Citation: British Journal of Haematology. 2019, 185, 161-62
Author: D'Arienzo P.; Shaw R.J.; Johnstone M.; Salim R.; Turtle L.
Abstract: Febrile neutropaenia is the commonest life-threatening complication of chemotherapy. Haemato-oncology patients represent a unique cohort regarding the severity and duration of immunosuppression. In this study we aim to compare our management of immunocompromised sepsis to local policy and NICE guidelines, and by reviewing microbiological isolates as well as patient outcomes, we aim to assess if our antimicrobial policy is optimal. Data was collected prospectively from 1st September 2018-15th December 2018; due to insufficient numbers, we extended this to a retrospective review from 15th July 2018 - 31st August 2018. All inpatients (N = 149) admitted under a Haemato-Oncology consultant were reviewed for febrile episodes. As per NICE guidance, a pyrexial episode was defined as temperature >=38degreeC. The electronic patient record was used to identify patient characteristics including age, sex, diagnosis, treatment & transplant status. The electronic prescribing system was used to identify antimicrobial data. The Integrated Clinical Environment software was used to identify neutrophil count, resistant organism screens and blood cultures. Statistical analyses were carried out using SPSS 25.0. Forty-one patients (median age 52 yrs, 61% male) experienced 55 pyrexial episodes. The underlying condition was high-grade lymphoma in 12 (29%), AML in 11 (27%), myeloma in 6 (15%), ALL in 4 (10%). Fourteen patients were stem cell transplant recipients (50% autologous, 50% allogeneic). Neutropenia (neutrophil count < 1.0) was present in 51% of episodes; median neutropenia duration was 7 days (range 1 - 365). Most episodes occurred out of hours (76%); 20% occurred in A&E or on outlying wards. National early warning score was recorded in all episodes (median 3, range 1 - 10). Resistant organism screens had been performed within 3 months in 89% of cases. On presentation, peripheral blood cultures were sent in 71%, line blood cultures in 81%. Amongst the 36 patients not already receiving antimicrobials, antibiotics were administrated within 1 hr in 22 (39%) cases (median time to antibiotic administration 75 min, range 9 - 368). Median time to administration of antibiotics was 77 min in the Haematology department vs. 68 in other departments (Mann-Whitney U test, p = 0.44). Similarly, there was no difference in time to administration between episodes occurring during working hours vs. out of hours (Mann-Whitney U test, p = 0.76). Prescribed antibiotics were in line with local policy (piperacillin/tazobactam plus gentamicin or meropenem) in 39 cases (71%); in 17 cases additional antimicrobials were given (teicoplanin in 12, daptomycin in 3, amikacin in 2). Microbiological isolates were grown in 15 episodes, the commonest organisms being E. coli (33%), K. pneumoniae (13%), Enterococcus sp (13%). Outcomes included resolution in 52% of cases, complications in 40% (ongoing bacteraemia, need for line removal or admission to critical care) and death in 8%. Our study demonstrated particular areas of management which need addressing: <40% of patients received antimicrobials within 1 hr and a significant proportion did not have paired peripheral and line blood cultures sent. Antimicrobial choice was variable; many patients had resistant organism screens, but the results were not always clearly reflected in the antimicrobials given. Gram negative bacilli were the most common organisms grown in our cohort; data collection of resistance profiles of these isolates is ongoing.
Wednesday, 5 June 2019
CCC publication: Incidence and evolution of imaging changes on cone-beam CT during and after radical radiotherapy for non-small cell lung cancer
Citation: Radiotherapy and Oncology. 2019, 132, 121-26
Author: Clarke E.; Brada M.; Curtis J.
Abstract: BACKGROUND AND PURPOSE: Cone beam CT (CBCT) is used to improve accuracy of radical radiotherapy by adjusting treatment to the observed imaging changes. To ensure appropriate adjustment, image interpretation should precede any changes to treatment delivery. This study provides the methodology for image interpretation and the frequency and evolution of the changes in patients undergoing radical radiotherapy for localised and locally advanced non-small cell lung cancer (NSCLC).
PATIENTS AND METHODS: From December 2012 to December 2014, 250 patients with localised and locally advanced NSCLC had 2462 chest CBCT scans during the course of fractionated radical radiotherapy (RT) (3-5 daily CBCTs in the first week followed by at least weekly imaging, mean 9.5 per patient, range 1-21). All CBCT images were reviewed describing changes and their evolution using diagnostic imaging definitions and validated by an independent chest radiologist.
RESULTS: During radical RT for NSCLC 328 imaging changes were identified on CBCT in 180 (72%) patients; 104 (32%) had reduction and 41 (13%) increase in tumour size; 48 (15%) had changes in consolidations contiguous to the primary lesion, 26 (8%) non-contiguous consolidations, 43 (13%) changes in tumour cavitation, 36 (11%) pleural effusion and 30 (9%) changes in atelectasis. In 105 patients imaging changes were noted in continuity with the treated tumour of which only 41 (39%) represented tumour enlargement; others included new or enlarging adjacent consolidation (34%), and new or enlarging atelectasis (19%). The changes evolved during treatment.
CONCLUSION: Imaging changes on CBCT include real and apparent changes in tumour size and parenchymal changes which evolve during treatment. Correct image interpretation, particularly when occurring adjacent to the tumour, is essential prior to adjustment to treatment delivery.
Copyright © 2018 Elsevier B.V. All rights reserved.
KEYWORDS: CBCT; Cone beam; IGRT; Imaging; Lung cancer; NSCLC; Radiotherapy
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Author: Clarke E.; Brada M.; Curtis J.
Abstract: BACKGROUND AND PURPOSE: Cone beam CT (CBCT) is used to improve accuracy of radical radiotherapy by adjusting treatment to the observed imaging changes. To ensure appropriate adjustment, image interpretation should precede any changes to treatment delivery. This study provides the methodology for image interpretation and the frequency and evolution of the changes in patients undergoing radical radiotherapy for localised and locally advanced non-small cell lung cancer (NSCLC).
PATIENTS AND METHODS: From December 2012 to December 2014, 250 patients with localised and locally advanced NSCLC had 2462 chest CBCT scans during the course of fractionated radical radiotherapy (RT) (3-5 daily CBCTs in the first week followed by at least weekly imaging, mean 9.5 per patient, range 1-21). All CBCT images were reviewed describing changes and their evolution using diagnostic imaging definitions and validated by an independent chest radiologist.
RESULTS: During radical RT for NSCLC 328 imaging changes were identified on CBCT in 180 (72%) patients; 104 (32%) had reduction and 41 (13%) increase in tumour size; 48 (15%) had changes in consolidations contiguous to the primary lesion, 26 (8%) non-contiguous consolidations, 43 (13%) changes in tumour cavitation, 36 (11%) pleural effusion and 30 (9%) changes in atelectasis. In 105 patients imaging changes were noted in continuity with the treated tumour of which only 41 (39%) represented tumour enlargement; others included new or enlarging adjacent consolidation (34%), and new or enlarging atelectasis (19%). The changes evolved during treatment.
CONCLUSION: Imaging changes on CBCT include real and apparent changes in tumour size and parenchymal changes which evolve during treatment. Correct image interpretation, particularly when occurring adjacent to the tumour, is essential prior to adjustment to treatment delivery.
Copyright © 2018 Elsevier B.V. All rights reserved.
KEYWORDS: CBCT; Cone beam; IGRT; Imaging; Lung cancer; NSCLC; Radiotherapy
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CCC publication: Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage
Citation: International Journal of Radiation Oncology, Biology, Physics. 2019, 104(3), 656-65
Author: Carter R.J.; Nickson C.M.; Parsons J.L. (j.parsons@liverpool.ac.uk); Thompson J.M.; Hill M.A.; Kacperek A.
Abstract: PURPOSE: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking.
METHODS AND MATERIALS: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay.
RESULTS: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA.
CONCLUSIONS: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Link to PubMed record
Author: Carter R.J.; Nickson C.M.; Parsons J.L. (j.parsons@liverpool.ac.uk); Thompson J.M.; Hill M.A.; Kacperek A.
Abstract: PURPOSE: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking.
METHODS AND MATERIALS: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay.
RESULTS: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA.
CONCLUSIONS: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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CCC publication: The UK myeloproliferative neoplasm registry for myelofibrosis (UK-MPN-MF registry)
Citation: British Journal of Haematology. 2019, 185, 54-5
Author: Butt N.M.; Curto-Garcia N.; Ianotto J.-C.; Harrison C.; Mead A.
Abstract: BACKGROUND: Bone marrow (BM) histology/immunohistochemistry, KIT D816V mutation analysis and serum tryptase measurements are mandatory tools for diagnosis of systemic mastocytosis (SM).
MATERIALS AND METHODS: Within the 'German Registry of Disorders on Eosinophils and Mast Cells', we identified 65 patients with SM who had two consecutive BM biopsies. The first biopsy was evaluated by a local pathologist (LP) and the second biopsy by a reference pathologist (RP) of the 'European Competence Network on Mastocytosis (ECNM)'.
RESULTS: Final diagnoses by RP were SM (n = 27), SM or aggressive SM (ASM) with associated clonal haematological non-mast cell lineage disease [(A)SM-AHNMD, n = 34)] or mast cell leukaemia ± AHNMD (n = 4). In 15 of 65 patients (23%), initial diagnoses by LP were incorrect (by overlooking SM), for example primary myelofibrosis (n = 3), myelodysplastic/myeloproliferative neoplasm unclassified (n = 3) or B-cell lymphoma (n = 2). Fourteen of 15 patients (93%) with incorrect diagnosis had an advanced SM, mostly (A)SM-AHNMD. In the 50 concordantly diagnosed patients, immunohistochemical markers for quantitative assessment of mast cell infiltration, for example CD117 (KIT) or CD25, were applied by LP in only 34 of 50 patients (68%), and mutational analysis for KIT D816V was performed or recommended in only 13 of 50 patients (26%). Finally, the subclassification of SM was discordant because LP did not diagnose AHNMD in nine of 50 (18%) patients.
CONCLUSIONS: In summary, adequate diagnosis and subclassification of SM requires an in-depth evaluation of the BM by experienced haematopathologists (preferably in a reference centre) in combination with molecular genetics, serum tryptase level and clinical parameters.
© 2016 Stichting European Society for Clinical Investigation Journal Foundation.
KEYWORDS: Bone marrow histology; European Competence Network on Mastocytosis; misdiagnosis; systemic mastocytosis
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Author: Butt N.M.; Curto-Garcia N.; Ianotto J.-C.; Harrison C.; Mead A.
Abstract: BACKGROUND: Bone marrow (BM) histology/immunohistochemistry, KIT D816V mutation analysis and serum tryptase measurements are mandatory tools for diagnosis of systemic mastocytosis (SM).
MATERIALS AND METHODS: Within the 'German Registry of Disorders on Eosinophils and Mast Cells', we identified 65 patients with SM who had two consecutive BM biopsies. The first biopsy was evaluated by a local pathologist (LP) and the second biopsy by a reference pathologist (RP) of the 'European Competence Network on Mastocytosis (ECNM)'.
RESULTS: Final diagnoses by RP were SM (n = 27), SM or aggressive SM (ASM) with associated clonal haematological non-mast cell lineage disease [(A)SM-AHNMD, n = 34)] or mast cell leukaemia ± AHNMD (n = 4). In 15 of 65 patients (23%), initial diagnoses by LP were incorrect (by overlooking SM), for example primary myelofibrosis (n = 3), myelodysplastic/myeloproliferative neoplasm unclassified (n = 3) or B-cell lymphoma (n = 2). Fourteen of 15 patients (93%) with incorrect diagnosis had an advanced SM, mostly (A)SM-AHNMD. In the 50 concordantly diagnosed patients, immunohistochemical markers for quantitative assessment of mast cell infiltration, for example CD117 (KIT) or CD25, were applied by LP in only 34 of 50 patients (68%), and mutational analysis for KIT D816V was performed or recommended in only 13 of 50 patients (26%). Finally, the subclassification of SM was discordant because LP did not diagnose AHNMD in nine of 50 (18%) patients.
CONCLUSIONS: In summary, adequate diagnosis and subclassification of SM requires an in-depth evaluation of the BM by experienced haematopathologists (preferably in a reference centre) in combination with molecular genetics, serum tryptase level and clinical parameters.
© 2016 Stichting European Society for Clinical Investigation Journal Foundation.
KEYWORDS: Bone marrow histology; European Competence Network on Mastocytosis; misdiagnosis; systemic mastocytosis
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CCC publication: Improving outcomes in non-small cell lung cancer; population analysis of radical radiotherapy
Citation: Radiotherapy and Oncology. 2019, 132, 204-10
Author: Brada M. (michael.brada@liverpool.ac.uk); Forbes H.; Ashley S.; Ball C.; Mitchell S.
Abstract: AIM: Regional utilisation of radical radiotherapy (RT) in non-small cell lung cancer (NSCLC) was used to define optimal utilisation to improve outcome and as a surrogate for evidence of RT efficacy.
PATIENTS & METHODS: 65,412 NSCLC cases diagnosed in England 2012-13 were linked to comprehensive national radiotherapy dataset, hospital admissions and the Office of National Statistics. Geographical variation in utilisation was determined using a multivariate binary logistic regression analysis after adjusting for age, stage, deprivation, comorbidity and other radical treatment and the effect of radical RT utilisation on survival was investigated. Survival was adjusted for dependent and independent variables and the effect of differing levels of utilisation was assessed by the log likelihood test.
RESULTS: 17.6% cases potentially eligible for radical RT (stages 0-III) received radiotherapy with radical intent. Utilisation of radical RT had an impact on survival (p < 0.00001). Adjusting for all prognostic and treatment variables counties with lowest utilisation (≤15%) had the worst survival (HR = 1.13). The highest utilisation quintile counties (≥25%) had worse survival compared to counties with lower utilisation (≈20%) (p < 0.0001). Analysis of stages II&III showed the same pattern; increase in utilisation from 20% to ≥25% resulting in a 3% drop in 2-year population survival (p = 0.001).
CONCLUSION: The utilisation of radical RT has a significant impact on NSCLC population survival. Improvement in survival of NSCLC population can be achieved by offering radical RT to a larger proportion of patients while avoiding excessive use. Geographical variation in RT utilisation provides indirect evidence of survival benefit of radical radiotherapy.
Copyright © 2018 Elsevier B.V. All rights reserved.
KEYWORDS: Big data; Dose fractionation; Non-small cell lung cancer; Radical radiotherapy; Radiotherapy utilisation
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Author: Brada M. (michael.brada@liverpool.ac.uk); Forbes H.; Ashley S.; Ball C.; Mitchell S.
Abstract: AIM: Regional utilisation of radical radiotherapy (RT) in non-small cell lung cancer (NSCLC) was used to define optimal utilisation to improve outcome and as a surrogate for evidence of RT efficacy.
PATIENTS & METHODS: 65,412 NSCLC cases diagnosed in England 2012-13 were linked to comprehensive national radiotherapy dataset, hospital admissions and the Office of National Statistics. Geographical variation in utilisation was determined using a multivariate binary logistic regression analysis after adjusting for age, stage, deprivation, comorbidity and other radical treatment and the effect of radical RT utilisation on survival was investigated. Survival was adjusted for dependent and independent variables and the effect of differing levels of utilisation was assessed by the log likelihood test.
RESULTS: 17.6% cases potentially eligible for radical RT (stages 0-III) received radiotherapy with radical intent. Utilisation of radical RT had an impact on survival (p < 0.00001). Adjusting for all prognostic and treatment variables counties with lowest utilisation (≤15%) had the worst survival (HR = 1.13). The highest utilisation quintile counties (≥25%) had worse survival compared to counties with lower utilisation (≈20%) (p < 0.0001). Analysis of stages II&III showed the same pattern; increase in utilisation from 20% to ≥25% resulting in a 3% drop in 2-year population survival (p = 0.001).
CONCLUSION: The utilisation of radical RT has a significant impact on NSCLC population survival. Improvement in survival of NSCLC population can be achieved by offering radical RT to a larger proportion of patients while avoiding excessive use. Geographical variation in RT utilisation provides indirect evidence of survival benefit of radical radiotherapy.
Copyright © 2018 Elsevier B.V. All rights reserved.
KEYWORDS: Big data; Dose fractionation; Non-small cell lung cancer; Radical radiotherapy; Radiotherapy utilisation
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CCC publication: Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer
Citation: Oncoimmunology. 2019, 8(6), e1593810
Author: Hardy-Werbin M, Rocha P, Arpi O, Taus Ã, Nonell L, Durán X, Villanueva X, Joseph-Pietras D, Nolan L, Danson S, Griffiths R, Lopez-Botet M, Rovira A, Albanell J, Ottensmeier C, Arriola E.
Abstract: Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival. Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC.
KEYWORDS: biomarkers; cytokines; immunotherapy; ipilimumab; small cell lung cancer
Link to PubMed record
Author: Hardy-Werbin M, Rocha P, Arpi O, Taus Ã, Nonell L, Durán X, Villanueva X, Joseph-Pietras D, Nolan L, Danson S, Griffiths R, Lopez-Botet M, Rovira A, Albanell J, Ottensmeier C, Arriola E.
Abstract: Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival. Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC.
KEYWORDS: biomarkers; cytokines; immunotherapy; ipilimumab; small cell lung cancer
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CCC publication: Toxicity and Patient-Reported Outcomes of a Phase 2 Randomized Trial of Prostate and Pelvic Lymph Node Versus Prostate only Radiotherapy in Advanced Localised Prostate Cancer (PIVOTAL).
Citation: International Journal of Radiation Oncology, Biology, Physics. 2019, 103(3), 605-17
Author: Dearnaley, David; Griffin, Clare L.; Lewis, Rebecca; Mayles, Philip; Mayles, Helen; Naismith, Olivia F.; Harris, Victoria; Scrase, Christopher D.; Staffurth, John; Syndikus, Isabel; Zarkar, Anjali; Ford, Daniel R.; Rimmer, Yvonne L.; Horan, Gail; Khoo, Vincent; Frew, John; Venkitaraman, Ramachandran; Hall, Emma
Abstract: PURPOSE: To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.
METHODS AND MATERIALS: In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.
RESULTS: One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.
CONCLUSIONS: PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Link to PubMed record
Author: Dearnaley, David; Griffin, Clare L.; Lewis, Rebecca; Mayles, Philip; Mayles, Helen; Naismith, Olivia F.; Harris, Victoria; Scrase, Christopher D.; Staffurth, John; Syndikus, Isabel; Zarkar, Anjali; Ford, Daniel R.; Rimmer, Yvonne L.; Horan, Gail; Khoo, Vincent; Frew, John; Venkitaraman, Ramachandran; Hall, Emma
Abstract: PURPOSE: To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.
METHODS AND MATERIALS: In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.
RESULTS: One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.
CONCLUSIONS: PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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CCC publication: Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT)
Citation: Journal of Clinical Oncology. 2019, 37
Author: Kudo M.; Finn R.S.; Qin S.; Han K.-H.; Ikeda K.; Cheng A.-L.; Piscaglia F.; Ueshima K.; Aikata H.; Vogel A.; Lopez C.; Pracht M.; Meng Z.; Daniele B.; Park J.-W.; Palmer D.H.; Dutcus C.E.; Tamai T.; Saito K.; Lencioni R.
Abstract: Background: In REFLECT, Lenvatinib (LEN) demonstrated treatment effect on overall survival (OS) by statistical confirmation of noninferiority to sorafenib (SOR). OR rates for LEN versus SOR were: 24% versus 9% by investigator review and 41% versus 12% by independent review (Kudo et al 2018). Since the relationship between OR and OS in phase III HCC studies is unclear, we explored the relationship between OR and OS in REFLECT. <br/>Method(s): OR assessed by investigators per mRECIST were used to analyze the association between OR and OS of pts treated with LEN or SOR. The median OS of responders (CR or PR) was compared to that of nonresponders (SD, PD, or UNK/NE) irrespective of treatment. Landmark analyses were performed by OR status at several fixed time points as sensitivity analyses, and the effect on OS was evaluated by Cox regression with OR as a time-dependent covariate, with other prognostic factors. <br/>Result(s): Median OS was 22.4 months for responders and 11.4 months for nonresponders. Hazard ratios (HR) of landmark analyses at 2, 4, and 6 months were 0.75 (95% CI, 0.57-0.98), 0.72 (95% CI, 0.56-0.92), and 0.73 (95% CI, 0.57-0.93). Independent predictors of OS based on unstratified Cox regression are in the table. <br/>Conclusion(s): In REFLECT, OR was an independent predictor of OS in pts with HCC regardless of treatment. The results indicate this correlation is worth further investigation. (Table Presented).
Author: Kudo M.; Finn R.S.; Qin S.; Han K.-H.; Ikeda K.; Cheng A.-L.; Piscaglia F.; Ueshima K.; Aikata H.; Vogel A.; Lopez C.; Pracht M.; Meng Z.; Daniele B.; Park J.-W.; Palmer D.H.; Dutcus C.E.; Tamai T.; Saito K.; Lencioni R.
Abstract: Background: In REFLECT, Lenvatinib (LEN) demonstrated treatment effect on overall survival (OS) by statistical confirmation of noninferiority to sorafenib (SOR). OR rates for LEN versus SOR were: 24% versus 9% by investigator review and 41% versus 12% by independent review (Kudo et al 2018). Since the relationship between OR and OS in phase III HCC studies is unclear, we explored the relationship between OR and OS in REFLECT. <br/>Method(s): OR assessed by investigators per mRECIST were used to analyze the association between OR and OS of pts treated with LEN or SOR. The median OS of responders (CR or PR) was compared to that of nonresponders (SD, PD, or UNK/NE) irrespective of treatment. Landmark analyses were performed by OR status at several fixed time points as sensitivity analyses, and the effect on OS was evaluated by Cox regression with OR as a time-dependent covariate, with other prognostic factors. <br/>Result(s): Median OS was 22.4 months for responders and 11.4 months for nonresponders. Hazard ratios (HR) of landmark analyses at 2, 4, and 6 months were 0.75 (95% CI, 0.57-0.98), 0.72 (95% CI, 0.56-0.92), and 0.73 (95% CI, 0.57-0.93). Independent predictors of OS based on unstratified Cox regression are in the table. <br/>Conclusion(s): In REFLECT, OR was an independent predictor of OS in pts with HCC regardless of treatment. The results indicate this correlation is worth further investigation. (Table Presented).
CCC publication: Real world experience of the medical and surgical management of HER2 positive early breast cancer treated with neoadjuvant trastuzumab and pertuzumab via the NHS England cancer drug fund
Citation: Cancer Research. 2019, 79(4)
Author: Hall B.; Bhojwani A.; Innes H.; Ahmed E.; Cliff J.; Malik Z.; O'Hagan J.; Tolan S.; Hall A.; Hayat K.; Errington D.; Alam F.; Thorp N.; Flint H.; Law A.; Wong H.; O'Reilly S.; Jackson R.; Cicconi S.; Palmieri C.
Abstract: Background: Studies of neoadjuvant (NA) dual HER2 blockade with trastuzumab (T) and pertuzumab (P) in combination with chemotherapy (CT) for early breast cancer (BC) have reported pathological complete response (pCR) rates of 39 to 62%. These studies also report manageable toxicity with diarrhoea reported in up to 73% of cases. To date no real-world studies have explored the efficacy and toxicity of this treatment. The objective of this study was to describe the medical and surgical management of women treated with neoadjuvant T-P in combination with CT (NAT-P-CT). As well as to determine the efficacy toxicity of NAT-P-CT in the context of a routine UK NHS clinical practice. <br/>Method(s): Patients with HER2+ BC treated neoadjuvantly with T-P accessed via the NHS England Cancer Drug Fund (CDF) at the Clatterbridge Cancer Centre NHS Foundation Trust between October 2016 and January 2018 were retrospectively identified. Clinico-pathological information, treatment data, nurse led toxicity review and echocardiographic were reviewed. Data lock was 19th June 2018. <br/>Result(s): 78 female patients were identified with a median age of 50 years (IQR: 44.4-60.2). At diagnosis: median tumour size 30mm (23.0-47.5mm), 62% (48/78) were LN positive & 56% (44/78) ER+. CT regimens: 81% (63/78) FEC-DHP of these 30% (19/63) switched to weekly paclitaxel (wP). or nab-paclitaxel; 5% (4/78); AC/EC-DHP; 9% (8/78) TCHP with 13% (1/8) switched to wP. At time of analysis, 88% (69/78) had undergone definitive surgery. Surgical details: Breast: 52% (36/69) mastectomy & 48% (33/69) WLE, Axillary management: 51% (35/69) axillary dissection (Ax Dx) & 49% (34/69) sentinel node biopsy (4 performed prior to NA treatment). 91% (32/35) of those undergoing Ax Dx were LN+ at presentation, of these 59% (19/32) had no evidence of axillary involvement at surgery. pCR rate (ypTO/is, NO) was 46% (32/69) [pCR by HR: ER+ 43% (21/49) & ER-55% (11/20]. pCR for 20 patients switched to wP was 60% (12/20). 7% (5/69) achieved pCR in the breast alone (in these LN status ITCx1, micrometsx3 & macrometsx1). Of the 54% (37/69) with residual breast tumour median size was 13mm (1-22mm). Toxicity Data: Ejection fraction (EF) did not decline beyond 10% of baseline in any patients. Diarrhoea (any grade) occurred in 74% of cases, and CTCAE grade 3-4 toxicity occurring in >2% of patients: diarrhoea, fatigue, and infection. Updated analysis regarding pCR rate and toxicity, as well as initial outcome data will be presented.
Conclusion(s): These results (1) confirm the efficacy of NA T-P in a real world population; (2) support the use of NA wP; (3) indicate significant proportion of patients axilla are downstaged & (4) reveal diarrhoea rates in keeping with the literature. Currently, NHS England rules do not allow wP to be used routinely in NA setting with T-P this should be reviewed in light of these data and those of the BERENICE study. Measures to identify patients who can avoid axillary dissection as well as to mitigate diarrhoea should be considered.
Author: Hall B.; Bhojwani A.; Innes H.; Ahmed E.; Cliff J.; Malik Z.; O'Hagan J.; Tolan S.; Hall A.; Hayat K.; Errington D.; Alam F.; Thorp N.; Flint H.; Law A.; Wong H.; O'Reilly S.; Jackson R.; Cicconi S.; Palmieri C.
Abstract: Background: Studies of neoadjuvant (NA) dual HER2 blockade with trastuzumab (T) and pertuzumab (P) in combination with chemotherapy (CT) for early breast cancer (BC) have reported pathological complete response (pCR) rates of 39 to 62%. These studies also report manageable toxicity with diarrhoea reported in up to 73% of cases. To date no real-world studies have explored the efficacy and toxicity of this treatment. The objective of this study was to describe the medical and surgical management of women treated with neoadjuvant T-P in combination with CT (NAT-P-CT). As well as to determine the efficacy toxicity of NAT-P-CT in the context of a routine UK NHS clinical practice. <br/>Method(s): Patients with HER2+ BC treated neoadjuvantly with T-P accessed via the NHS England Cancer Drug Fund (CDF) at the Clatterbridge Cancer Centre NHS Foundation Trust between October 2016 and January 2018 were retrospectively identified. Clinico-pathological information, treatment data, nurse led toxicity review and echocardiographic were reviewed. Data lock was 19th June 2018. <br/>Result(s): 78 female patients were identified with a median age of 50 years (IQR: 44.4-60.2). At diagnosis: median tumour size 30mm (23.0-47.5mm), 62% (48/78) were LN positive & 56% (44/78) ER+. CT regimens: 81% (63/78) FEC-DHP of these 30% (19/63) switched to weekly paclitaxel (wP). or nab-paclitaxel; 5% (4/78); AC/EC-DHP; 9% (8/78) TCHP with 13% (1/8) switched to wP. At time of analysis, 88% (69/78) had undergone definitive surgery. Surgical details: Breast: 52% (36/69) mastectomy & 48% (33/69) WLE, Axillary management: 51% (35/69) axillary dissection (Ax Dx) & 49% (34/69) sentinel node biopsy (4 performed prior to NA treatment). 91% (32/35) of those undergoing Ax Dx were LN+ at presentation, of these 59% (19/32) had no evidence of axillary involvement at surgery. pCR rate (ypTO/is, NO) was 46% (32/69) [pCR by HR: ER+ 43% (21/49) & ER-55% (11/20]. pCR for 20 patients switched to wP was 60% (12/20). 7% (5/69) achieved pCR in the breast alone (in these LN status ITCx1, micrometsx3 & macrometsx1). Of the 54% (37/69) with residual breast tumour median size was 13mm (1-22mm). Toxicity Data: Ejection fraction (EF) did not decline beyond 10% of baseline in any patients. Diarrhoea (any grade) occurred in 74% of cases, and CTCAE grade 3-4 toxicity occurring in >2% of patients: diarrhoea, fatigue, and infection. Updated analysis regarding pCR rate and toxicity, as well as initial outcome data will be presented.
Conclusion(s): These results (1) confirm the efficacy of NA T-P in a real world population; (2) support the use of NA wP; (3) indicate significant proportion of patients axilla are downstaged & (4) reveal diarrhoea rates in keeping with the literature. Currently, NHS England rules do not allow wP to be used routinely in NA setting with T-P this should be reviewed in light of these data and those of the BERENICE study. Measures to identify patients who can avoid axillary dissection as well as to mitigate diarrhoea should be considered.
CCC publication: Identification of microRNAs differentially expressed in brain metastasis secondary to breast cancer
Citation: Cancer Research. 2019, 79(4)
Author: Giannoudis A.; Clarke K.; Zakaria R.; Vareslija D.; Farahani M.; Rainbow L.; Platt-Higgins A.; Ruthven S.; Brougham K.; Rudland P.S.; Jenkinson M.D.; Young L.; Falciani F.; Palmieri C.
Abstract: Background: Despite sequential improvements in the adjuvant treatment of breast cancer (BC), recurrence and metastasis remains a major clinical problem and in particular, brain metastasis (BCBM). A number of microRNAs (miRNAs) have been linked to the metastatic process in BC, but to date there is limited work on the microRNAs involved in BCBM. The current study aim to identify differentially expressed miRNAs within primary breast cancer who did not recur (BCNR) versus primary BC cases which did recur (BCR) and their matched BCBM cases.
Method(s): Formalin-fixed paraffin-embedded (FFPE) material was collected of 12 primary BCNRs from the Liverpool tissue bank and of 40 paired primary BCR samples and their matched BCBM from the Walton Research Tissue Bank and RCSI National Breast Cancer Bioresource. miRNA was extracted (Qiagen miRNeasy FFPE kit) and profiled using the NanoStringTM nCounterTM miRNA Expression Assay (Human v3 miRNA). The differentially expressed miRNAs between BCNR versus BCR and BCR versus their matched BCBM were identified by significance of microarray analysis (SAM) on the MeV4.9 software. Pathway analysis was performed using the DIANA-mirPath v3.0 software and the Ingenuity Pathway Analysis (IPA) to identify a network of genes/pathways regulated by the differentially expressed miRNAs.
Result(s): 12 BCNR and 30 matched pairs of BCR and BCBM passed the quality control and normalisation processes. Principal component analysis (PCA) performed on 166 miRNAs after QC/normalisation clearly distinguishes the BCNR and the primary BCR from the matched BCBM cases, whereas SAM revealed 58 differentially expressed miRNAs with a 10% FDR (false discovery rate) and an absolute log2 fold-change (FC) >1 between BCNR and BCR and 11 between the matched BCs and BCBMs. Pathway clustering revealed that these differentially expressed miRNAs (10% FDR, log2FC>1) within both BCNR vs BCR and BCR vs BCBM cohorts are highly enriched for genes involved in extracellular matrix (ECM)-receptor interactions, proteoglycans, adherens junctions, TGF-beta, P53 and Hippo signalling. IPA identified a network of genes, implicated in the processes of breast cancer invasion and metastasis, regulated by the identified miRNAs, such as, TWIST, MET, TP53, MYC, EZH2, ZEB1, TAGLN and BIRC5. Four of the significantly differentially expressed miRNAs, hsa-miR-132-3p, hsa-miR-199a-5p, hsa-miR-150-5p and hsa-miR-155-5p were present within both cohorts (BCNR vs BCR and BCR vs BCBM) and regulate genes involved in Hippo and TGF-beta signalling (DIANA-mirPath v3.0 analysis: p=5.23x10<sup>-08</sup> and p=2.67x10<sup>-07</sup> respectively).
Conclusion(s): The current study, utilising a large cohort of paired BCR and BCBM cases, provides novel insight into the molecular mechanisms and role of miRNAs in BCBM. Four miRNAs (hsa-miR-132-3p, hsa-miR-199a-5p, hsa-miR-150-5p and hsa-miR-155-5p) in particular could be potentially used to identify patients with increased risk of developing brain metastasis and help facilitate the development of specific treatments for BCBM, which to date have proved elusive. The miRNAs identified require further exploration as potential biomarkers as well as novel therapeutic targets.
Author: Giannoudis A.; Clarke K.; Zakaria R.; Vareslija D.; Farahani M.; Rainbow L.; Platt-Higgins A.; Ruthven S.; Brougham K.; Rudland P.S.; Jenkinson M.D.; Young L.; Falciani F.; Palmieri C.
Abstract: Background: Despite sequential improvements in the adjuvant treatment of breast cancer (BC), recurrence and metastasis remains a major clinical problem and in particular, brain metastasis (BCBM). A number of microRNAs (miRNAs) have been linked to the metastatic process in BC, but to date there is limited work on the microRNAs involved in BCBM. The current study aim to identify differentially expressed miRNAs within primary breast cancer who did not recur (BCNR) versus primary BC cases which did recur (BCR) and their matched BCBM cases.
Method(s): Formalin-fixed paraffin-embedded (FFPE) material was collected of 12 primary BCNRs from the Liverpool tissue bank and of 40 paired primary BCR samples and their matched BCBM from the Walton Research Tissue Bank and RCSI National Breast Cancer Bioresource. miRNA was extracted (Qiagen miRNeasy FFPE kit) and profiled using the NanoStringTM nCounterTM miRNA Expression Assay (Human v3 miRNA). The differentially expressed miRNAs between BCNR versus BCR and BCR versus their matched BCBM were identified by significance of microarray analysis (SAM) on the MeV4.9 software. Pathway analysis was performed using the DIANA-mirPath v3.0 software and the Ingenuity Pathway Analysis (IPA) to identify a network of genes/pathways regulated by the differentially expressed miRNAs.
Result(s): 12 BCNR and 30 matched pairs of BCR and BCBM passed the quality control and normalisation processes. Principal component analysis (PCA) performed on 166 miRNAs after QC/normalisation clearly distinguishes the BCNR and the primary BCR from the matched BCBM cases, whereas SAM revealed 58 differentially expressed miRNAs with a 10% FDR (false discovery rate) and an absolute log2 fold-change (FC) >1 between BCNR and BCR and 11 between the matched BCs and BCBMs. Pathway clustering revealed that these differentially expressed miRNAs (10% FDR, log2FC>1) within both BCNR vs BCR and BCR vs BCBM cohorts are highly enriched for genes involved in extracellular matrix (ECM)-receptor interactions, proteoglycans, adherens junctions, TGF-beta, P53 and Hippo signalling. IPA identified a network of genes, implicated in the processes of breast cancer invasion and metastasis, regulated by the identified miRNAs, such as, TWIST, MET, TP53, MYC, EZH2, ZEB1, TAGLN and BIRC5. Four of the significantly differentially expressed miRNAs, hsa-miR-132-3p, hsa-miR-199a-5p, hsa-miR-150-5p and hsa-miR-155-5p were present within both cohorts (BCNR vs BCR and BCR vs BCBM) and regulate genes involved in Hippo and TGF-beta signalling (DIANA-mirPath v3.0 analysis: p=5.23x10<sup>-08</sup> and p=2.67x10<sup>-07</sup> respectively).
Conclusion(s): The current study, utilising a large cohort of paired BCR and BCBM cases, provides novel insight into the molecular mechanisms and role of miRNAs in BCBM. Four miRNAs (hsa-miR-132-3p, hsa-miR-199a-5p, hsa-miR-150-5p and hsa-miR-155-5p) in particular could be potentially used to identify patients with increased risk of developing brain metastasis and help facilitate the development of specific treatments for BCBM, which to date have proved elusive. The miRNAs identified require further exploration as potential biomarkers as well as novel therapeutic targets.
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