• Outcome of weekly carboplatin-paclitaxel-based definitive chemoradiation in oesophageal cancer in patients not considered to be suitable for platinum-fluoropyrimidine-based treatment: a multicentre, retrospective review

      Owens, R; Cox, C; Gomberg, S; Pan, Shermaine; Radhakrishna, Ganesh; Parikh, S; Goody, R; Hingorani, M; Prince, S; Bird, T; et al. (2019)
      AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ?75 years; 18.7% ? 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.
    • Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres

      Frizziero, Melissa; Wang, Xin; Chakrabarty, Bipasha; Childs, A; Luong, TV; Walter, T; Khan, MS; Morgan, M; Christian, A; Elshafie, M; et al. (2019)
      AIM: To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS: Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS: Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (vs surgery alone) did not improve RFS (P = 0.375), or OS (P = 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (vs best supportive care) prolonged PFS and OS (both, P < 0.001). CONCLUSION: MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.
    • Cancer patterns and association with mortality and renal outcomes in non-dialysis dependent chronic kidney disease: a matched cohort study

      Chinnadurai, R; Flanagan, E; Jayson, Gordon C; Kalra, PA; Department of Renal Medicine, Salford Royal NHS Foundation Trust, M6 8HD, Salford, UK. (2019)
      BACKGROUND: Cancer in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. Cancer can be a cause or an effect of CKD. In CKD patients, a better understanding of cancer distribution and associations can aid in the proper planning of renal replacement therapy (RRT) and in the choice of chemotherapeutic agents, many of which are precluded in more advanced CKD. This study aims to investigate the distribution and the association of cancer with mortality, renal progression and RRT assignment in a non-dialysis dependent CKD cohort, few studies have investigated this in the past. METHODS: The study was carried out on 2952 patients registered in the Salford Kidney Study (SKS) between October 2002 and December 2016. A comparative analysis was performed between 339 patients with a history of cancer (previous and current) and 2613 patients without cancer at recruitment. A propensity score matched cohort of 337 patients was derived from each group and used for analysis. Cox-regression models and Kaplan-Meier estimates were used to compare the association of cancer with mortality and end-stage renal disease (ESRD) outcomes. Linear regression analysis was applied to generate the annual rate of decline in estimated glomerular filtration rate (delta eGFR). RESULTS: Of our cohort, 13.3% had a history of cancer at recruitment and the annual rate of de novo cancers in the non-cancer patients was 1.6%. Urogenital cancers including kidney and bladder, and prostate and testicle in males, ovary and uterus in females, were the most prevalent cancers (46%), as expected from the anatomical or physiological roles of these organs and relationship to nephrology. Over a median follow-up of 48?months, 1084 (36.7%) of patients died. All-cause mortality was higher in the previous and current cancer group (49.6% vs 35%, p?<?0.001), primarily because of cancer-specific mortality. Multivariate Cox regression analysis showed a strong association of cancer with all-cause mortality (HR:1.41; 95%CI: 1.12-1.78; p?=?0.004). There was no difference between the groups regarding reaching end-stage renal disease (26% in both groups) or the rate of decline in eGFR (-?0.97 for cancer vs -?0.93?mL/min/year for non-cancer, p?=?0.93). RRT uptake was similar between the groups (17.2% vs 19.3%, p?=?0.49). CONCLUSIONS: Cancer status proved to be an added burden and an independent risk factor for all-cause mortality but not for renal progression. CKD patients with a previous or current history of cancer should be assessed on a case by case basis in planning for renal replacement therapy options, and the presence of cancer should not be a limitation for RRT provision including transplantation.
    • Recent developments in limited stage small cell lung cancer

      Higgins, KA; Gorgens, S; Sudmeier, LJ; Faivre-Finn, Corinne; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA (2019)
      Limited stage small cell lung cancer (LS-SCLC) remains a challenging disease, with 5-year overall survival ranging from 30-35% with current standard of care treatment consisting of thoracic radiation to 45 Gy in 30 fractions delivered twice daily, with concurrent platinum/etoposide chemotherapy, followed by prophylactic cranial irradiation (PCI). The randomized, phase III CONVERT study confirmed 45 Gy delivered twice daily to be the optimal radiation fractionation regimen, without significantly increased toxicity when compared to daily radiation to 66 Gy. Immunotherapy is now being studied in addition to chemoradiation, in both the concurrent and consolidative setting. These randomized trials are ongoing. Additionally, the role of PCI compared to MRI surveillance is being evaluated in patients with LS-SCLC in both the North America and Europe. Ideally these ongoing studies will continue to improve outcomes for LS-SCLC.
    • The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

      Figlioli, G; Bogliolo, M; Catucci, I; Caleca, L; Lasheras, SV; Pujol, R; Kiiski, JI; Muranen, TA; Barnes, DR; Dennis, J; et al. (2019)
      Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR?=?2.44, P?=?0.034 and OR?=?3.79; P?=?0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR?=?1.96; P?=?0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
    • Scientific rationale underpinning the development of biosimilar rituximab in hematological cancers and inflammatory diseases

      Jurczak, W; Cohen, S; Illidge, Timothy M; Silva, AD; Amersdorffer, J; Maria Sklodowska-Curie Institute, Oncology Centre, Krakow, Poland (2019)
      Sandoz rituximab (SDZ-RTX; Rixathon; GP2013), a rituximab biosimilar, was approved in June 2017 in Europe in all indications of reference rituximab. The stepwise SDZ-RTX development program generated extensive physicochemical, structural, functional, and biological data demonstrating a match with reference rituximab on all clinically relevant attributes. A focused clinical development program followed, in two indications selected for sensitivity to detect potential differences versus reference rituximab: rheumatoid arthritis (pivotal pharmacokinetics and efficacy evaluation) and follicular lymphoma (pivotal efficacy/safety evaluation). These trials demonstrated highly similar pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity profiles. The totality of evidence for biosimilarity for SDZ-RTX, combined with knowledge that B-cell depletion is common to each approved indication, allowed SDZ-RTX approval for use in all indications of reference rituximab.
    • Attending community-based lung cancer screening influences smoking behaviour in deprived populations

      Balata, H; Traverse-Healy, L; Blandin-Knight, S; Armitage, C; Barber, P; Colligan, D; Elton, P; Kirwan, M; Lyons, J; McWilliams, L; et al. (2019)
      OBJECTIVES: The impact of lung cancer screening on smoking is unclear, especially in deprived populations who are underrepresented in screening trials. The aim of this observational cohort study was to investigate whether a community-based lung cancer screening programme influenced smoking behaviour and smoking attitude in socio-economically deprived populations. MATERIAL AND METHODS: Ever-smokers, age 55-74, registered at participating General Practices were invited to a community-based Lung Health Check (LHC). This included an assessment of respiratory symptoms, lung cancer risk (PLCOm2012), spirometry and signposting to stop smoking services. Those at high risk (PLCOM2012?1.51%) were offered annual low-dose CT screening over two rounds. Self-reported smoking status and behaviour were recorded at the LHC and again 12 months later, when attitudes to smoking were also assessed. RESULTS: 919 participants (51% women) were included in the analysis (77% of attendees); median deprivation rank in the lowest decile for England. At baseline 50.3% were current smokers. One-year quit rate was 10.2%, quitting was associated with increased baseline symptoms (adjOR 2.62, 95% CI 1.07-6.41; p?=?0.035) but not demographics or screening results. 55% attributed quitting to the LHC. In current smokers, 44% reported the LHC had made them consider stopping, 29% it made them try to stop and 25% made them smoke less whilst only 1.7% and 0.7% said it made them worry less about smoking or think it acceptable to smoke. CONCLUSIONS: Our data suggest a community-based lung cancer screening programme in deprived areas positively impacts smoking behaviour, with no evidence of a 'licence to smoke' in those screened.
    • EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees.

      Horwich, A; Babjuk, M; Bellmunt, J; Bruins, HM; Reijke, TM; Santis, M; Gillessen, Silke; James, N; Maclennan, S; Palou, J; et al. (2019)
      BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ?70% agreement and ?15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.
    • PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

      Buckley, HL; Collinson, FJ; Ainsworth, G; Poad, H; Flanagan, L; Katona, E; Howard, HC; Murden, G; Banks, RE; Brown, J; et al. (2019)
      BACKGROUND: The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. METHODS: The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12?months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. DISCUSSION: The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. TRIAL REGISTRATION: PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). TRIAL STATUS: At the time of submission, PRISM is open to recruitment and data collection is ongoing.
    • Outcomes of patients with Nelson's syndrome after primary treatment: a multicenter study from 13 UK Pituitary centers

      Fountas, A; Lim, ES; Drake, WM; Powlson, AS; Gurnell, M; Martin, NM; Seejore, K; Murray, RD; MacFarlane, J; Ahluwalia, R; et al. (2019)
      CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n=30, eight patients had two and one had three pituitary operations), surgery+radiotherapy+adrenalectomy (n=17, two received >1 courses of irradiation, two had ?2 pituitary surgeries), radiotherapy+adrenalectomy (n=2) and adrenalectomy (n=19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (HR 4.6; 95% CI, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.
    • Health-related quality of life in patients with advanced soft tissue sarcomas treated with chemotherapy: The HOLISTIC study

      Younger, E; Husson, O; Desar, IME; Young, R; Leahy, Michael G; Oosten, A; Gelderblom, H; de Haan, J; Steeghs, N; Jones, RL; et al. (2019)
    • A phase Ib/ II trial to assess the safety and efficacy of CXD101 in combination with the PD-1 inhibitor nivolumab in patients with metastatic, previously-treated, microsatellite-stable (MSS) colorectal carcinoma (short title CAROSELL)

      Saunders, Mark P; Graham, J; Cunningham, D; Plummer, R; Cook, S; Church, D; Kerr, R; La Thangue, N; Kerr, DJ; Oncology, The Christie NHS Foundation Trust, Oxford, UK (2019)
    • A phase Ib study of E7046 (AN0025) in combination with radiotherapy/chemoradiotherapy (RT/CRT) in preoperative treatment of rectal cancer

      Wyrwicz, L; Saunders, Mark P; Hall, M; Ng, J; Prasad, VB; Lautermilch, N; Rashford, MM; Jin, J; Formenti, S; Glynne-Jones, R; et al. (2019)
    • Final results of the STEM trial: SFX-01 in the treatment and evaluation of ER+Her2-metastatic breast cancer (mBC)

      Howell, Sacha J; Campone, M; Cortes, J; Duhoux, FP; Ross, S; Morris, T; Franklin, S; Division of Cancer Sciences, The University of Manchester, Manchester, UK (2019)
    • Effect of response to last platinum-based chemotherapy in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma in the phase III study ARIEL3 of rucaparib maintenance treatment

      Ledermann, JA; Oza, AM; Lorusso, D; Aghajanian, C; Oaknin, A; Dean, A; Colombo, N; Weberpals, JI; Clamp, Andrew R; Scambia, G; et al. (2019)
    • Timing of radiotherapy (RT) after radical prostatectomy (RP): First results from the RADICALS RT randomised controlled trial (RCT) [NCT00541047]

      Parker, C; Clarke, Noel W; Cook, A; Kynaston, HG; Petersen, PM; Cross, W; Persad, R; Catton, C; Logue, John P; Payne, H; et al. (2019)
    • SELPAC: A 3 arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel (PT) in metastatic uveal melanoma (UM)

      Nathan, P; Needham, A; Corrie, PG; Danson, S; Evans, J; Ochsenreither, S; Kumar, S; Goodman, A; Larkin, JMG; Karydis, I; et al. (2019)