Citation: BMC Cancer. 2019, 19(1), 1209
Author: Nigel Fleeman, Rachel Houten, Marty Chaplin, Sophie Beale, Angela Boland, Yenal Dundar, Janette Greenhalgh, Rui Duarte, Aditya Shenoy
Abstract: Background: Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC).
Methods: We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments.
Results: Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited.
Conclusions: Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.
Keywords: Clinical effectiveness; Lenvatinib; Sorafenib; Systematic review; Thyroid cancer; Tyrosine kinase inhibitor.
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Friday 20 December 2019
CCC publication: Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Gene Aberrations (TOPARP-B): A Multicentre, Open-Label, Randomised, Phase 2 Trial
Citation: The Lancet. Oncology. 2020, 21(1), 162-174. 2019 Dec 2 [Online ahead of print]
Author: Joaquin Mateo, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Varughese, Omi Parikh, Simon Crabb, Angus Robinson, Duncan McLaren, Alison Birtle, Jacob Tanguay, Susana Miranda, Ines Figueiredo, George Seed, Claudia Bertan, Penny Flohr, Berni Ebbs, Pasquale Rescigno, Gemma Fowler, Ana Ferreira, Ruth Riisnaes, Rita Pereira, Andra Curcean, Robert Chandler, Matthew Clarke, Bora Gurel, Mateus Crespo, Daniel Nava Rodrigues, Shahneen Sandhu, Aude Espinasse, Peter Chatfield, Nina Tunariu, Wei Yuan, Emma Hall, Suzanne Carreira, Johann S de Bono
Abstract: Background: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.
Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.
Findings: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.
Interpretation: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.
Funding: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
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Author: Joaquin Mateo, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Varughese, Omi Parikh, Simon Crabb, Angus Robinson, Duncan McLaren, Alison Birtle, Jacob Tanguay, Susana Miranda, Ines Figueiredo, George Seed, Claudia Bertan, Penny Flohr, Berni Ebbs, Pasquale Rescigno, Gemma Fowler, Ana Ferreira, Ruth Riisnaes, Rita Pereira, Andra Curcean, Robert Chandler, Matthew Clarke, Bora Gurel, Mateus Crespo, Daniel Nava Rodrigues, Shahneen Sandhu, Aude Espinasse, Peter Chatfield, Nina Tunariu, Wei Yuan, Emma Hall, Suzanne Carreira, Johann S de Bono
Abstract: Background: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.
Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.
Findings: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.
Interpretation: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.
Funding: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
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CCC publication: Weekly Dose-Dense Chemotherapy in First-Line Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma Treatment (ICON8): Primary Progression Free Survival Analysis Results From a GCIG Phase 3 Randomised Controlled Trial
Citation: Lancet. 2019, 394(10214), 2084-95
Author: Andrew R Clamp, Elizabeth C James, Iain A McNeish, Andrew Dean, Jae-Weon Kim, Dearbhaile M O'Donnell, Jane Hook, Christopher Coyle, Sarah Blagden, James D Brenton, Raj Naik, Tim Perren, Sudha Sundar, Adrian D Cook, Gosala S Gopalakrishnan, Hani Gabra, Rosemary Lord, Graham Dark, Helena M Earl, Marcia Hall, Susana Banerjee, Rosalind M Glasspool, Rachel Jones, Sarah Williams, Ann Marie Swart, Sally Stenning, Mahesh Parmar, Richard Kaplan, Jonathan A Ledermann
Abstract: Background: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.
Methods: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).
Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.
Interpretation: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.
Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
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Author: Andrew R Clamp, Elizabeth C James, Iain A McNeish, Andrew Dean, Jae-Weon Kim, Dearbhaile M O'Donnell, Jane Hook, Christopher Coyle, Sarah Blagden, James D Brenton, Raj Naik, Tim Perren, Sudha Sundar, Adrian D Cook, Gosala S Gopalakrishnan, Hani Gabra, Rosemary Lord, Graham Dark, Helena M Earl, Marcia Hall, Susana Banerjee, Rosalind M Glasspool, Rachel Jones, Sarah Williams, Ann Marie Swart, Sally Stenning, Mahesh Parmar, Richard Kaplan, Jonathan A Ledermann
Abstract: Background: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.
Methods: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).
Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.
Interpretation: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.
Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
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CCC publication: Long-term Results From the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-Small Cell Lung Cancer
Citation: International Journal of Radiation Oncology, Biology, Physics. 2020, 106(4), 733-742
Author: J D Fenwick, D B Landau, A Baker, A T Bates, C Eswar, A Garcia-Alonso, S V Harden, M C Illsley, V Laurence, Z Malik, W P M Mayles, E Miles, N Mohammed, J Spicer, P Wells, S Vivekanandan, A M Mullin, L Hughes, L Farrelly, Y Ngai, N Counsell
Abstract: Purpose: The XTRIAL phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiotherapy for stage II/III non-small cell lung cancer (NSCLC) investigated two 30-fraction schedules of 5 and 6 weeks duration. We report toxicity, tumor response, progression-free survival (PFS) and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule.
Patients and methods: Patients received isotoxically-individualized tumor radiation doses of 63-71 Gy in 5 weeks or 63-73 Gy in 6 weeks, delivered concurrently with two cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules.
Results: 120 patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall, and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with two considered RT-related. After 51.8 and 26.4 months median follow-up for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (HR=0.56, 95%CI: 0.32-0.98, p=0.04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR=0.88, 95%CI: 0.77-1.00, p=0.05). PFS was also significantly associated with schedule (HR=0.53, 95%CI: 0.33-0.86, p=0.01).
Conclusions: Toxicity in XTRIAL was acceptable. Survival was promising for 6-week patients, and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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Author: J D Fenwick, D B Landau, A Baker, A T Bates, C Eswar, A Garcia-Alonso, S V Harden, M C Illsley, V Laurence, Z Malik, W P M Mayles, E Miles, N Mohammed, J Spicer, P Wells, S Vivekanandan, A M Mullin, L Hughes, L Farrelly, Y Ngai, N Counsell
Abstract: Purpose: The XTRIAL phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiotherapy for stage II/III non-small cell lung cancer (NSCLC) investigated two 30-fraction schedules of 5 and 6 weeks duration. We report toxicity, tumor response, progression-free survival (PFS) and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule.
Patients and methods: Patients received isotoxically-individualized tumor radiation doses of 63-71 Gy in 5 weeks or 63-73 Gy in 6 weeks, delivered concurrently with two cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules.
Results: 120 patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall, and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with two considered RT-related. After 51.8 and 26.4 months median follow-up for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (HR=0.56, 95%CI: 0.32-0.98, p=0.04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR=0.88, 95%CI: 0.77-1.00, p=0.05). PFS was also significantly associated with schedule (HR=0.53, 95%CI: 0.33-0.86, p=0.01).
Conclusions: Toxicity in XTRIAL was acceptable. Survival was promising for 6-week patients, and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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CCC publication: A Novel Panel of Differentially-Expressed microRNAs in Breast Cancer Brain Metastasis May Predict Patient Survival
Citation: Scientific Reports. 2019, 9(1), 18518
Author: Athina Giannoudis, Kim Clarke, Rasheed Zakaria, Damir Varešlija, Mosavar Farahani, Lucille Rainbow, Angela Platt-Higgins, Stuart Ruthven, Katherine A Brougham, Philip S Rudland, Michael D Jenkinson, Leonie S Young, Francesco Falciani, Carlo Palmieri
Abstract: Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.
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Author: Athina Giannoudis, Kim Clarke, Rasheed Zakaria, Damir Varešlija, Mosavar Farahani, Lucille Rainbow, Angela Platt-Higgins, Stuart Ruthven, Katherine A Brougham, Philip S Rudland, Michael D Jenkinson, Leonie S Young, Francesco Falciani, Carlo Palmieri
Abstract: Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.
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WUTH publication: Programmed death ligand 1 expression in EBUS aspirates of non-small cell lung cancer: Is interpretation affected by type of fixation?
Citation: Cancer Cytopathology. 2020, 128(2), 100-106. Epub 2019 Dec 18
Author: Gosney JR, Haragan A, Chadwick C, Giles TE, Grundy S, Tippett V, Gumparthy KP, Wight A, Tan HG
Abstract: BACKGROUND: Much of the reluctance about using cytology specimens rather than histology specimens to assess programmed death ligand 1 (PD-L1) expression for guiding the use of immune modulating drugs in the management of non-small cell lung cancer (NSCLC) is based on the belief that the alcohol-based fixatives favored by cytopathologists might reduce the antigenicity of PD-L1 and lead to artifactually low expression levels and false-negative reporting. Therefore, this study was performed to determine whether there is any difference in PD-L1 expression between endobronchial ultrasound (EBUS)-guided aspirates of NSCLC fixed in alcohol-based fixatives and those fixed in neutral buffered formalin (NBF), the standard laboratory fixative for histology specimens.
METHODS: The expression of PD-L1 was compared in 50 paired EBUS aspirates of NSCLC taken from the same lymph node during the same procedure. One aspirate of each pair was fixed in an alcohol-based fixative, and the other was fixed in NBF.
RESULTS: In none of the 50 pairs was there any significant difference, qualitative or quantitative, in the strength, pattern, or extent of PD-L1 expression. In the great majority, the expression was identical, regardless of fixation.
CONCLUSIONS: There is no evidence from this study showing that the use of alcohol-based fixatives has any effect on the expression of PD-L1 or its interpretation. Notwithstanding the general challenges in accurately assessing such expression in cytology specimens, pathologists should feel able to interpret them with confidence, and clinicians should feel able to rely on the results.
© 2019 American Cancer Society.
KEYWORDS: cytology; fixation; immunochemistry; lung cancer; programmed death ligand 1 (PD-L1)
Link to PubMed record
Author: Gosney JR, Haragan A, Chadwick C, Giles TE, Grundy S, Tippett V, Gumparthy KP, Wight A, Tan HG
Abstract: BACKGROUND: Much of the reluctance about using cytology specimens rather than histology specimens to assess programmed death ligand 1 (PD-L1) expression for guiding the use of immune modulating drugs in the management of non-small cell lung cancer (NSCLC) is based on the belief that the alcohol-based fixatives favored by cytopathologists might reduce the antigenicity of PD-L1 and lead to artifactually low expression levels and false-negative reporting. Therefore, this study was performed to determine whether there is any difference in PD-L1 expression between endobronchial ultrasound (EBUS)-guided aspirates of NSCLC fixed in alcohol-based fixatives and those fixed in neutral buffered formalin (NBF), the standard laboratory fixative for histology specimens.
METHODS: The expression of PD-L1 was compared in 50 paired EBUS aspirates of NSCLC taken from the same lymph node during the same procedure. One aspirate of each pair was fixed in an alcohol-based fixative, and the other was fixed in NBF.
RESULTS: In none of the 50 pairs was there any significant difference, qualitative or quantitative, in the strength, pattern, or extent of PD-L1 expression. In the great majority, the expression was identical, regardless of fixation.
CONCLUSIONS: There is no evidence from this study showing that the use of alcohol-based fixatives has any effect on the expression of PD-L1 or its interpretation. Notwithstanding the general challenges in accurately assessing such expression in cytology specimens, pathologists should feel able to interpret them with confidence, and clinicians should feel able to rely on the results.
© 2019 American Cancer Society.
KEYWORDS: cytology; fixation; immunochemistry; lung cancer; programmed death ligand 1 (PD-L1)
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Thursday 19 December 2019
Research Scholars Programme - Cohort 3 - We're Recruiting!
The Research Scholars Programme is aimed at research-interested individuals who may or may not have NIHR clinical research experience already. We are encouraging applications from the whole cross section of clinical staffing roles including doctors, nurse’s pharmacists, radiographers, occupational therapists, physiologists, physiotherapists, radiotherapists and biomedical scientists. The Programme is an interactive developmental programme aimed at equipping tomorrow's clinical research leaders with the skills, knowledge and experience needed to become the Principal and Chief Investigators of the future. Successful candidates receive funding (half funded by the CRN NWC award and the other half 'match' funded by the applicants employer) to cover one full day per week as dedicated time for research. Scholars commit to attending a day per month at the CRN NWC offices in Liverpool for an exciting programme of face-to-face sessions.
The Research Scholars Programme offers the following benefits:
· Protected & funded time to enable you to support and deliver NIHR Funded research within your service
· A development pathway towards becoming a Principal or Chief investigator
· Full support from CRN NWC & your employer
· Support & guidance from being matched with a mentor who is an experienced Principal or Chief Investigator
Am I eligible to apply?
The Research Scholars Programme is an initiative to develop early career researchers. In order to be eligible for the Programme you should be:
· New Consultants or General Practitioners within the last 5 years of taking up their post
· Nurses (usually Band 7 or above)
· Allied Health Professionals (usually Band 7 or above)
To apply to be part of the programme, please email rspadmin@nihr.ac.uk for an application form. Applications will be accepted until Monday 27th January 2020 and interviews will be held on Monday 24th and Tuesday 25th February 2020.
Course
Lead: Professor Enitan
Carrol, MBChB, MRCP, FRCPCH, MD, FHEA, PG Cert (Higher Education)
Course Co-Lead: Dr Chris Smith, Deputy Chief Operating Officer, CRN North West Coast
Course
administrator: Mrs Clare Donnelly,
Research Administrator, CRN North West Coast
The Research Scholars Programme
The NWC region has a diverse range of research leaders,
but it is recognised to increase its outputs this leadership community requires
investment and support to further flourish. Without this medium and longer-term
support the region’s ability to attract and participate in a larger proportion
of the national NIHR research portfolio would be limited. This is already
evidenced by the fact that the NWC region has a proportionately lower number of
Chief Investigators leading studies on the NIHR portfolio than other Local
Clinical Research Networks (LCRNs) across the country. Given the size of CRN
NWC and the inherent health challenges across the local population, it is key
this is addressed if the region is to ensure it remains competitive in the
future.
The Research Scholars Programme (RSP) is designed to
develop ‘research-interested’ individuals in the earlier phase of their clinical
research careers. Such individuals may not have previously been involved in
NIHR portfolio research or they may have had some involvement in delivery of
NIHR trials but not in a significant leadership role. The RSP is open to
medical consultants and General Practitioners in the first five years (career
breaks excluded) of their careers as well as established colleagues from across
other clinical professions such as Allied Health Professionals and Nursing,
Physiotherapy, Occupational therapy, Radiography and Pharmacy.
The aim of
the programme is to provide successful applicants with remunerated time to
enable recruitment into NIHR research studies and establish themselves as
Principal Investigators / future Chief Investigators. The RSP award will provide protected time to support
the generation of research outputs including trial delivery and the development
of research collaborations / future NIHR grant submissions. Successful scholars
will be allocated a two-year award to support research career development and
NIHR research delivery from NIHR CRN NWC.
The RSP is a collaborative initiative that is being
offered in partnership with NHS stakeholders across the CRN NWC region. CRN NWC
will provide SPA funding (or equivalent value in other professions) of 1.0 SPA per
week (equivalent for AHP’s and nurses), which will be matched by NHS
partners/employers supporting the scheme. It is the intention that after the
initial two year period, sufficient experience will have been generated for the
scholar to sustain the sessional time for research within their employing
organisation and may become eligible to apply for further developmental funding
from NIHR.
The course content is based
on the Vitae Researcher Development Framework (RDF). The RDF is a new approach to researcher development, to enhance research
capacity in the UK workforce, develop world-class researchers and build the UK research base. It is a professional development
framework for planning, promoting and supporting the personal, professional and career development
of researchers in higher education. It articulates the knowledge, behaviours and attributes of successful
researchers and encourages them to realise their potential. The four
domains are; Engagement, influence and impact, Knowledge and intellectual
abilities, Research governance and organisation and Personal effectiveness. https://www.vitae.ac.uk/researchers-professional-development/about-the-vitae-researcher-development-framework
Time commitment
The
scholars have protected time of one day a week to conduct research, which
includes time to fulfil their Principal Investigator roles at their respective
NHS Trusts (industry or NIHR studies developed by others), and to develop
proposals for grant funding. In addition, there is a mandatory monthly
face-to-face teaching day at the CRN Liverpool office, the delivery of which
includes lectures, workshops, and action learning sets. 80 % attendance is
mandatory, dates provided in advance.
Assessment
Year1: Promotional video of research profile, Dragon’s Den
presentation in front of external panel, Summative Year 1 review presentation
(review of achievements in year 1 and goals for year 2).
Year
2: Submission of a 4-page research
proposal to include: background and rationale, aims and objectives, research
plan, dissemination and impact, research timetable, ethics, patient and public
involvement and lay summary, Summative Year 2 review presentation (review of
achievements in year 2), Co-development of an NIHR application as co-applicant,
lead applicant, co-Chief Investigator or deputy Chief Investigator, to be
submitted within 6 months of course completion.
Feedback
Scholars
are required to sign in and out of each face-to face session and complete
course feedback after each face-to-face session.
Monday 2 December 2019
WUTH publication: Tuberous Sclerosis Complex (TSC): Expert Recommendations for Provision of Coordinated Care
Citation: Frontiers in nerology. 2019 Nov 6, eCollection 2019.
Author: Annear NMP, Appleton RE, Bassi Z, Bhatt R, Bolton PF, Crawford P, Crowe A, Tossi M, Elmslie F, Finlay E, Gale DP, Henderson A, Jones EA, Johnson SR, Joss S, Kerecuk L, Lipkin G, Morrison PJ, O'Callaghan FJ, Cadwgan J, Ong ACM, Sampson JR, Shepherd C, Kingswood JC
Abstract: KEYWORDS: United Kingdom; clinics; commissioning; guidelines; rare disease; service specification; surveillance; tuberous sclerosis complex
Link to PubMed record
Author: Annear NMP, Appleton RE, Bassi Z, Bhatt R, Bolton PF, Crawford P, Crowe A, Tossi M, Elmslie F, Finlay E, Gale DP, Henderson A, Jones EA, Johnson SR, Joss S, Kerecuk L, Lipkin G, Morrison PJ, O'Callaghan FJ, Cadwgan J, Ong ACM, Sampson JR, Shepherd C, Kingswood JC
Abstract: KEYWORDS: United Kingdom; clinics; commissioning; guidelines; rare disease; service specification; surveillance; tuberous sclerosis complex
Link to PubMed record
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