused on centralization of services.
    • Molecular characterisation and liquid biomarkers in carcinoma of unknown primary (CUP): taking the 'U' out of 'CUP'.

      Conway, Alicia-Marie; Mitchell, Claire L; Kilgour, Elaine; Brady, Ged; Dive, Caroline; Cook, Natalie; The Christie NHS Foundation Trust, Wilmslow Road, Manchester (2019)
      Cancers of Unknown Primary (CUP) comprise a heterogeneous clinical entity of confirmed metastatic cancer where the primary site of origin is undetectable. It has a poor prognosis with limited treatment options. CUP is historically under-researched; however, understanding its biology has the potential to not only improve treatment and survival by implementation of biomarkers for patient management, but also to greatly contribute to our understanding of carcinogenesis and metastasis across all cancer types. Here we review the current advances in CUP research and explore the debated hypotheses underlying its biology. The evolution of molecular profiling and tissue-of-origin classifiers have the potential to transform the diagnosis, classification and therapeutic management of patients with CUP but robust evidence to support widespread use is lacking. Precision medicine has transformed treatment strategy in known tumour types; in CUP, however, there remains a clinical need for a better understanding of molecular characteristics to establish the potential role of novel or existing therapeutics. The emergence of liquid biopsies as a source of predictive and prognostic biomarkers within known tumour types is gaining rapid ground and this review explores the potential utility of liquid biopsies in CUP.
    • Driving developments in UK oesophageal radiotherapy through the SCOPE trials.

      Gwynne, S; Higgins, E; Poon, K; Radhakrishna, Ganesh; Wills, L; Mukherjee, S; Hawkins, M; Jones, G; Staffurth, J; Crosby, T; South West Wales Cancer Centre, Swansea, UK. (2019)
      BACKGROUND: The SCOPE trials (SCOPE 1, NeoSCOPE and SCOPE 2) have been the backbone of oesophageal RT trials in the UK. Many changes in oesophageal RT techniques have taken place in this time. The SCOPE trials have, in addition to adopting these new techniques, been influential in aiding centres with their implementation. We discuss the progress made through the SCOPE trials and include details of a questionnaire sent to participating centres. to establish the role that trial participation played in RT changes in their centre. METHODS: Questionnaires were sent to 47 centres, 27 were returned. RESULTS: 100% of centres stated their departmental protocol for TVD was based on the relevant SCOPE trial protocol. 4DCT use has increased from 42 to 71%. Type B planning algorithms, mandated in the NeoSCOPE trial, were used in 79.9% pre NeoSCOPE and now in 83.3%. 12.5% of centres were using a stomach filling protocol pre NeoSCOPE, now risen to 50%. CBCT was mandated for IGRT in the NeoSCOPE trial. 66.7% used this routinely pre NeoSCOPE/SCOPE 2 which has risen to 87.5% in the survey. CONCLUSION: The results of the questionnaires show how participation in national oesophageal RT trials has led to the adoption of newer RT techniques in UK centres, leading to better patient care.
    • Immunogenic effects of radiotherapy for bladder cancer.

      Walshaw, Richard; Roberts, J; Swan, J; Honeychurch, Jamie; Choudhury, Ananya; Illidge, Timothy M; The University of Manchester, Manchester (2019)
    • Palliative radiotherapy to bladder cancer - futile or utile?

      Ali, A; Song, Yee Pei; Logue, John P; Wylie, James P; Choudhury, Ananya; The Christie NHS Foundation Trust, Manchester (2019)
    • OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.

      Robson, M; Tung, N; Conte, P; Im, S; Senkus, E; Xu, B; Masuda, N; Delaloge, S; Li, W; Armstrong, Anne C; Wu, W; Goessl, C; Runswick, S; Domchek, S; Memorial Sloan Kettering Cancer Center, New York, NY, USA (2019)
      Background: In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population. Patients and methods: OlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ?2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300?mg BID) or predeclared TPC (capecitabine, vinorelbine or eribulin). OS and safety were secondary endpoints. Results: 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3 months with olaparib versus 17.1 months with TPC (HR 0.90, 95% CI 0.66-1.23; P=0.513); median follow-up was 25.3 and 26.3 months, respectively. HR for OS with olaparib vs TPC in prespecified subgroups were: prior chemotherapy for mBC (no [first-line setting]: 0.51, 95% CI 0.29-0.90); yes [second/third-line]: 1.13, 0.79-1.64); receptor status (triple negative: 0.93, 0.62-1.43; hormone receptor positive: 0.86, 0.55-1.36); prior platinum (yes: 0.83, 0.49-1.45; no: 0.91, 0.64-1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure. Conclusions: While there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure.
    • Accelerated, dose escalated, sequential chemoradiotherapy in non-small-cell lung cancer (ADSCaN): a protocol for a randomised phase II study.

      Hatton, M; Lawless, C; Faivre-Finn, Corinne; Landau, D; Lester, J; Fenwick, J; Simoes, R; McCartney, E; Boyd, K; Haswell, T; Shaw, A; Paul, J; Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK (2019)
      INTRODUCTION: Lung cancer is the most common cause of cancer mortality in the UK, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Most patients present with inoperable disease; therefore, radiotherapy plays a major role in treatment. However, the majority of patients are not suitable for the gold standard treatment (concurrent chemoradiotherapy) due to performance status and comorbidities. Novel strategies integrating radiotherapy advances and radiobiological knowledge need to be evaluated in patients treated with sequential chemoradiotherapy. Four separate dose escalation accelerated radiotherapy schedules have been completed in UK (CHART-ED, IDEAL-CRT, I-START and Isotoxic IMRT). This study will compare these schedules with a UK standard sequential chemoradiotherapy schedule of 55 Gy in 20 fractions over 4 weeks. As it would be impossible to test all schedules in a phase III study, the aim is to use a combined randomised phase II screening/'pick the winner' approach to identify the best schedule to take into a randomised phase III study against conventionally fractionated radiotherapy. METHODS AND ANALYSIS: Suitable patients will have histologically/cytologically confirmed, stage III NSCLC and are able to undergo chemoradiotherapy treatment. The study will recruit 360 patients; 120 on the standard arm and 60 on each experimental arm. Patients will complete 2-4 cycles of platinum-based chemotherapy before being randomised to one of the radiotherapy schedules. The primary endpoint is progression-free survival, with overall survival, time to local-regional failure, toxicity and cost-effectiveness as secondary objectives. ETHICS AND DISSEMINATION: The study has received ethical approval (research ethics committee (REC) reference: 16/WS/0165) from the West of Scotland REC 1. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Trial results will be published in a peer-reviewed journal and presented internationally. TRIAL REGISTRATION NUMBER: ISRCTN47674500.
    • The role of continuing perioperative chemotherapy post surgery in patients with esophageal or gastroesophageal junction adenocarcinoma: a multicenter cohort study.

      Papaxoinis, Georgios; Kamposioras, K; Weaver, Jamie M; Kordatou, Zoe; Stamatopoulou, Sofia; Germetaki, Theodora; Nasralla, Magdy; Owen-Holt, Vikki; Anthoney, A; Mansoor, Was; Department of Medical Oncology, The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK (2019)
      PURPOSE: The aim of this cohort study was to assess the benefit that patients with lower esophageal or gastroesophageal junction (E/GEJ) adenocarcinoma receive by continuing perioperative chemotherapy post-surgery. METHODS: Three hundred twelve patients underwent radical tumor surgical resection after preoperative chemotherapy. Chemotherapy was mainly ECX (epirubicin, cisplatin, capecitabine). Propensity score matching (PSM) was used to compare continuation of chemotherapy post-surgery vs. no postoperative treatment. RESULTS: Two hundred ten patients (67.3%) had GEJ and 102 (32.7%) lower esophageal adenocarcinoma. Microscopically clear surgical margins (R0), according to the Royal College of Pathologists, were achieved in 208 patients (66.7%). In total, 225 patients (72.1%) continued perioperative chemotherapy post-surgery. PSM was used to create two patient groups, well-balanced for basic epidemiological, clinical, and histopathological characteristics. The first included 148 patients who continued perioperative chemotherapy after surgery and the second 86, who did not receive postoperative treatment. The first group had non-significantly different median time-to-relapse (TTR 22.2 vs. 25.7 months, p?=?0.627), overall survival (OS 46.1 vs. 36.7 months, p?=?0.199), and post-relapse survival (15.3 vs. 8.7 months, p?=?0.122). Subgroup analysis showed that only patients with microscopically residual disease after surgery (R1 resection) benefited from continuation of chemotherapy post-surgery for both TTR (hazard ratio [HR] 0.556, 95% CI 0.330-0.936, p?=?0.027) and OS (HR 0.530, 95% CI 0.313-0.898, p?=?0.018). CONCLUSIONS: Continuation of perioperative chemotherapy post-surgery was not associated with improved outcome in patients with E/GEJ adenocarcinoma. Patients with microscopically residual disease post-surgery might receive a potential benefit from adjuvant chemotherapy