Citation: Brachytherapy. 2019, 18(3), S29-30
Author: Stewart A.J.; Myint A.S.
Thursday 27 June 2019
CCC publication: Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity- Modulated Radiotherapy in Prostate Cancer
Citation: Clinical Oncology. 2019 Jun 11 [Epub ahead of print]
Author: Naismith O. (Olivia.naismith@rmh.nhs.uk); Bidmead M.; Khoo V.; Roberts K.; Dearnaley D.; Mayles H.; ClarkC.H.; South C.; Gulliford S.; Hassan S.; Hall E.
Abstract: AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme.
MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire.
RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT.
CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.
Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: CHHiP trial; hypofractionation; prostate cancer; quality assurance; radiotherapy
Link to PubMed record
Author: Naismith O. (Olivia.naismith@rmh.nhs.uk); Bidmead M.; Khoo V.; Roberts K.; Dearnaley D.; Mayles H.; ClarkC.H.; South C.; Gulliford S.; Hassan S.; Hall E.
Abstract: AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme.
MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire.
RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT.
CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.
Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: CHHiP trial; hypofractionation; prostate cancer; quality assurance; radiotherapy
Link to PubMed record
CCC publication: Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response
Citation: Lung Cancer. 2019, 134, 79-84
Author: Haragan A. (Alex.Haragan@nhs.net); Field J.K. (J.K.Field@liverpool.ac.uk); Davies M.P.A.(Michael.Davies@liverpool.ac.uk); Escriu C. (Carles.escriu@nhs.net); Gruver A. (gruver_aaron_m@lilly.com);Gosney J.R. (J.Gosney@rlbuht.nhs.uk)
Author: Haragan A. (Alex.Haragan@nhs.net); Field J.K. (J.K.Field@liverpool.ac.uk); Davies M.P.A.(Michael.Davies@liverpool.ac.uk); Escriu C. (Carles.escriu@nhs.net); Gruver A. (gruver_aaron_m@lilly.com);Gosney J.R. (J.Gosney@rlbuht.nhs.uk)
CCC publication: Assembling the brain trust: the multidisciplinary imperative in neuro-oncology
Citation: Nature reviews. Clinical Oncology. 2019 May 31 [Epub ahead of print]
Author: Ludmir E.B.; Bishop A.J.; Chung C.; Ghia A.J.; Grosshans D.R.; Li J.; McGovern S.L.; Paulino A.C.; Woodhouse K.D.;Yeboa D.N.; McAleer M.F. (mfmcalee@mdanderson.org); Mahajan A.; Brown P.D.; Laack N.N.; Merrell K.W.;Ahern V.; Ajithkumar T.; Horan G.; Alapetite C.; Bernier-Chastagner V.; Bindra R.S.; Bolle S.; Carrie C.; ChalmersA.J.; Chang E.L.; Dieckmann K.; Esiashvili N.; Gandola L.; Gondi V.; Harrabi S.B.; Indelicato D.J.; Jalali R.; JanssensG.O.; Krause M.; Laperriere N.; Laprie A.; Marcus K.J.; Merchant T.E.; Padovani L.; Parkes J.; Schwarz R.; ShihH.A.; Yock T.I.; Souhami L.; Sulman E.P.; Taylor R.E.; Thorp N.; Timmermann B.; Wheeler G.; Wolden S.L.;Kortmann R.-D.
Author: Ludmir E.B.; Bishop A.J.; Chung C.; Ghia A.J.; Grosshans D.R.; Li J.; McGovern S.L.; Paulino A.C.; Woodhouse K.D.;Yeboa D.N.; McAleer M.F. (mfmcalee@mdanderson.org); Mahajan A.; Brown P.D.; Laack N.N.; Merrell K.W.;Ahern V.; Ajithkumar T.; Horan G.; Alapetite C.; Bernier-Chastagner V.; Bindra R.S.; Bolle S.; Carrie C.; ChalmersA.J.; Chang E.L.; Dieckmann K.; Esiashvili N.; Gandola L.; Gondi V.; Harrabi S.B.; Indelicato D.J.; Jalali R.; JanssensG.O.; Krause M.; Laperriere N.; Laprie A.; Marcus K.J.; Merchant T.E.; Padovani L.; Parkes J.; Schwarz R.; ShihH.A.; Yock T.I.; Souhami L.; Sulman E.P.; Taylor R.E.; Thorp N.; Timmermann B.; Wheeler G.; Wolden S.L.;Kortmann R.-D.
CCC publication: Meta-Analysis in Metastatic Uveal Melanoma to Determine Progression-Free and Overall Survival Benchmarks: an International Rare Cancers Initiative (IRCI) Ocular Melanoma study
Citation: Annals of Oncology. 2019 May 31
Author: Khoja L.; Atenafu E.G.; Suciu S.; Leyvraz S.; Sato T.; Marshall E.; Keilholz U.; Zimmer L.; Patel S.P.; Piperno-Neumann S.; Piulats J.; Kivela T.T.; Pfoehler C.; Bhatia S.; Huppert P.; Van Iersel L.B.J.; De Vries I.J.M.; Penel N.;Vogl T.; Cheng T.; Fiorentini G.; Mouriaux F.; Tarhini A.; Patel P.M.; Carvajal R.; Joshua A.M.
Abstract: BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we performed a meta-analysis using individual patient level trial data.
METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000-2016. Univariable and multivariable analysis were performed for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95%CI 2.9 to 3.6) and 6-month PFS rate was 27% (95% CI 24 to 30). Univariable analysis showed male sex, elevated (i.e. > vs ≤ upper limit of normal (ULN)) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm vs < 3cm) to be significantly associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH, and elevated ALP were significantly associated with shorter PFS. The most significant factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5 to 11.0) and 1 year OS was 43% (95% CI 40 to 47). The most significant prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
© The Author 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
KEYWORDS: meta-analysis; survival benchmarks; trial design; uveal melanoma
Link to PubMed record
Author: Khoja L.; Atenafu E.G.; Suciu S.; Leyvraz S.; Sato T.; Marshall E.; Keilholz U.; Zimmer L.; Patel S.P.; Piperno-Neumann S.; Piulats J.; Kivela T.T.; Pfoehler C.; Bhatia S.; Huppert P.; Van Iersel L.B.J.; De Vries I.J.M.; Penel N.;Vogl T.; Cheng T.; Fiorentini G.; Mouriaux F.; Tarhini A.; Patel P.M.; Carvajal R.; Joshua A.M.
Abstract: BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we performed a meta-analysis using individual patient level trial data.
METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000-2016. Univariable and multivariable analysis were performed for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95%CI 2.9 to 3.6) and 6-month PFS rate was 27% (95% CI 24 to 30). Univariable analysis showed male sex, elevated (i.e. > vs ≤ upper limit of normal (ULN)) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm vs < 3cm) to be significantly associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH, and elevated ALP were significantly associated with shorter PFS. The most significant factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5 to 11.0) and 1 year OS was 43% (95% CI 40 to 47). The most significant prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
© The Author 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
KEYWORDS: meta-analysis; survival benchmarks; trial design; uveal melanoma
Link to PubMed record
CCC publication: Observational Study to Assess Quality of Life in Patients with Pancreatic Neuroendocrine Tumors Receiving Treatment with Everolimus: The OBLIQUE Study (UK Phase IV Trial)
Citation: Neuroendocrinology. 2019, 108(4), 317-27
Author: Ramage J.K. (john.ramage@hhft.nhs.uk); Punia P.; Faluyi O.; Frilling A.; Meyer T.; Saharan R.; Valle J.W.
Abstract: BACKGROUND/AIMS: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice.
METHODS: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety.
RESULTS: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference -1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference -8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: -11.5 points [p = 0.001, n = 44] and -8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected.
CONCLUSIONS: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.
© 2019 S. Karger AG, Basel.
KEYWORDS: Everolimus; Health-related quality of life; Pancreatic neuroendocrine tumours; Real-world study
Link to PubMed record
Author: Ramage J.K. (john.ramage@hhft.nhs.uk); Punia P.; Faluyi O.; Frilling A.; Meyer T.; Saharan R.; Valle J.W.
Abstract: BACKGROUND/AIMS: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice.
METHODS: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety.
RESULTS: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference -1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference -8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: -11.5 points [p = 0.001, n = 44] and -8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected.
CONCLUSIONS: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.
© 2019 S. Karger AG, Basel.
KEYWORDS: Everolimus; Health-related quality of life; Pancreatic neuroendocrine tumours; Real-world study
Link to PubMed record
CCC publication: Primary analysis results of the single-arm phase II study of MOR208 plus Lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND)
Citation: Hematological Oncology. 2019. 37. 173-4
Author: Salles, G.; Duell, J.; González Barca, E.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; Andre, M.;Kalakonda, N.; Dreyling, M.; Zinzani, P.L.; Dirnberger-Hertweck, M.; Weirather, J.; Ambarkhane, S.; Maddocks, K.
Author: Salles, G.; Duell, J.; González Barca, E.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; Andre, M.;Kalakonda, N.; Dreyling, M.; Zinzani, P.L.; Dirnberger-Hertweck, M.; Weirather, J.; Ambarkhane, S.; Maddocks, K.
CCC publication: Long term follow-up of FoRT: A phase 3 multi-center prospective randomized trial of radiation therapy for follicular and marginal zone lymphoma
Citation: Hematological Oncology. 2019, 37, 219-20
Author: Hoskin, P.; Kirkwood, A.; Popova, B.; Schofield, O.; Brammer, C.; Robinson, M.; Brunt, M.; Krishnaswamy, M.;Illidge, T.; Gallop-Evans, E.; Syndikus, I.; Clifton-Hadley, L.
Author: Hoskin, P.; Kirkwood, A.; Popova, B.; Schofield, O.; Brammer, C.; Robinson, M.; Brunt, M.; Krishnaswamy, M.;Illidge, T.; Gallop-Evans, E.; Syndikus, I.; Clifton-Hadley, L.
CCC publication: Primary analysis results of the single-arm phase II study of MOR208 plus Lanalidomide in patients with relapsed or refactory diffuse large B-cell lymphoma (L-Mind)
Citation: Hematological Oncology. 2019, 37, 173-4
Author: Salles, G.; Duell, J.; González Barca, E.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; Andre, M.;Kalakonda, N.; Dreyling, M.; Zinzani, P.L.; Dirnberger-Hertweck, M.; Weirather, J.; Ambarkhane, S.; Maddocks, K.
Author: Salles, G.; Duell, J.; González Barca, E.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; Andre, M.;Kalakonda, N.; Dreyling, M.; Zinzani, P.L.; Dirnberger-Hertweck, M.; Weirather, J.; Ambarkhane, S.; Maddocks, K.
CCC publication: Forward- and Inverse-Planned Intensity-Modulated Radiotherapy in the CHHiP Trial: A Comparison of Dosimetry and Normal Tissue Toxicity
Citation: Clinical Oncology. 2019 Jun 6 [Epub ahead of print]
Author: Naismith OF, Griffin C, Syndikus I, South C, Mayles H, Mayles P, Khoo V, Scrase C, Graham J, Hassan S, Hall E, Dearnaley DP; CHHiP Investigators
Abstract: AIMS: The CHHiP (Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy In Prostate Cancer; CRUK/06/016) trial investigated hypofractionated radiotherapy for localised prostate cancer. Forward- (FP) or inverse-planned (IP) intensity-modulated techniques were permitted. Dose-volume histogram and toxicity data were compared to explore the effects of planning method.
MATERIALS AND METHODS: In total, 337 participants with intermediate-risk disease and prospectively collected toxicity data were included. Patients were matched on prostate and rectum/bladder volumes and on radiotherapy dose for toxicity comparisons. The primary outcome was grade 2 or higher Radiation Therapy Oncology Group (RTOG) bowel or bladder toxicity at 2 years.
RESULTS: IP patients had smaller volumes of rectum irradiated to 50-70 Gy (P < 0.001); FP patients had smaller volumes of bladder irradiated to 74 Gy (P = 0.001). Acute grade 2 + bowel toxicity was worse with FP (27/53 [52%]; 11/53 [21%] IP; P = 0.0002); with no significant differences in acute urinary toxicity. At 2 years, RTOG grade 2 + bowel toxicity rates were FP 0/53 and IP 2/53 and RTOG grade 2 + bladder rates were FP 0/54 and IP 1/57.
CONCLUSIONS: Significant differences were found between dose-volume histograms from FP and IP methods. IP may result in small reductions in acute bowel toxicity but both techniques were associated with low rates of late radiotherapy side-effects.
Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: DVH; forward planning; intensity-modulated radiotherapy; inverse planning; prostate cancer; toxicity
Link to PubMed record
Author: Naismith OF, Griffin C, Syndikus I, South C, Mayles H, Mayles P, Khoo V, Scrase C, Graham J, Hassan S, Hall E, Dearnaley DP; CHHiP Investigators
Abstract: AIMS: The CHHiP (Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy In Prostate Cancer; CRUK/06/016) trial investigated hypofractionated radiotherapy for localised prostate cancer. Forward- (FP) or inverse-planned (IP) intensity-modulated techniques were permitted. Dose-volume histogram and toxicity data were compared to explore the effects of planning method.
MATERIALS AND METHODS: In total, 337 participants with intermediate-risk disease and prospectively collected toxicity data were included. Patients were matched on prostate and rectum/bladder volumes and on radiotherapy dose for toxicity comparisons. The primary outcome was grade 2 or higher Radiation Therapy Oncology Group (RTOG) bowel or bladder toxicity at 2 years.
RESULTS: IP patients had smaller volumes of rectum irradiated to 50-70 Gy (P < 0.001); FP patients had smaller volumes of bladder irradiated to 74 Gy (P = 0.001). Acute grade 2 + bowel toxicity was worse with FP (27/53 [52%]; 11/53 [21%] IP; P = 0.0002); with no significant differences in acute urinary toxicity. At 2 years, RTOG grade 2 + bowel toxicity rates were FP 0/53 and IP 2/53 and RTOG grade 2 + bladder rates were FP 0/54 and IP 1/57.
CONCLUSIONS: Significant differences were found between dose-volume histograms from FP and IP methods. IP may result in small reductions in acute bowel toxicity but both techniques were associated with low rates of late radiotherapy side-effects.
Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: DVH; forward planning; intensity-modulated radiotherapy; inverse planning; prostate cancer; toxicity
Link to PubMed record
CCC publication: Serious illness care Programme UK: assessing the 'face validity', applicability and relevance of the serious illness conversation guide for use within the UK health care setting
Citation: BMC Health Services Research. 2019, 19(1), 384
Author: McGlinchey T, Mason S, Coackley A, Roberts A, Maguire M, Sanders J, Maloney F, Block S, Ellershaw J, Kirkbride P
Abstract: BACKGROUND: When doctors have honest conversations with patients about their illness and involve them in decisions about their care, patients express greater satisfaction with care and lowered anxiety and depression. The Serious Illness Care Programme (the Programme), originally developed in the United States (U.S), promotes meaningful, realistic and focused conversations about patient's wishes, fears and worries for the future with their illness. The Serious Illness Conversation Guide (the guide) provides a framework to structure these conversations. The aim of this paper is to present findings from a study to examine the 'face validity', acceptability and relevance of the Guide for use within the United Kingdom (UK) health care setting.
METHODS: A multi-stage approach was undertaken, using three separate techniques: 1. Nominal Group Technique with clinician 'expert groups' to review the Serious Illness Conversation Guide: 14 'experts' in Oncology, Palliative Care and Communication Skills; 2. Cognitive Interviews with 6 patient and public representatives, using the 'think aloud technique'; to explore the cognitive processes involved in answering the questions in the guide, including appropriateness of language, question wording and format 3. Final stakeholder review and consensus.
RESULTS: Nominal Group Technique Unanimous agreement the conversation guide could provide a useful support to clinicians. Amendments are required but should be informed directly from the cognitive interviews. Training highlighted as key to underpin the use of the guide. Cognitive interviews The 'holistic' attention to the person as a whole was valued rather than a narrow focus on their disease. Some concern was raised regarding the 'formality' of some wording however and suggestions for amendments were made. Final stakeholder review Stakeholders agreed amendments to 5/13 prompts and unanimously agreed the UK guide should be implemented as a part of the pilot implementation of the Serious Illness Care Programme UK.
CONCLUSION: Use of the guide has the potential to benefit patients, facilitating a 'person-centred' approach to these important conversations, and providing a framework to promote shared decision making and care planning. Further research is ongoing, to understand the impact of these conversations on patients, families and clinicians and on concordance of care delivery with expressed patient wishes.
KEYWORDS: Care planning; Communication; Intervention; Person Centred; Serious illness
Link to PubMed record
Author: McGlinchey T, Mason S, Coackley A, Roberts A, Maguire M, Sanders J, Maloney F, Block S, Ellershaw J, Kirkbride P
Abstract: BACKGROUND: When doctors have honest conversations with patients about their illness and involve them in decisions about their care, patients express greater satisfaction with care and lowered anxiety and depression. The Serious Illness Care Programme (the Programme), originally developed in the United States (U.S), promotes meaningful, realistic and focused conversations about patient's wishes, fears and worries for the future with their illness. The Serious Illness Conversation Guide (the guide) provides a framework to structure these conversations. The aim of this paper is to present findings from a study to examine the 'face validity', acceptability and relevance of the Guide for use within the United Kingdom (UK) health care setting.
METHODS: A multi-stage approach was undertaken, using three separate techniques: 1. Nominal Group Technique with clinician 'expert groups' to review the Serious Illness Conversation Guide: 14 'experts' in Oncology, Palliative Care and Communication Skills; 2. Cognitive Interviews with 6 patient and public representatives, using the 'think aloud technique'; to explore the cognitive processes involved in answering the questions in the guide, including appropriateness of language, question wording and format 3. Final stakeholder review and consensus.
RESULTS: Nominal Group Technique Unanimous agreement the conversation guide could provide a useful support to clinicians. Amendments are required but should be informed directly from the cognitive interviews. Training highlighted as key to underpin the use of the guide. Cognitive interviews The 'holistic' attention to the person as a whole was valued rather than a narrow focus on their disease. Some concern was raised regarding the 'formality' of some wording however and suggestions for amendments were made. Final stakeholder review Stakeholders agreed amendments to 5/13 prompts and unanimously agreed the UK guide should be implemented as a part of the pilot implementation of the Serious Illness Care Programme UK.
CONCLUSION: Use of the guide has the potential to benefit patients, facilitating a 'person-centred' approach to these important conversations, and providing a framework to promote shared decision making and care planning. Further research is ongoing, to understand the impact of these conversations on patients, families and clinicians and on concordance of care delivery with expressed patient wishes.
KEYWORDS: Care planning; Communication; Intervention; Person Centred; Serious illness
Link to PubMed record
CCC publication: Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity-Modulated Radiotherapy in Prostate Cancer
Citation: Clinical Oncology. 2019 Jun 11 [Epub ahead of print]
Author: Naismith O, Mayles H, Bidmead M, Clark CH, Gulliford S, Hassan S, Khoo V, Roberts K, South C, Hall E, Dearnaley D; CHHiP Investigators
Abstract: AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme.
MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire.
RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT.
CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.
Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: CHHiP trial; hypofractionation; prostate cancer; quality assurance; radiotherapy
Link to PubMed record
Author: Naismith O, Mayles H, Bidmead M, Clark CH, Gulliford S, Hassan S, Khoo V, Roberts K, South C, Hall E, Dearnaley D; CHHiP Investigators
Abstract: AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme.
MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire.
RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT.
CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.
Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: CHHiP trial; hypofractionation; prostate cancer; quality assurance; radiotherapy
Link to PubMed record
CCC publication: Transanal endoscopic microsurgery for rectal lesions in a specialist regional early rectal Cancer Centre - the Mersey experience
Citation: Colorectal Disease. 2019 Jun 17 [Epub ahead of print]
Author: Ondhia M, Tamvakeras P, O'Toole P, Montazerri A, Andrews T, Farrell C, Ahmed S, Slawik S, Ahmed S; Merseyside Early Rectal Cancer Network
Abstract: BACKGROUND: Organ-preserving local excision (LE) by transanal endoscopic microsurgery (TEM) for early rectal cancer offers significantly less morbidity with acceptable oncological outcomes. This study presents our 6-year experience of TEM for rectal lesions referred to a specialist early rectal cancer centre in the UK.
METHODS: Data were collected for all patients referred for Transanal Endoscopic Microsurgery (TEM) of suspected early rectal cancer at a regional Specialist Early Rectal Cancer MDT over a 6-year period.
RESULTS: 141 patients who underwent full thickness TEM for suspected or confirmed early rectal cancer were included. 30 patients were referred for TEM following incomplete endoscopic polypectomy. Final pathology was benign in 77 (54.6%) cases and malignant in 64 (45.4%). Of the 61 confirmed adenocarcinomas, TEM resections were pT0 in 17 (27.9%); 32 (51.7%) pT1; 11 (18.0%) pT2 and 1 (1.6%) pT3. 3861 (62.3%) had ≥1 poor histological prognostic feature and these patients were offered further treatment. 23/61 (37.7%) patients with rectal adenocarcinoma required no further treatment following TEM. 43 cases of rectal adenocarcinoma were available for establishing recurrence rates. 2/43 patients (4.7%) developed a recurrence in a median follow-up of 28.7 months (12.1-66.5 months). The overall estimated five-year overall survival rate was 87.9% and the disease-free survival rate was 82.9%.
CONCLUSION: Acceptable outcomes are possible for TEM surgery with appropriate patient selection, effective technique, expert histopathology, appropriate referral for adjuvant treatment and meticulous follow-up. This can be achieved through an early rectal cancer MDT in a dedicated specialist regional centre This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS: Early rectal cancer; Local excision rectal cancer
Link to PubMed record
Author: Ondhia M, Tamvakeras P, O'Toole P, Montazerri A, Andrews T, Farrell C, Ahmed S, Slawik S, Ahmed S; Merseyside Early Rectal Cancer Network
Abstract: BACKGROUND: Organ-preserving local excision (LE) by transanal endoscopic microsurgery (TEM) for early rectal cancer offers significantly less morbidity with acceptable oncological outcomes. This study presents our 6-year experience of TEM for rectal lesions referred to a specialist early rectal cancer centre in the UK.
METHODS: Data were collected for all patients referred for Transanal Endoscopic Microsurgery (TEM) of suspected early rectal cancer at a regional Specialist Early Rectal Cancer MDT over a 6-year period.
RESULTS: 141 patients who underwent full thickness TEM for suspected or confirmed early rectal cancer were included. 30 patients were referred for TEM following incomplete endoscopic polypectomy. Final pathology was benign in 77 (54.6%) cases and malignant in 64 (45.4%). Of the 61 confirmed adenocarcinomas, TEM resections were pT0 in 17 (27.9%); 32 (51.7%) pT1; 11 (18.0%) pT2 and 1 (1.6%) pT3. 3861 (62.3%) had ≥1 poor histological prognostic feature and these patients were offered further treatment. 23/61 (37.7%) patients with rectal adenocarcinoma required no further treatment following TEM. 43 cases of rectal adenocarcinoma were available for establishing recurrence rates. 2/43 patients (4.7%) developed a recurrence in a median follow-up of 28.7 months (12.1-66.5 months). The overall estimated five-year overall survival rate was 87.9% and the disease-free survival rate was 82.9%.
CONCLUSION: Acceptable outcomes are possible for TEM surgery with appropriate patient selection, effective technique, expert histopathology, appropriate referral for adjuvant treatment and meticulous follow-up. This can be achieved through an early rectal cancer MDT in a dedicated specialist regional centre This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS: Early rectal cancer; Local excision rectal cancer
Link to PubMed record
CCC publication: Safety and Efficacy of the Addition of Lapatinib to Perioperative Chemotherapy for Resectable HER2-Positive Gastroesophageal Adenocarcinoma: A Randomized Phase 2 Clinical Trial.
Citation: JAMA Oncology. 2019 Jun 20 [Epub ahead of print]
Author: Smyth EC, Rowley S, Cafferty FH, Allum W, Grabsch HI, Stenning S, Wotherspoon A, Alderson D, Crosby T, Mansoor W, Waters JS, Neville-Webbe H, Darby S, Dent J, Seymour M, Thompson J, Sothi S, Blazeby J, Langley RE, Cunningham D
Abstract: Importance: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed.
Objectives: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial.
Design, Setting, and Participants: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017.
Interventions: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients.
Main Outcomes and Measures: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned.
Results: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm.
Conclusions and Relevance: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management.
Trial Registration: ISRCTN.org identifier: 46020948; clinicaltrialsregister.eu identifier: 2006-000811-12.
Link to PubMed record
Author: Smyth EC, Rowley S, Cafferty FH, Allum W, Grabsch HI, Stenning S, Wotherspoon A, Alderson D, Crosby T, Mansoor W, Waters JS, Neville-Webbe H, Darby S, Dent J, Seymour M, Thompson J, Sothi S, Blazeby J, Langley RE, Cunningham D
Abstract: Importance: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed.
Objectives: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial.
Design, Setting, and Participants: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017.
Interventions: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients.
Main Outcomes and Measures: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned.
Results: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm.
Conclusions and Relevance: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management.
Trial Registration: ISRCTN.org identifier: 46020948; clinicaltrialsregister.eu identifier: 2006-000811-12.
Link to PubMed record
Tuesday 18 June 2019
WUTH publication: Legal, regulatory, and ethical frameworks for development of standards in artificial intelligence (AI) and autonomous robotic surgery
Citation: The international journal of medical robotics and computer assisted surgery. 2019, 15(1), e1968
Author: O'Sullivan S, Nevejans N, Allen C, Blyth A, Leonard S, Pagallo U, Holzinger K, Holzinger A, Sajid MI, Ashrafian H
Abstract: BACKGROUND: This paper aims to move the debate forward regarding the potential for artificial intelligence (AI) and autonomous robotic surgery with a particular focus on ethics, regulation and legal aspects (such as civil law, international law, tort law, liability, medical malpractice, privacy and product/device legislation, among other aspects).
METHODS: We conducted an intensive literature search on current or emerging AI and autonomous technologies (eg, vehicles), military and medical technologies (eg, surgical robots), relevant frameworks and standards, cyber security/safety- and legal-systems worldwide. We provide a discussion on unique challenges for robotic surgery faced by proposals made for AI more generally (eg, Explainable AI) and machine learning more specifically (eg, black box), as well as recommendations for developing and improving relevant frameworks or standards.
CONCLUSION: We classify responsibility into the following: (1) Accountability; (2) Liability; and (3) Culpability. All three aspects were addressed when discussing responsibility for AI and autonomous surgical robots, be these civil or military patients (however, these aspects may require revision in cases where robots become citizens). The component which produces the least clarity is Culpability, since it is unthinkable in the current state of technology. We envision that in the near future a surgical robot can learn and perform routine operative tasks that can then be supervised by a human surgeon. This represents a surgical parallel to autonomously driven vehicles. Here a human remains in the 'driving seat' as a 'doctor-in-the-loop' thereby safeguarding patients undergoing operations that are supported by surgical machines with autonomous capabilities.
Link to PubMed record
Author: O'Sullivan S, Nevejans N, Allen C, Blyth A, Leonard S, Pagallo U, Holzinger K, Holzinger A, Sajid MI, Ashrafian H
Abstract: BACKGROUND: This paper aims to move the debate forward regarding the potential for artificial intelligence (AI) and autonomous robotic surgery with a particular focus on ethics, regulation and legal aspects (such as civil law, international law, tort law, liability, medical malpractice, privacy and product/device legislation, among other aspects).
METHODS: We conducted an intensive literature search on current or emerging AI and autonomous technologies (eg, vehicles), military and medical technologies (eg, surgical robots), relevant frameworks and standards, cyber security/safety- and legal-systems worldwide. We provide a discussion on unique challenges for robotic surgery faced by proposals made for AI more generally (eg, Explainable AI) and machine learning more specifically (eg, black box), as well as recommendations for developing and improving relevant frameworks or standards.
CONCLUSION: We classify responsibility into the following: (1) Accountability; (2) Liability; and (3) Culpability. All three aspects were addressed when discussing responsibility for AI and autonomous surgical robots, be these civil or military patients (however, these aspects may require revision in cases where robots become citizens). The component which produces the least clarity is Culpability, since it is unthinkable in the current state of technology. We envision that in the near future a surgical robot can learn and perform routine operative tasks that can then be supervised by a human surgeon. This represents a surgical parallel to autonomously driven vehicles. Here a human remains in the 'driving seat' as a 'doctor-in-the-loop' thereby safeguarding patients undergoing operations that are supported by surgical machines with autonomous capabilities.
Link to PubMed record
Wednesday 5 June 2019
CCC publication: A systematic review comparing radiation toxicity after various endorectal techniques.
Citation: Brachytherapy. 2019, 18(1), 71-86. Erratum in: Brachytherapy. 2019, 18(3), 427
Author: Verrijssen AS, Opbroek T, Bellezzo M, Fonseca GP, Verhaegen F, Gerard JP, Sun Myint A, Van Limbergen EJ, Berbee M.
Abstract: PURPOSE: A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%-20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer.
METHODS AND MATERIALS/RESULTS: Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. ≥ Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient.
CONCLUSION: All techniques reported some ≥ Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting.
Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
KEYWORDS: Contact therapy; Endorectal brachytherapy; HDR; LDR; Rectal cancer; Toxicity
Link to PubMed record
Author: Verrijssen AS, Opbroek T, Bellezzo M, Fonseca GP, Verhaegen F, Gerard JP, Sun Myint A, Van Limbergen EJ, Berbee M.
Abstract: PURPOSE: A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%-20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer.
METHODS AND MATERIALS/RESULTS: Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. ≥ Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient.
CONCLUSION: All techniques reported some ≥ Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting.
Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
KEYWORDS: Contact therapy; Endorectal brachytherapy; HDR; LDR; Rectal cancer; Toxicity
Link to PubMed record
CCC publication: PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa)
Citation: Journal of Clinical Oncology. 2019, 37
Author: Van As N.J.; Brand D.; Tree A.; Ostler P.J.; Chu W.; Loblaw A.; Ford D.; Tolan S.P.; Jain S.; Martin A.S.; Staffurth J.; Brown S.; Burnett S.M.; Duffton A.; Griffin C.; Hinder V.; Morrison K.; Naismith O.F.; Hall E.
Abstract: Background: External beam radiotherapy (EBRT) is a curative treatment for LPCa. Large randomised controlled trials (RCTs) have shown moderately hypofractionated regimens (2.5-3 Gy/fraction(f)) as non-inferior to conventionally fractionated regimens (2 Gy/f). PACE-B aims to demonstrate non-inferiority of SBRT compared to CFMHRT for biochemical or clinical failure. Compared to CFMHRT, SBRT reduces patient (pt) attendances but compressed overall treatment time may influence acute toxicity severity. <br/>Method(s): PACE is a phase III open-label multiple-cohort RCT. Men with LPCa, stage T1-T2, <= Gleason 3 + 4, PSA <= 20 ng/mL, unsuitable for surgery or preferring EBRT, were eligible for the PACE-B cohort. Between 08/12-01/18, 874 pts (38 centres) were randomised (1:1) to SBRT or CFMHRT. SBRT dose was 36.25 Gy/5f in 1-2 weeks (wks), CFMHRT as 78 Gy/39f over 7.5 wks, or 62 Gy/20f in 4 wks. Androgen deprivation therapy was not permitted. Clinician reported acute toxicity was assessed at baseline, 2-weekly during CFMHRT and at 2, 4, 8 & 12 wks post-treatment. Key toxicity outcomes were worst grade 2+ Radiation Therapy Oncology Group (RTOG) genitourinary (GU) and gastrointestinal (GI) acute toxicities, compared by Chi-square test with alpha 0.05 divided between the two measures. <br/>Result(s): By per protocol analysis n=430 received CFMHRT, n=414 received SBRT. Key characteristics seen in the CFMHRT and SBRT groups respectively were: mean age: 69.5 vs 69.3 years; T-stage >=T2b: 51.8% vs 56.6%; Gleason Score 3+4: 80.2% vs 85.0%; PSA 10-20 ng/mL: 30.9% vs 31.6%. RTOG G2+ toxicity was not significantly different for GI events (CMFHRT 52/430 (12.1%) vs SBRT 42/414 (10.1%), p=0.368), nor GU events (CFMHRT 117/430 (27.2%) vs SBRT 96/414 (23.2%), p=0.179). <br/>Conclusion(s): Despite an accelerated treatment schedule, RTOG assessments show similar rates of acute GI and GU toxicity for SBRT and CFHFRT. Pt follow-up in PACE-B continues and results of late toxicity and biochemical/clinical failure are awaited.
Author: Van As N.J.; Brand D.; Tree A.; Ostler P.J.; Chu W.; Loblaw A.; Ford D.; Tolan S.P.; Jain S.; Martin A.S.; Staffurth J.; Brown S.; Burnett S.M.; Duffton A.; Griffin C.; Hinder V.; Morrison K.; Naismith O.F.; Hall E.
Abstract: Background: External beam radiotherapy (EBRT) is a curative treatment for LPCa. Large randomised controlled trials (RCTs) have shown moderately hypofractionated regimens (2.5-3 Gy/fraction(f)) as non-inferior to conventionally fractionated regimens (2 Gy/f). PACE-B aims to demonstrate non-inferiority of SBRT compared to CFMHRT for biochemical or clinical failure. Compared to CFMHRT, SBRT reduces patient (pt) attendances but compressed overall treatment time may influence acute toxicity severity. <br/>Method(s): PACE is a phase III open-label multiple-cohort RCT. Men with LPCa, stage T1-T2, <= Gleason 3 + 4, PSA <= 20 ng/mL, unsuitable for surgery or preferring EBRT, were eligible for the PACE-B cohort. Between 08/12-01/18, 874 pts (38 centres) were randomised (1:1) to SBRT or CFMHRT. SBRT dose was 36.25 Gy/5f in 1-2 weeks (wks), CFMHRT as 78 Gy/39f over 7.5 wks, or 62 Gy/20f in 4 wks. Androgen deprivation therapy was not permitted. Clinician reported acute toxicity was assessed at baseline, 2-weekly during CFMHRT and at 2, 4, 8 & 12 wks post-treatment. Key toxicity outcomes were worst grade 2+ Radiation Therapy Oncology Group (RTOG) genitourinary (GU) and gastrointestinal (GI) acute toxicities, compared by Chi-square test with alpha 0.05 divided between the two measures. <br/>Result(s): By per protocol analysis n=430 received CFMHRT, n=414 received SBRT. Key characteristics seen in the CFMHRT and SBRT groups respectively were: mean age: 69.5 vs 69.3 years; T-stage >=T2b: 51.8% vs 56.6%; Gleason Score 3+4: 80.2% vs 85.0%; PSA 10-20 ng/mL: 30.9% vs 31.6%. RTOG G2+ toxicity was not significantly different for GI events (CMFHRT 52/430 (12.1%) vs SBRT 42/414 (10.1%), p=0.368), nor GU events (CFMHRT 117/430 (27.2%) vs SBRT 96/414 (23.2%), p=0.179). <br/>Conclusion(s): Despite an accelerated treatment schedule, RTOG assessments show similar rates of acute GI and GU toxicity for SBRT and CFHFRT. Pt follow-up in PACE-B continues and results of late toxicity and biochemical/clinical failure are awaited.
CCC publication: Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers,
Citation: European Urology Oncology. 2020, 3(5), 671-79. Epub 2019 Jan 31
Author: Nieves Martinez Chanza, Lillian Werner, Elizabeth Plimack, Evan Y. Yu, Ajjai S. Alva, Simon J. Crabb, Thomas Powles, Jonathan E. Rosenberg, Jack Baniel, Ulka N. Vaishampayan, Dominik R. Berthold, Sylvain Ladoire, Syed A. Hussain, Matthew I. Milowsky, Neeraj Agarwal, Andrea Necchi, Sumanta K. Pal, Cora N. Sternberg, Joaquim Bellmunt, Matthew D. Galsky, Lauren C. Harshman,
Abstract: Abstract: Background. Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence. Objective: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC. Design, setting, and participants: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN+). Outcome measurements and statistical analysis: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses. Results and limitations: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1–108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN+ patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21–0.89). No difference in OS was found. Limitations include the retrospective design. Conclusions: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials. Patient summary: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system. Keywords: Adjuvant chemotherapy; Muscle-invasive bladder cancer; Muscle-invasive urinary tract cancer; Neoadjuvant chemotherapy; Residual disease; Risk of relapse; Time to recurrence
Author: Nieves Martinez Chanza, Lillian Werner, Elizabeth Plimack, Evan Y. Yu, Ajjai S. Alva, Simon J. Crabb, Thomas Powles, Jonathan E. Rosenberg, Jack Baniel, Ulka N. Vaishampayan, Dominik R. Berthold, Sylvain Ladoire, Syed A. Hussain, Matthew I. Milowsky, Neeraj Agarwal, Andrea Necchi, Sumanta K. Pal, Cora N. Sternberg, Joaquim Bellmunt, Matthew D. Galsky, Lauren C. Harshman,
Abstract: Abstract: Background. Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence. Objective: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC. Design, setting, and participants: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN+). Outcome measurements and statistical analysis: Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses. Results and limitations: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1–108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN+ patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21–0.89). No difference in OS was found. Limitations include the retrospective design. Conclusions: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials. Patient summary: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system. Keywords: Adjuvant chemotherapy; Muscle-invasive bladder cancer; Muscle-invasive urinary tract cancer; Neoadjuvant chemotherapy; Residual disease; Risk of relapse; Time to recurrence
CCC publication: Ambulatory management in low risk neutropenic sepsis - A plea for integrated acute cancer care
Citation: Acute Medicine. 2019, 18(1), 6-7
Author: Marshall E.
Author: Marshall E.
CCC publication: Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)–Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study,
Citation: Journal of Thoracic Oncology. 2019
Author: Byoung Chul Cho, Radka Obermannova, Alessandra Bearz, Mark McKeage, Dong-Wang Kim, Ullas Batra, Gloria Borra, Sergey Orlov, Sang-We Kim, Sarayut L. Geater, Pieter E. Postmus, Scott A. Laurie, Keunchil Park, Cheng-Ta Yang, Andrea Ardizzoni, Anna C. Bettini, Gilberto de Castro, Flavia Kiertsman, Zhe Chen, Yvonne Y. Lau, Kalyanee Viraswami-Appanna, Vanessa Q. Passos, Rafal Dziadziuszko,
Abstract: INTRODUCTION: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.
METHODS: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1.
RESULTS: In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%).
CONCLUSION: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
KEYWORDS: ALK receptor tyrosine kinase; Ceritinib; Food effect; NSCLC
Link to PubMed record
Author: Byoung Chul Cho, Radka Obermannova, Alessandra Bearz, Mark McKeage, Dong-Wang Kim, Ullas Batra, Gloria Borra, Sergey Orlov, Sang-We Kim, Sarayut L. Geater, Pieter E. Postmus, Scott A. Laurie, Keunchil Park, Cheng-Ta Yang, Andrea Ardizzoni, Anna C. Bettini, Gilberto de Castro, Flavia Kiertsman, Zhe Chen, Yvonne Y. Lau, Kalyanee Viraswami-Appanna, Vanessa Q. Passos, Rafal Dziadziuszko,
Abstract: INTRODUCTION: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.
METHODS: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1.
RESULTS: In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%).
CONCLUSION: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
KEYWORDS: ALK receptor tyrosine kinase; Ceritinib; Food effect; NSCLC
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CCC publication: Corrigendum to A systematic review comparing radiation toxicity after various endorectal techniques
Citation: Brachytherapy. 2019, 18(3), 427
Author: Verrijssen A.-S. (averrijssen@gmail.com); Bellezzo M.; Fonseca G.P.; Verhaegen F.; Van Limbergen E.J.; Berbee M.; Opbroek T.; Gerard J.-P.; Myint A.S.
Abstract: Erratum for
A systematic review comparing radiation toxicity after various endorectal techniques. [Brachytherapy. 2019]
The authors regret to rectify the below mentioned errors that were noted in their published article. On page 83, in the last sentence in the first complete paragraph: the authors would like to add the phrase "in the 8 Gy group" to the end of the sentence "The dose limiting-toxicity was set at 7 Gy after 3 of 10 patients (30%)experienced acute Grade 3 radiation proctitis" In Table 1 in the column "RT Dose (Gy)" for Rijkmans et al 2017 (46)it says "EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 1 fx)". The "1 fx" at the end should be "3 fx." The new statement should read " EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 3 fx)". The same typing error was made in Supplemental Table 2 in the column "RT Dose (Gy)" for Rijkmans et al 2017 (46)where it says "EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 1 fr)". The "1 fr" at the end should be "3 fx." The new statement should read " EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 3 fx)". Also, in the next column the calculation for Rijkmans et al was made for 1 fraction brachytherapy dose instead of 3 fractions, and the corrected calculation should therefore read: "47 Gy + (24 - 54 Gy boost)= 71 - 100 Gy.<br/>Copyright © 2019 American Brachytherapy Society
Link to PubMed record
Author: Verrijssen A.-S. (averrijssen@gmail.com); Bellezzo M.; Fonseca G.P.; Verhaegen F.; Van Limbergen E.J.; Berbee M.; Opbroek T.; Gerard J.-P.; Myint A.S.
Abstract: Erratum for
A systematic review comparing radiation toxicity after various endorectal techniques. [Brachytherapy. 2019]
The authors regret to rectify the below mentioned errors that were noted in their published article. On page 83, in the last sentence in the first complete paragraph: the authors would like to add the phrase "in the 8 Gy group" to the end of the sentence "The dose limiting-toxicity was set at 7 Gy after 3 of 10 patients (30%)experienced acute Grade 3 radiation proctitis" In Table 1 in the column "RT Dose (Gy)" for Rijkmans et al 2017 (46)it says "EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 1 fx)". The "1 fx" at the end should be "3 fx." The new statement should read " EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 3 fx)". The same typing error was made in Supplemental Table 2 in the column "RT Dose (Gy)" for Rijkmans et al 2017 (46)where it says "EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 1 fr)". The "1 fr" at the end should be "3 fx." The new statement should read " EBRT (39 Gy/13 fx)+ HDR BT (5-8 Gy / 3 fx)". Also, in the next column the calculation for Rijkmans et al was made for 1 fraction brachytherapy dose instead of 3 fractions, and the corrected calculation should therefore read: "47 Gy + (24 - 54 Gy boost)= 71 - 100 Gy.<br/>Copyright © 2019 American Brachytherapy Society
Link to PubMed record
CCC publication: Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)-PathIES
Citation: Breast Cancer Research and Treatment. 2019, 175(1), 149-63
Author: Szijgyarto Z. (Zsolt.Szijgyarto@icr.ac.uk); Bliss J.M. (Judith.Bliss@icr.ac.uk); Cheang M.C.U. (Maggie.Cheang@icr.ac.uk); Flach K.D. (k.flach@nki.nl); Zwart W. (w.zwart@nki.nl); Opdam M. (m.opdam@nki.nl); Linn S.C. (s.linn@nki.nl); Wesseling J. (j.wesseling@nki.nl); Palmieri C. (C.Palmieri@liverpool.ac.uk); Ali S. (simak.ali@imperial.ac.uk); Coombes R.C. (c.coombes@imperial.ac.uk)
Abstract: PURPOSE: The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES).
METHODS: Of the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini-Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (pBH).
RESULTS: Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (pBH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (pBH > 0.05 for all).
CONCLUSIONS: This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.
KEYWORDS: Aromatase; Biomarkers; Breast cancer; Prognosis; Tamoxifen
Link to PubMed record
Author: Szijgyarto Z. (Zsolt.Szijgyarto@icr.ac.uk); Bliss J.M. (Judith.Bliss@icr.ac.uk); Cheang M.C.U. (Maggie.Cheang@icr.ac.uk); Flach K.D. (k.flach@nki.nl); Zwart W. (w.zwart@nki.nl); Opdam M. (m.opdam@nki.nl); Linn S.C. (s.linn@nki.nl); Wesseling J. (j.wesseling@nki.nl); Palmieri C. (C.Palmieri@liverpool.ac.uk); Ali S. (simak.ali@imperial.ac.uk); Coombes R.C. (c.coombes@imperial.ac.uk)
Abstract: PURPOSE: The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES).
METHODS: Of the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini-Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (pBH).
RESULTS: Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (pBH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (pBH > 0.05 for all).
CONCLUSIONS: This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.
KEYWORDS: Aromatase; Biomarkers; Breast cancer; Prognosis; Tamoxifen
Link to PubMed record
CCC publication: Pharmacodynamic and clinical results from a phase 1/2 study of the HSP90 inhibitor onalespib in combination with abiraterone acetate in prostate cancer.
Citation: Clin Cancer Res. 2019 May 21 [Epub ahead of print]
Author: Slovin SF, Hussain S, Saad F, Garcia JA, Picus J, Ferraldeschi R, Crespo M, Flohr PR, Riisnaes R, Lin C, Keer H, Oganesian A, Workman P, de Bono JS.
Abstract: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This Phase 1/2 trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P Experimental Design: Subjects with progressing CRPC were randomized to receive one of two regimens of onalespib combined with AA/P. Onalespib was administered as intravenous (IV) infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (Regimen 1); or at 120 mg/m2 on Day 1 and Day 2 weekly for 3 of 4 weeks (Regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTCs) and in fresh tumor tissue biopsies Results: Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥ Grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose-limiting at 260 mg/m2 and 160 mg/m2 for Regimen 1 and Regimen 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly up-regulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and post-treatment tumor biopsy samples. No subjects showed an objective or PSA response Conclusions:Onalespib in combination with AA/P, showed mild evidence of some biological effect, however this effect did not translate into clinical activity, hence further exploration of this combination was not justified.
Copyright ©2019, American Association for Cancer Research.
Link to PubMed record
Author: Slovin SF, Hussain S, Saad F, Garcia JA, Picus J, Ferraldeschi R, Crespo M, Flohr PR, Riisnaes R, Lin C, Keer H, Oganesian A, Workman P, de Bono JS.
Abstract: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This Phase 1/2 trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P Experimental Design: Subjects with progressing CRPC were randomized to receive one of two regimens of onalespib combined with AA/P. Onalespib was administered as intravenous (IV) infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (Regimen 1); or at 120 mg/m2 on Day 1 and Day 2 weekly for 3 of 4 weeks (Regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTCs) and in fresh tumor tissue biopsies Results: Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥ Grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose-limiting at 260 mg/m2 and 160 mg/m2 for Regimen 1 and Regimen 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly up-regulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and post-treatment tumor biopsy samples. No subjects showed an objective or PSA response Conclusions:Onalespib in combination with AA/P, showed mild evidence of some biological effect, however this effect did not translate into clinical activity, hence further exploration of this combination was not justified.
Copyright ©2019, American Association for Cancer Research.
Link to PubMed record
CCC publication: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study
Citation: The Lancet Oncology. 2019, 20(5), 663-73
Author: Primrose J.N. (j.n.primrose@soton.ac.uk); Raftery J.; Zhu S.; Fox R.P.; Palmer D.H.; Malik H.Z.; Prasad R.; Stocken D.; Mirza D.; Ma Y.T.; Anthony A.; Corrie P.; Falk S.; Finch-Jones M.; Wasan H.; Ross P.; Wall L.; Wadsley J.; Evans J.T.R.; Praseedom R.; Davidson B.; Neoptolemos J.P.; Iveson T.; Cunningham D.; Garden O.J.; Stubbs C.; Valle J.W.; Bridgewater J. (j.bridgewater@ucl.ac.uk); Morement H.; Chan O.; Rees C.; Hickish T.; Pope I.; Crosby T.; Sothi S.; Sharkland K.; Adamson D.; Evans J.; Dent J.; Hombaiah U.; Iwuji C.; Anthoney A.; Gillmore R.; Slater S.; Waters J.; Palmer D.; Malik H.; Neoptolemos J.; Faluyi O.; Sumpter K.; Dernedde U.; Maduhusudan S.; Cogill G.; Archer C.; Darby S.; Peterson M.; Mukhtar A.A.; Thorpe J.G.; Bateman A.; Tsang D.; Cummins S.; Nolan L.; Beaumont E.; Garden J.; Coxon F.
Abstract: BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.
METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.
FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related.
INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.
FUNDING: Cancer Research UK and Roche.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Link to PubMed record
Author: Primrose J.N. (j.n.primrose@soton.ac.uk); Raftery J.; Zhu S.; Fox R.P.; Palmer D.H.; Malik H.Z.; Prasad R.; Stocken D.; Mirza D.; Ma Y.T.; Anthony A.; Corrie P.; Falk S.; Finch-Jones M.; Wasan H.; Ross P.; Wall L.; Wadsley J.; Evans J.T.R.; Praseedom R.; Davidson B.; Neoptolemos J.P.; Iveson T.; Cunningham D.; Garden O.J.; Stubbs C.; Valle J.W.; Bridgewater J. (j.bridgewater@ucl.ac.uk); Morement H.; Chan O.; Rees C.; Hickish T.; Pope I.; Crosby T.; Sothi S.; Sharkland K.; Adamson D.; Evans J.; Dent J.; Hombaiah U.; Iwuji C.; Anthoney A.; Gillmore R.; Slater S.; Waters J.; Palmer D.; Malik H.; Neoptolemos J.; Faluyi O.; Sumpter K.; Dernedde U.; Maduhusudan S.; Cogill G.; Archer C.; Darby S.; Peterson M.; Mukhtar A.A.; Thorpe J.G.; Bateman A.; Tsang D.; Cummins S.; Nolan L.; Beaumont E.; Garden J.; Coxon F.
Abstract: BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.
METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.
FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related.
INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.
FUNDING: Cancer Research UK and Roche.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Link to PubMed record
CCC publication: Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial - ANZGOG 0903.
Citation: Gynecol Oncol. 2019 May 23 [Epub ahead of print]
Author: Mileshkin L, Edmondson R, O'Connell RL, Sjoquist KM, Andrews J, Jyothirmayi R, Beale P, Bonaventura T, Goh J, Hall M, Clamp A, Green J, Lord R, Amant F, Alexander L, Carty K, Paul J, Scurry J, Millan D, Nottley S, Friedlander M; PARAGON study group..
Abstract: BACKGROUND: The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer.
METHODS: Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity.
RESULTS: Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34-55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3-15%). The median PFS was 3.2 months (95% CI: 2.8-5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0-13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003).
CONCLUSION: Although the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.
Copyright © 2019. Published by Elsevier Inc.
KEYWORDS: Aromatase inhibitor; Clinical trial; Endometrial cancer; Quality of life
Link to PubMed record
Author: Mileshkin L, Edmondson R, O'Connell RL, Sjoquist KM, Andrews J, Jyothirmayi R, Beale P, Bonaventura T, Goh J, Hall M, Clamp A, Green J, Lord R, Amant F, Alexander L, Carty K, Paul J, Scurry J, Millan D, Nottley S, Friedlander M; PARAGON study group..
Abstract: BACKGROUND: The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer.
METHODS: Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity.
RESULTS: Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34-55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3-15%). The median PFS was 3.2 months (95% CI: 2.8-5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0-13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003).
CONCLUSION: Although the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.
Copyright © 2019. Published by Elsevier Inc.
KEYWORDS: Aromatase inhibitor; Clinical trial; Endometrial cancer; Quality of life
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CCC publication: Advanced intrahepatic cholangiocarcinoma: post-hoc analysis of the ABC-01, -02 and -03 clinical trials
Citation: Journal of the National Cancer Institute. 2019 May 11 [Epub ahead of print]
Author: Lamarca A.; Hubner R.A.; McNamara M.G.; Valle J.W.; Ross P.; Wasan H.S.; Lopes A.; Manoharan P.; Palmer D.; Bridgewater J.
Abstract: BACKGROUND: The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care).
METHODS: Individual data from patients with iCCA recruited into the prospective, randomised Advanced Biliary tract Cancer (ABC)-01, -02 and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox Regression. All statistical tests were two-sided.
RESULTS: Of 534 patients recruited into the ABC-01, -02 and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86; 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following randomisation, 66 (60.6%) iCCA patients received cisplatin/gemcitabine. The median progression-free (PFS) and overall survival (OS) was 8.4 months (95%confdence interval [CI] = 5.9-8.9) and 15.4 months (95%CI = 11.1-17.9), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression free at 3 and 6 months from chemotherapy commencement, respectively. Median OS for patients with liver-only iCCA at diagnosis, and after 3 and 6 months of chemotherapy was 16.7 months (95% confidence interval [CI] = 8.7-20.2), 17.9 (95%CI = 11.7-20.9) and 18.9 (95%CI = 16.7-25.9) months, respectively. Multivariable analysis confirmed that iCCA had a longer OS compared to other non-iCCA BTCs (hazard ratio = 0.58, 95%CI = 0.35-0.95; p-value = 0.03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95%CI = 0.36-1.19; p-value = 0.16).
CONCLUSIONS: Patients diagnosed with advanced iCCA have a better OS compared to other BTCs; similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.
© The Author(s) 2019. Published by Oxford University Press.
KEYWORDS: FGFR; IDH; SIRT; biliary tract; chemosaturation; cholangiocarcinoma; intrahepatic; liver; liver-directed; radioembolisation; survival; targeted therapies
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Author: Lamarca A.; Hubner R.A.; McNamara M.G.; Valle J.W.; Ross P.; Wasan H.S.; Lopes A.; Manoharan P.; Palmer D.; Bridgewater J.
Abstract: BACKGROUND: The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care).
METHODS: Individual data from patients with iCCA recruited into the prospective, randomised Advanced Biliary tract Cancer (ABC)-01, -02 and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox Regression. All statistical tests were two-sided.
RESULTS: Of 534 patients recruited into the ABC-01, -02 and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86; 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following randomisation, 66 (60.6%) iCCA patients received cisplatin/gemcitabine. The median progression-free (PFS) and overall survival (OS) was 8.4 months (95%confdence interval [CI] = 5.9-8.9) and 15.4 months (95%CI = 11.1-17.9), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression free at 3 and 6 months from chemotherapy commencement, respectively. Median OS for patients with liver-only iCCA at diagnosis, and after 3 and 6 months of chemotherapy was 16.7 months (95% confidence interval [CI] = 8.7-20.2), 17.9 (95%CI = 11.7-20.9) and 18.9 (95%CI = 16.7-25.9) months, respectively. Multivariable analysis confirmed that iCCA had a longer OS compared to other non-iCCA BTCs (hazard ratio = 0.58, 95%CI = 0.35-0.95; p-value = 0.03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95%CI = 0.36-1.19; p-value = 0.16).
CONCLUSIONS: Patients diagnosed with advanced iCCA have a better OS compared to other BTCs; similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.
© The Author(s) 2019. Published by Oxford University Press.
KEYWORDS: FGFR; IDH; SIRT; biliary tract; chemosaturation; cholangiocarcinoma; intrahepatic; liver; liver-directed; radioembolisation; survival; targeted therapies
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CCC publication: Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis
Citation: British Journal of Haematology. 2019, 185(4), 656-69
Author: Eyre T.A. (toby.eyre@ouh.nhs.uk); Schuh A.H.; Kirkwood A.A.; Gohill S.; Follows G.; Walewska R.; Walter H.; Cross M.; Forconi F.; Shah N.; Chasty R.; Hart A.; Broom A.; Marr H.; Patten P.E.M.; Dann A.; Arumainathan A.; Munir T.; Shankara P.; Bloor A.; Johnston R.; Orchard K.; Fox C.P.
Abstract: Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.
© 2019 British Society for Haematology and John Wiley & Sons Ltd.
KEYWORDS: B cell receptor inhibitor, ibrutinib, idelalisib, p53 venetoclax; BCL2; chronic lymphocytic leukaemia
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Author: Eyre T.A. (toby.eyre@ouh.nhs.uk); Schuh A.H.; Kirkwood A.A.; Gohill S.; Follows G.; Walewska R.; Walter H.; Cross M.; Forconi F.; Shah N.; Chasty R.; Hart A.; Broom A.; Marr H.; Patten P.E.M.; Dann A.; Arumainathan A.; Munir T.; Shankara P.; Bloor A.; Johnston R.; Orchard K.; Fox C.P.
Abstract: Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.
© 2019 British Society for Haematology and John Wiley & Sons Ltd.
KEYWORDS: B cell receptor inhibitor, ibrutinib, idelalisib, p53 venetoclax; BCL2; chronic lymphocytic leukaemia
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CCC publication: Therapeutic Radiographers' perceptions of the barriers and enablers to effective smoking cessation support
Citation: Radiography (Lond). 2019, 25(2), 121-128
Author: Charlesworth L. (l.pattinson@shu.ac.uk); Hutton D. (daniel.hutton@nhs.net); Hussain H. (hannankhussain@gmail.com)
Abstract: INTRODUCTION: Tobacco smoking during and post radiotherapy is associated with increased treatment toxicity and increased cancer related mortality. Routine delivery of smoking cessation advice is inconsistent in practice. This study identifies the key barriers and facilitators to the provision of effective smoking cessation conversations in radiotherapy practice.
METHODS: A baseline questionnaire (n = 43) was used to identify current practice, barriers and facilitators to smoking cessation in radiotherapy and to inform a topic guide for follow up focus groups (n = 5). Ethical approval was obtained through the 4 NHS trusts and the Health Research Authority. Focus group transcription was coded by two researchers.
RESULTS: Therapeutic Radiographers initiate health behaviour conversations with patients; there are a number of factors that facilitate the likelihood of a health behaviour conversation; indication that a patient smokes anatomical site and presence of acute effects. Key barriers to smoking cessation provision include; lack of training, limited knowledge, limitations as a result of poor clinical infrastructure, local culture and perceptions that patients do not prioritise smoking cessation during treatment.
CONCLUSION: Therapeutic Radiographers have the motivation to provide smoking cessation advice, however they require further training to develop knowledge and skills in relation to benefits of smoking cessation and cessation strategies. Therapeutic Radiographers also expect that patients will respond negatively to smoking cessation advice, and that this might be damaging to the therapeutic relationship. Departmental culture and trust infrastructure can also significantly inhibit the provision of smoking cessation in radiotherapy practice and further support to implement NICE guidance is required.
Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: Barriers; Facilitators; Health behaviour; Radiotherapy; Smoking cessation; Therapeutic Radiographer
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Author: Charlesworth L. (l.pattinson@shu.ac.uk); Hutton D. (daniel.hutton@nhs.net); Hussain H. (hannankhussain@gmail.com)
Abstract: INTRODUCTION: Tobacco smoking during and post radiotherapy is associated with increased treatment toxicity and increased cancer related mortality. Routine delivery of smoking cessation advice is inconsistent in practice. This study identifies the key barriers and facilitators to the provision of effective smoking cessation conversations in radiotherapy practice.
METHODS: A baseline questionnaire (n = 43) was used to identify current practice, barriers and facilitators to smoking cessation in radiotherapy and to inform a topic guide for follow up focus groups (n = 5). Ethical approval was obtained through the 4 NHS trusts and the Health Research Authority. Focus group transcription was coded by two researchers.
RESULTS: Therapeutic Radiographers initiate health behaviour conversations with patients; there are a number of factors that facilitate the likelihood of a health behaviour conversation; indication that a patient smokes anatomical site and presence of acute effects. Key barriers to smoking cessation provision include; lack of training, limited knowledge, limitations as a result of poor clinical infrastructure, local culture and perceptions that patients do not prioritise smoking cessation during treatment.
CONCLUSION: Therapeutic Radiographers have the motivation to provide smoking cessation advice, however they require further training to develop knowledge and skills in relation to benefits of smoking cessation and cessation strategies. Therapeutic Radiographers also expect that patients will respond negatively to smoking cessation advice, and that this might be damaging to the therapeutic relationship. Departmental culture and trust infrastructure can also significantly inhibit the provision of smoking cessation in radiotherapy practice and further support to implement NICE guidance is required.
Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: Barriers; Facilitators; Health behaviour; Radiotherapy; Smoking cessation; Therapeutic Radiographer
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CCC publication: Integration of Checkpoint Inhibitors into the Management of Locally Advanced Head and Neck Cancer - Future Perspectives
Citation: Clinical Oncology. 2019
Author: Brooker R.C. (Rachel.brooker@liverpool.ac.uk); Sacco J.J.; Schache A.G.
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Author: Brooker R.C. (Rachel.brooker@liverpool.ac.uk); Sacco J.J.; Schache A.G.
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CCC publication: When is chronic myeloid leukaemia 'cured'? relapse post allogeneic bone marrow transplantation after 32 years
Citation: British Journal of Haematology. 2019, 185, 202
Author: Bolaji M.; Knight K.; Patel A.
Abstract: We present a 60 year-old male with chronic myeloid leukaemia (CML) recurrence 32 years after allogeneic bone marrow transplantation. Our case seems to be the longest late relapse post allogeneic transplantation described in the literature. This raises fundamental questions in relation to the biology of CML with major implications relating to monitoring strategies for patients with treatment-free remission. The patient initially presented in 1986 at the age of 28 years age, and was treated for five months with bulsuphan and thioguanine. In October 1986, the patient received a myeloablative conditioned (MAC) sibling donor allogeneic bone marrow transplant after high dose cyclophosphamide and total body irradiation (TBI). He subsequently experienced minimal skin acute graft versus host disease (GvHD) that did not require systemic treatment. Cyclosporin was discontinued after six months. His last in-patient episode was February 1987. He was in complete remission which was maintained with annual bone marrow assessments for a further five years. The patient received a revaccination schedule and was discharged from our haematology service in 2014, and remained in clinical remission. He re-presented at the age of 60 years, with a mildly elevated white blood cell count discovered during routine blood testing, with no other associated symptoms at a 'well man' clinic. He had basophilia of 0.9x 10<sup>9</sup>/l and a total white blood cell count (WBC) of 13.7 9 109/l; haemoglobin and platelet parameters were normal. The patient was otherwise asymptomatic with no features of splenic enlargement. Peripheral blood BCR-ABL1 PCR was 30.638%, confirming CML. His blood film and bone marrow assessments confirmed chronic phase disease. Donor chimerism (mixed whole blood and myeloid chimerism of 20% with 100% T cell chimerism) confirmed the recurrence of patient-derived CML rather than de novo donor-derived CML. He was treated with imatinib 400 mg daily. The patient responded well with a 3 month BCR-ABL1 PCR of 0.980%. At 6 months this was 0.109%. The patient tolerated this treatment well with minimal side effects. He now has full donor chimerism (whole blood, myeloid, T cell) and continues to be monitored every three months. This case challenges the current perception of the mechanisms surrounding control and cure of CML. Long-term, life-long, follow up of patients in TFR may be necessary to detect very late disease recurrence of CML.
Author: Bolaji M.; Knight K.; Patel A.
Abstract: We present a 60 year-old male with chronic myeloid leukaemia (CML) recurrence 32 years after allogeneic bone marrow transplantation. Our case seems to be the longest late relapse post allogeneic transplantation described in the literature. This raises fundamental questions in relation to the biology of CML with major implications relating to monitoring strategies for patients with treatment-free remission. The patient initially presented in 1986 at the age of 28 years age, and was treated for five months with bulsuphan and thioguanine. In October 1986, the patient received a myeloablative conditioned (MAC) sibling donor allogeneic bone marrow transplant after high dose cyclophosphamide and total body irradiation (TBI). He subsequently experienced minimal skin acute graft versus host disease (GvHD) that did not require systemic treatment. Cyclosporin was discontinued after six months. His last in-patient episode was February 1987. He was in complete remission which was maintained with annual bone marrow assessments for a further five years. The patient received a revaccination schedule and was discharged from our haematology service in 2014, and remained in clinical remission. He re-presented at the age of 60 years, with a mildly elevated white blood cell count discovered during routine blood testing, with no other associated symptoms at a 'well man' clinic. He had basophilia of 0.9x 10<sup>9</sup>/l and a total white blood cell count (WBC) of 13.7 9 109/l; haemoglobin and platelet parameters were normal. The patient was otherwise asymptomatic with no features of splenic enlargement. Peripheral blood BCR-ABL1 PCR was 30.638%, confirming CML. His blood film and bone marrow assessments confirmed chronic phase disease. Donor chimerism (mixed whole blood and myeloid chimerism of 20% with 100% T cell chimerism) confirmed the recurrence of patient-derived CML rather than de novo donor-derived CML. He was treated with imatinib 400 mg daily. The patient responded well with a 3 month BCR-ABL1 PCR of 0.980%. At 6 months this was 0.109%. The patient tolerated this treatment well with minimal side effects. He now has full donor chimerism (whole blood, myeloid, T cell) and continues to be monitored every three months. This case challenges the current perception of the mechanisms surrounding control and cure of CML. Long-term, life-long, follow up of patients in TFR may be necessary to detect very late disease recurrence of CML.
CCC publication: Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome.
Citation: Pigment Cell Melanoma Res. 2019 Jan 23 [Epub ahead of print]
Author: Kenawy N, Kalirai H, Sacco JJ, Lake SL, Heegaard S, Larsen AC, Finger PT, Milman T, Chin K, Mosci C, Lanza F, Moulin A, Schmitt CA, Caujolle JP, Maschi C, Marinkovic M, Taktak AF, Heimann H, Damato BE, Coupland SE.
Abstract: Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.
© 2019 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons Ltd.
KEYWORDS: BRAF/NRAS mutation; allele-specific copy number; conjunctival melanoma; copy number alteration; metastasishttps://www.ncbi.nlm.nih.gov/pubmed?term=Conjunctival+melanoma+copy+number+alterations+and+correlation+with+mutation+status%2C+tumor+features%2C+and+clinical+outcome.&TransSchema=title&cmd=detailssearch
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Author: Kenawy N, Kalirai H, Sacco JJ, Lake SL, Heegaard S, Larsen AC, Finger PT, Milman T, Chin K, Mosci C, Lanza F, Moulin A, Schmitt CA, Caujolle JP, Maschi C, Marinkovic M, Taktak AF, Heimann H, Damato BE, Coupland SE.
Abstract: Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.
© 2019 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons Ltd.
KEYWORDS: BRAF/NRAS mutation; allele-specific copy number; conjunctival melanoma; copy number alteration; metastasishttps://www.ncbi.nlm.nih.gov/pubmed?term=Conjunctival+melanoma+copy+number+alterations+and+correlation+with+mutation+status%2C+tumor+features%2C+and+clinical+outcome.&TransSchema=title&cmd=detailssearch
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CCC publication: An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor,
Citation: Gynecologic Oncology. 2019, 153(3), 541-8
Author: Martin Gore, Allan Hackshaw, William E. Brady, Richard T. Penson, Richard Zaino, W. Glenn McCluggage, Raji Ganesan, Nafisa Wilkinson, Timothy Perren, Ana Montes, Jeffrey Summers, Rosemary Lord, Graham Dark, Gordon Rustin, Melanie Mackean, Nicholas Reed, Sean Kehoe, Michael Frumovitz, Helen Christensen, Amanda Feeney, Jonathan Ledermann, David M. Gershenson,
Abstract: OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer.
METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL).
RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms.
CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS: Chemotherapy; Factorial design; Mucinous ovarian cancer; Rare tumor trial
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Author: Martin Gore, Allan Hackshaw, William E. Brady, Richard T. Penson, Richard Zaino, W. Glenn McCluggage, Raji Ganesan, Nafisa Wilkinson, Timothy Perren, Ana Montes, Jeffrey Summers, Rosemary Lord, Graham Dark, Gordon Rustin, Melanie Mackean, Nicholas Reed, Sean Kehoe, Michael Frumovitz, Helen Christensen, Amanda Feeney, Jonathan Ledermann, David M. Gershenson,
Abstract: OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer.
METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL).
RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms.
CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS: Chemotherapy; Factorial design; Mucinous ovarian cancer; Rare tumor trial
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CCC publication: The impact of the 21-gene recurrence score (Oncotype DX) on concordance of adjuvant therapy decision making as measured by the Liverpool Systemic Therapy Adjuvant Decision Tool,
Citation: The Breast. 2019, 44, 94-100
Author: Anna Olsson-Brown, Pavlos Piskilidis, Julie O'Hagan, Nicky Thorp, Peter Robson, Helen Innes, Helen Wong, Silvia Cicconi, Richard Jackson, Tamara Kiernan, Christopher Holcombe, Susan O'Reilly, Carlo Palmieri,
Abstract: PURPOSE: The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations.
PATIENTS AND METHODS: The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations.
RESULTS: Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ2 = 79.35, p < 0.001] and altered the LASTDT category in 68% (34/50) of cases (p < 0.001), 74% of which were to forgo chemotherapy. With knowledge of RS, universal concordance rose from 14% to 64% [K = 0.328: K = 0.729].
CONCLUSIONS: The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care.
Copyright © 2019 Elsevier Ltd. All rights reserved.
KEYWORDS: 21 gene recurrence score; Breast cancer; Decision making; MDT
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Author: Anna Olsson-Brown, Pavlos Piskilidis, Julie O'Hagan, Nicky Thorp, Peter Robson, Helen Innes, Helen Wong, Silvia Cicconi, Richard Jackson, Tamara Kiernan, Christopher Holcombe, Susan O'Reilly, Carlo Palmieri,
Abstract: PURPOSE: The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations.
PATIENTS AND METHODS: The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations.
RESULTS: Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ2 = 79.35, p < 0.001] and altered the LASTDT category in 68% (34/50) of cases (p < 0.001), 74% of which were to forgo chemotherapy. With knowledge of RS, universal concordance rose from 14% to 64% [K = 0.328: K = 0.729].
CONCLUSIONS: The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care.
Copyright © 2019 Elsevier Ltd. All rights reserved.
KEYWORDS: 21 gene recurrence score; Breast cancer; Decision making; MDT
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CCC publication: Monte Carlo modelling of the Clatterbridge proton therapy beam line
Citation: Australasian Physical and Engineering Sciences in Medicine. 2019, 42(1), 329
Author: Yap J.S.L. (Jacinta.yap@cockcroft.ac.uk); Schnuerer R. (Roland.schnuerer@cockcroft.ac.uk); Welsch C.P. (carsten.welsch@cockcroft.ac.uk); Hentz M. (m.hentz.13@ucl.ac.uk); Jolly S. (s.jolly@ucl.ac.uk); Kacperek A. (andrzej.kacperek@nhs.net))
Abstract: Introduction The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world's first hospital proton beam therapy facility, providing successful treatments for the past 30 years. A 60 MeV beam of protons is produced and transported through a passive delivery system enabling the precise delivery of uniform dose to ocular tumour sites. The QUASAR group is developing an online beam monitor based on LHCb VErtex LOcator (VELO) detector technology for implementation into the CCC clinical proton beamline. The design of the monitoring system allows real time measurements by correlation of the beam halo with the beam current. In order to investigate the capability of the system as a dose monitor, accurate and validated simulations are needed for the integration of the detector and also for the full characterisation of the beam. Method A model of the beamline has been developed using the Monte Carlo simulation toolkit GEANT4 which describes the treatment line starting from the vacuum tube containing the double scattering foils, through to the nozzle. The geometry of the delivery system components are accurately defined, along with the VELO sensors positioned within a designated integration zone between the modulator box and treatment head. The simulation model has been validated against experimental data, including depth dose and transverse profiles. Results The CCC beamline model is described in detail and experimental measurements are presented alongside simulated results achieved with the validated Geant4 model. The integration of the VELO detectors within the delivery system and recent progress to correlate halo measurements with delivered dose is also shown. Conclusion An accurate and validated simulation model of the CCC beamline is essential to investigate the implementation of the VELO detector system and its viability as a candidate for online dose monitoring. This will also facilitate future work into radiobiological studies and facility upgrades.
Author: Yap J.S.L. (Jacinta.yap@cockcroft.ac.uk); Schnuerer R. (Roland.schnuerer@cockcroft.ac.uk); Welsch C.P. (carsten.welsch@cockcroft.ac.uk); Hentz M. (m.hentz.13@ucl.ac.uk); Jolly S. (s.jolly@ucl.ac.uk); Kacperek A. (andrzej.kacperek@nhs.net))
Abstract: Introduction The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world's first hospital proton beam therapy facility, providing successful treatments for the past 30 years. A 60 MeV beam of protons is produced and transported through a passive delivery system enabling the precise delivery of uniform dose to ocular tumour sites. The QUASAR group is developing an online beam monitor based on LHCb VErtex LOcator (VELO) detector technology for implementation into the CCC clinical proton beamline. The design of the monitoring system allows real time measurements by correlation of the beam halo with the beam current. In order to investigate the capability of the system as a dose monitor, accurate and validated simulations are needed for the integration of the detector and also for the full characterisation of the beam. Method A model of the beamline has been developed using the Monte Carlo simulation toolkit GEANT4 which describes the treatment line starting from the vacuum tube containing the double scattering foils, through to the nozzle. The geometry of the delivery system components are accurately defined, along with the VELO sensors positioned within a designated integration zone between the modulator box and treatment head. The simulation model has been validated against experimental data, including depth dose and transverse profiles. Results The CCC beamline model is described in detail and experimental measurements are presented alongside simulated results achieved with the validated Geant4 model. The integration of the VELO detectors within the delivery system and recent progress to correlate halo measurements with delivered dose is also shown. Conclusion An accurate and validated simulation model of the CCC beamline is essential to investigate the implementation of the VELO detector system and its viability as a candidate for online dose monitoring. This will also facilitate future work into radiobiological studies and facility upgrades.
CCC publication: Management of Ependymoma in Children, Adolescents and Young Adults
Citation: Clinical Oncology. 2019, 31(3), 162-70
Author: Thorp N. (nicky.thorp@nhs.net); Gandola L.
Abstract: Paediatric ependymomas are rare, malignant tumours arising throughout the central nervous system, but most frequently (in children) the posterior fossa. The standard of care for localised disease is gross total resection and focal radiotherapy, resulting in overall survival rates of up to 85%. Despite improvements in survival, treatment remains challenging, with persistently high rates of (rarely curable) relapse alongside risks of significant tumour and treatment-related toxicity. Systemic therapy is currently used to delay radiotherapy in very young children and in the management of metastatic or recurrent disease. Its use in the adjuvant setting is the subject of ongoing studies. Current research efforts are aimed at eliciting a better understanding of molecular biology, correlating this with tumour behaviour and defining targets for potential new agents. Prognosis seems to be related to the extent of surgical resection and the age at presentation. This article reviews clinical aspects of ependymoma management in children and young people.
Copyright © 2018 The Royal College of Radiologists. All rights reserved.
KEYWORDS: Adolescents; children; ependymoma; gross total resection; proton beam therapy; radiotherapy
Link to PubMed record
Author: Thorp N. (nicky.thorp@nhs.net); Gandola L.
Abstract: Paediatric ependymomas are rare, malignant tumours arising throughout the central nervous system, but most frequently (in children) the posterior fossa. The standard of care for localised disease is gross total resection and focal radiotherapy, resulting in overall survival rates of up to 85%. Despite improvements in survival, treatment remains challenging, with persistently high rates of (rarely curable) relapse alongside risks of significant tumour and treatment-related toxicity. Systemic therapy is currently used to delay radiotherapy in very young children and in the management of metastatic or recurrent disease. Its use in the adjuvant setting is the subject of ongoing studies. Current research efforts are aimed at eliciting a better understanding of molecular biology, correlating this with tumour behaviour and defining targets for potential new agents. Prognosis seems to be related to the extent of surgical resection and the age at presentation. This article reviews clinical aspects of ependymoma management in children and young people.
Copyright © 2018 The Royal College of Radiologists. All rights reserved.
KEYWORDS: Adolescents; children; ependymoma; gross total resection; proton beam therapy; radiotherapy
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CCC publication: Hypofractionated dose painting IMRT using 20 fractions for intermediate to high-risk localized prostate cancer: Two-year outcome data (BIOPROP20, NCT02125175)
Citation: Journal of Clinical Oncology. 2019, 37
Author: Syndikus I.; Chan J.K.C.; Rowntree T.; Howard L.; Staffurth J.
Abstract: Background: Prostate dose painting (boosting intraprostatic tumour volumes) may improve biochemical relapsefree survival similar to whole organ dose-escalation without the associated increased toxicity. We present a predefined secondary endpoint of 2 year outcome for patients at one of two UK centres in a phase II trial (BIOPROP20) on dose-painting radiotherapy for intermediate to high risk patients treated with 60Gy/20# and concurrent 68Gy boost. <br/>Method(s): Pinnacle software was used for VMAT planning and boost volumes were outlined by F choline PET/CT and mp-MRI. Patients with positive lymph nodes also had concurrent pelvic radiotherapy of 45Gy with boost to 50Gy. Patients were followed up until year 2 with PSA and toxicity scores. <br/>Result(s): Overall 56 patients were treated, 5 with pelvic radiotherapy. Median age and PSA was 67.5 years (range 50-77) and 10.0ng/ml (3.9-39.4). All patients had tumour volumes > 10mm diameter on prebiopsy mp-MRI. 13 and 43 patients had intermediate and high risk disease. Median % LN risk was 18% (15 40). ADT duration was 6 months, 2 years, and 3 years for 42, 5, and 9 patients. At the 2 year follow up review, no grade 3 late toxicity was observed. For prostate only dose painting, grade 2 GU and GI toxicity was noted in 6% and 2% respectively. For prostate and nodal dose painting, no grade 2 toxicity was noted. Median IPSS score was 5 and 9, and median PSA was 0.3 and 0.1, in the two groups respectively. 1 patient had biochemical and metastatic relapse at 18 months (prostate, pelvic nodes and bone metastasis) and 1 patient had died of unrelated disease. <br/>Conclusion(s): Prostate radiotherapy with hypofractionated dose painting schedule of 60Gy/20# with 68Gy boost to intraprostatic lesions was well tolerated at 2 years follow up.
Author: Syndikus I.; Chan J.K.C.; Rowntree T.; Howard L.; Staffurth J.
Abstract: Background: Prostate dose painting (boosting intraprostatic tumour volumes) may improve biochemical relapsefree survival similar to whole organ dose-escalation without the associated increased toxicity. We present a predefined secondary endpoint of 2 year outcome for patients at one of two UK centres in a phase II trial (BIOPROP20) on dose-painting radiotherapy for intermediate to high risk patients treated with 60Gy/20# and concurrent 68Gy boost. <br/>Method(s): Pinnacle software was used for VMAT planning and boost volumes were outlined by F choline PET/CT and mp-MRI. Patients with positive lymph nodes also had concurrent pelvic radiotherapy of 45Gy with boost to 50Gy. Patients were followed up until year 2 with PSA and toxicity scores. <br/>Result(s): Overall 56 patients were treated, 5 with pelvic radiotherapy. Median age and PSA was 67.5 years (range 50-77) and 10.0ng/ml (3.9-39.4). All patients had tumour volumes > 10mm diameter on prebiopsy mp-MRI. 13 and 43 patients had intermediate and high risk disease. Median % LN risk was 18% (15 40). ADT duration was 6 months, 2 years, and 3 years for 42, 5, and 9 patients. At the 2 year follow up review, no grade 3 late toxicity was observed. For prostate only dose painting, grade 2 GU and GI toxicity was noted in 6% and 2% respectively. For prostate and nodal dose painting, no grade 2 toxicity was noted. Median IPSS score was 5 and 9, and median PSA was 0.3 and 0.1, in the two groups respectively. 1 patient had biochemical and metastatic relapse at 18 months (prostate, pelvic nodes and bone metastasis) and 1 patient had died of unrelated disease. <br/>Conclusion(s): Prostate radiotherapy with hypofractionated dose painting schedule of 60Gy/20# with 68Gy boost to intraprostatic lesions was well tolerated at 2 years follow up.
CCC publication: Treatment: the role of contact X-ray brachytherapy (Papillon) in the management of early rectal cancer.
Citation: Colorectal Disease. 2019, 21(Sup 1), 45-52
Author: Sun Myint A, Stewart A, Mills J, Sripadam R, Whitmarsh K, Roy R, Franklin A, Dhadda A; UK Papillon team..
Abstract: KEYWORDS: Contact X-ray brachytherapy (Papillon); clinical complete response; early rectal cancer; low-energy X-rays
Link to PubMed record
Author: Sun Myint A, Stewart A, Mills J, Sripadam R, Whitmarsh K, Roy R, Franklin A, Dhadda A; UK Papillon team..
Abstract: KEYWORDS: Contact X-ray brachytherapy (Papillon); clinical complete response; early rectal cancer; low-energy X-rays
Link to PubMed record
CCC publication: Forward view in multiple myeloma: Streamlining care at diagnosis, a tertiary centre experience
Citation: British Journal of Haematology. 2019, 185, 181-82
Author: Shaw R.J.; Johnstone M.; Simon C.; Brearton G.
Abstract: Myeloma is a serious haematological cancer developing from the proliferation of clonal plasma cells. The presenting symptoms can be varied and include anaemia, bone pain or renal dysfunction; therefore patients may present to a number of different specialties. Delay in diagnosis and treatment can cause psychological distress, and may also mean the disease presents at a more advanced stage with increased end organ damage. In October 2014, the five year forward view was produced by NHS England to set out a direction for the NHS in a changing society. To improve outcomes specifically for cancer, targets were set with an aim to streamline cancer care by 2020. Local practice was compared against national standards as per the 5 year forward view: including time from referral to seeing a specialist being no more than 14 days and time from referral to diagnosis being confirmed / excluded being no more than 28 days. Local practice was also reviewed against local standards: time from internal referral of suspected malignancy to review by a specialist should be within 24 hours. Local outcomes were then compared pre and post introduction of the "one-stop" clinic model. A retrospective review was performed over a two year period from 01/07/2016 - 30/06/2018. A local database identified patients with a new diagnosis of multiple myeloma or plasmacytoma. The patient electronic medical record was used to identify patient characteristics including age, diagnosis and treatments. Unity was used to identify referral dates. Data was collected and analysed using Microsoft Excel 2013 and episodes were analysed pre and post introduction of a streamlined "one-stop" clinic model. 81 patient episodes were reviewed, 22 were excluded either due to incomplete data or due to patient decision to decline therapy. The mean age was 71 years (range 35-92 years). 54 had a new diagnosis of multiple myeloma, 19 with myeloma progressed from known MGUS and 8 with plasmacytoma. Referrals were received from GPs and various hospital specialties. Twenty-five patients were referred directly from their GP; frequently referring hospital specialties included Nephrology (N = 12), Orthopaedic/Spinal (N = 12), General Medicine (N = 13). The Trust is unique in providing care for patients from the Isle of Man, with 16 patients referred. The mean time from referral to seeing a specialist prior to the "one-stop" clinic model was 14 days vs. 7 days post implementation. Excluding those with plasmacytoma; the mean time from referral to diagnosis (on bone marrow biopsy) prior to the "one-stop" clinic model was 31 days vs. 22 days post implementation. The median time from date of clinically suspected diagnosis to commencement of treatment prior to the "one-stop" clinic model was 49 days vs. 36 days post implementation. This data demonstrates that the "one-stop" clinic model has improved time from suspected diagnosis to specialist review, diagnosis and commencement of treatment. The improvements implemented include: Identifying those with highly suspected diagnosis of myeloma at time of referral to facilitate bone marrow biopsy on the same day as 1st clinic review Telephoning patient ahead of 1st follow up appointment if further diagnostic testing required (eg PET-CT / MRI) The data highlighted the significant number of referrals from other specialties and therefore potential areas for ongoing improvement include education for trainees in frequently referring specialties.
Author: Shaw R.J.; Johnstone M.; Simon C.; Brearton G.
Abstract: Myeloma is a serious haematological cancer developing from the proliferation of clonal plasma cells. The presenting symptoms can be varied and include anaemia, bone pain or renal dysfunction; therefore patients may present to a number of different specialties. Delay in diagnosis and treatment can cause psychological distress, and may also mean the disease presents at a more advanced stage with increased end organ damage. In October 2014, the five year forward view was produced by NHS England to set out a direction for the NHS in a changing society. To improve outcomes specifically for cancer, targets were set with an aim to streamline cancer care by 2020. Local practice was compared against national standards as per the 5 year forward view: including time from referral to seeing a specialist being no more than 14 days and time from referral to diagnosis being confirmed / excluded being no more than 28 days. Local practice was also reviewed against local standards: time from internal referral of suspected malignancy to review by a specialist should be within 24 hours. Local outcomes were then compared pre and post introduction of the "one-stop" clinic model. A retrospective review was performed over a two year period from 01/07/2016 - 30/06/2018. A local database identified patients with a new diagnosis of multiple myeloma or plasmacytoma. The patient electronic medical record was used to identify patient characteristics including age, diagnosis and treatments. Unity was used to identify referral dates. Data was collected and analysed using Microsoft Excel 2013 and episodes were analysed pre and post introduction of a streamlined "one-stop" clinic model. 81 patient episodes were reviewed, 22 were excluded either due to incomplete data or due to patient decision to decline therapy. The mean age was 71 years (range 35-92 years). 54 had a new diagnosis of multiple myeloma, 19 with myeloma progressed from known MGUS and 8 with plasmacytoma. Referrals were received from GPs and various hospital specialties. Twenty-five patients were referred directly from their GP; frequently referring hospital specialties included Nephrology (N = 12), Orthopaedic/Spinal (N = 12), General Medicine (N = 13). The Trust is unique in providing care for patients from the Isle of Man, with 16 patients referred. The mean time from referral to seeing a specialist prior to the "one-stop" clinic model was 14 days vs. 7 days post implementation. Excluding those with plasmacytoma; the mean time from referral to diagnosis (on bone marrow biopsy) prior to the "one-stop" clinic model was 31 days vs. 22 days post implementation. The median time from date of clinically suspected diagnosis to commencement of treatment prior to the "one-stop" clinic model was 49 days vs. 36 days post implementation. This data demonstrates that the "one-stop" clinic model has improved time from suspected diagnosis to specialist review, diagnosis and commencement of treatment. The improvements implemented include: Identifying those with highly suspected diagnosis of myeloma at time of referral to facilitate bone marrow biopsy on the same day as 1st clinic review Telephoning patient ahead of 1st follow up appointment if further diagnostic testing required (eg PET-CT / MRI) The data highlighted the significant number of referrals from other specialties and therefore potential areas for ongoing improvement include education for trainees in frequently referring specialties.
CCC publication: Feasibility, safety and efficacy of concomitant ponatinib with apixaban, as prophylaxis for arterial and venous thrombosis in patients with chronic myeloid leukaemia (CML) pre- and post-allogeneic stem cell transplantation
Citation: British Journal of Haematology. 2019, 185, 192-93
Author: Schofield J.; Knight K.; Salim R.; Patel A.
Abstract: Ponatinib is indicated for Philadelphia (Ph+) chromosome associated leukaemia (chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL)), including patients with a T315I mutation or advanced phase disease.1 Ponatinib is subject to additional monitoring requirements due to a significant risk of vascular occlusive events. High rates of arterial (25%) and venous (6%) thrombotic events contribute to significant morbidity and treatment interruption. 1 Apixaban prophylaxis is indicated for both arterial and venous thrombosis in patients with cancer.2 Most patients prefer oral rather than subcutaneous anti-thrombotic prophylaxis. We are unaware of published or pharmaceutical data regarding the feasibility, safety and efficacy of concurrent apixaban use with ponatinib, given their potential interaction. Our primary study objective to was to assess the feasibility of this combination, and our secondary objective was to assess safety and efficacy. This retrospective study identified and included all patients with CML or Ph+ ALL that preferred oral (instead of subcutaneous) antithrombotic prophylaxis, and that who commenced on ponatinib with apixaban. Data were collected and analysed from patients treated at our regional UK centre during 2017-2018. Relevant information on patient characteristics, BCR-ABL1 transcript levels (efficacy measure), and the development of thrombotic and bleeding events was identified. Relevant adverse events, bleeding, and thrombotic events were used to measure safety, and were classified using criteria from the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Bleeding was also assessed using the World Health Organisation (WHO) bleeding scale for cancer.3 Major bleeding was assessed using the International Society on Thrombosis and Haemostasis (ISTH) criteria.2 The study was conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects outlined in the Declaration of Helsinki. Five patients with CML were commenced on combination ponatinib and apixaban therapy (Table). Two patients had a T315I mutation and three were in accelerated phase. Median age was 43 years (range 26 to 66 years). No patients had a history of thrombosis prior to treatment. The median duration of treatment was 4 months (range 1 to 9 months). Two patients recommenced combination therapy post-allogeneic stem cell transplantation. There were no arterial or venous thromboembolic or bleeding (including gastrointestinal) events observed after 24 months combination therapy exposure, by CTCAE, WHO, and ISTH criteria. There were no other relevant treatment emergent adverse events attributable to the ponatinib and apixaban combination. Our experience demonstrates the feasibly of concurrent ponatinib and apixaban therapy, including in the post-allogeneic stem cell transplant setting. This approach might be safe and efficacious but our observations should serve as a basis for a larger confirmatory clinical trial.
Author: Schofield J.; Knight K.; Salim R.; Patel A.
Abstract: Ponatinib is indicated for Philadelphia (Ph+) chromosome associated leukaemia (chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL)), including patients with a T315I mutation or advanced phase disease.1 Ponatinib is subject to additional monitoring requirements due to a significant risk of vascular occlusive events. High rates of arterial (25%) and venous (6%) thrombotic events contribute to significant morbidity and treatment interruption. 1 Apixaban prophylaxis is indicated for both arterial and venous thrombosis in patients with cancer.2 Most patients prefer oral rather than subcutaneous anti-thrombotic prophylaxis. We are unaware of published or pharmaceutical data regarding the feasibility, safety and efficacy of concurrent apixaban use with ponatinib, given their potential interaction. Our primary study objective to was to assess the feasibility of this combination, and our secondary objective was to assess safety and efficacy. This retrospective study identified and included all patients with CML or Ph+ ALL that preferred oral (instead of subcutaneous) antithrombotic prophylaxis, and that who commenced on ponatinib with apixaban. Data were collected and analysed from patients treated at our regional UK centre during 2017-2018. Relevant information on patient characteristics, BCR-ABL1 transcript levels (efficacy measure), and the development of thrombotic and bleeding events was identified. Relevant adverse events, bleeding, and thrombotic events were used to measure safety, and were classified using criteria from the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Bleeding was also assessed using the World Health Organisation (WHO) bleeding scale for cancer.3 Major bleeding was assessed using the International Society on Thrombosis and Haemostasis (ISTH) criteria.2 The study was conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects outlined in the Declaration of Helsinki. Five patients with CML were commenced on combination ponatinib and apixaban therapy (Table). Two patients had a T315I mutation and three were in accelerated phase. Median age was 43 years (range 26 to 66 years). No patients had a history of thrombosis prior to treatment. The median duration of treatment was 4 months (range 1 to 9 months). Two patients recommenced combination therapy post-allogeneic stem cell transplantation. There were no arterial or venous thromboembolic or bleeding (including gastrointestinal) events observed after 24 months combination therapy exposure, by CTCAE, WHO, and ISTH criteria. There were no other relevant treatment emergent adverse events attributable to the ponatinib and apixaban combination. Our experience demonstrates the feasibly of concurrent ponatinib and apixaban therapy, including in the post-allogeneic stem cell transplant setting. This approach might be safe and efficacious but our observations should serve as a basis for a larger confirmatory clinical trial.
CCC publication: Validation of a non-invasive beam monitor at a 60 MeV proton therapy beamline
Citation: Australasian Physical and Engineering Sciences in Medicine. 2019, 42(1), 400-1
Author: Schnuerer R. (Roland.schnuerer@cockcroft.ac.uk); Yap J.S.L. (Jacinta.yap@cockcroft.ac.uk); Zhang H. (Hao.zhang@cockcroft.ac.uk); Welsch C.P. (carsten.welsch@cockcroft.ac.uk); Szumlak T. (szumlak@agh.edu.pl); Kacperek A. (andrzej.kacperek@nhs.net)
Abstract: Introduction Online beam monitoring in medical accelerators is essential in assuring patient's safety as well as high quality and efficacy of cancer treatment. In clinical practice for proton therapy, currently used ionization chambers are interceptive devices, degrading both the beam profile and its energy spread. Therefore, a new noninterceptive approach of online beam monitoring is highly desirable. Method The Vertex Locator (VELO) detector is a multi-strip silicon detector used in the LHCb experiment at CERN. The semi-circular design and position of its sensitive silicon detector offers a non-invasive way to measure the beam intensity through a precise measurement of the beam halo without interfering with the beam core. The adapted standalone VELO detector is integrated at the 60 MeV proton therapy beamline at the Clatterbridge Cancer Centre (CCC), UK. Synchronised with a Faraday Cup and the RF cyclotron frequency, the quality of the beam monitor is assessed by measuring the beam current at different dose rates and by monitoring the beam halo profile at different positions along the beamline. Results The integration zone of the VELO detector is after the double scattering foils, range shifter and modulation wheel. The detector can move along 15 cm along the beamline. The beam current is measured for the dose rate of 10 Monitor Units (MU)/min to 60 MU/min at position 0 cm, 8 cm and 15 cm each. Also, 2D and 3D beam profile measurements are presented for non-skewed and skewed beams. The results are benchmarked against GEANT4 simulations. Conclusion The full setup optimized for implementation in the proton beam line at CCC is described. The capability of VELO as a beam monitor is assessed by measuring the beam current at different dose rates and by monitoring the beam profile. Further measurements in other proton therapy facilities with scanning systems are desirable.
Author: Schnuerer R. (Roland.schnuerer@cockcroft.ac.uk); Yap J.S.L. (Jacinta.yap@cockcroft.ac.uk); Zhang H. (Hao.zhang@cockcroft.ac.uk); Welsch C.P. (carsten.welsch@cockcroft.ac.uk); Szumlak T. (szumlak@agh.edu.pl); Kacperek A. (andrzej.kacperek@nhs.net)
Abstract: Introduction Online beam monitoring in medical accelerators is essential in assuring patient's safety as well as high quality and efficacy of cancer treatment. In clinical practice for proton therapy, currently used ionization chambers are interceptive devices, degrading both the beam profile and its energy spread. Therefore, a new noninterceptive approach of online beam monitoring is highly desirable. Method The Vertex Locator (VELO) detector is a multi-strip silicon detector used in the LHCb experiment at CERN. The semi-circular design and position of its sensitive silicon detector offers a non-invasive way to measure the beam intensity through a precise measurement of the beam halo without interfering with the beam core. The adapted standalone VELO detector is integrated at the 60 MeV proton therapy beamline at the Clatterbridge Cancer Centre (CCC), UK. Synchronised with a Faraday Cup and the RF cyclotron frequency, the quality of the beam monitor is assessed by measuring the beam current at different dose rates and by monitoring the beam halo profile at different positions along the beamline. Results The integration zone of the VELO detector is after the double scattering foils, range shifter and modulation wheel. The detector can move along 15 cm along the beamline. The beam current is measured for the dose rate of 10 Monitor Units (MU)/min to 60 MU/min at position 0 cm, 8 cm and 15 cm each. Also, 2D and 3D beam profile measurements are presented for non-skewed and skewed beams. The results are benchmarked against GEANT4 simulations. Conclusion The full setup optimized for implementation in the proton beam line at CCC is described. The capability of VELO as a beam monitor is assessed by measuring the beam current at different dose rates and by monitoring the beam profile. Further measurements in other proton therapy facilities with scanning systems are desirable.
CCC publication: A retrospective real world evidence study to review the current treatment pathways for myelofibrosis from across the united kingdom (the realism UK study)
Citation: British Journal of Haematology. 2019, 185, 8-9
Author: Mead A.; Butt N.; Nagi W.; Whiteway A.; Kirkpatrick S.; Rinaldi C.; Roughley C.; Ackroyd S.; Ewing J.; Neelakantan P.; Garg M.; Harrison C.; Tucker D.; Collington S.; Chiu G.; Hickey J.; Somervaille T.
Abstract: Current treatment options for myelofibrosis (MF) are diverse; typically active treatments manage MF-related symptoms and are not disease modifying. Patients who are initially asymptomatic and those at low risk for progression are often observed without active treatment ('watch and wait') until the appearance of symptoms or progression. There are limited real-world data on the management of patients with MF in the United Kingdom (UK). The REALISM UK study aims to document the early management pathways for patients with MF in routine clinical practice. REALISM UK is a multi-centre, retrospective, non-interventional study ongoing in 15 UK secondary care centres. Eligible patients were those aged >= 18 years at diagnosis of MF, with diagnosis > 6 months and <= 5 years prior to data collection and with >= 1 follow-up visits. Data on patient demographics, clinical characteristics MF management strategies and outcomes were collected from patients' medical records; the observation period was from the date of MF diagnosis until data collection. The primary endpoint was the time from diagnosis to active treatment. Herein we report results from an interim analysis. A total of 200 patients were recruited (64% [127/200] with primary MF (PMF), 36% [73/200] with secondary [2degree] MF). The median age at MF diagnosis was 69.7 (Interquartile range [IQR] 63.5-75.7) years and 63% (125/200) had a JAK2 mutation. 60% (119/200) of patients had International Prognostic Scoring System (IPSS) categories of intermediate-2 (int-2) or high at diagnosis. Common documented features of disease at diagnosis included an enlarged spleen (47%, 94/200), anaemia (44%, 88/200), and constitutional symptoms (e.g. night sweats, unexplained fever or weight loss, [30%, 60/200]). The median time from diagnosis to active treatment was 0.0 (IQR 0.0-369.3) days (n = 200). During the study observation period 'watch and wait' was the first management strategy for 47% (94/200) of patients (PMF, 56% [71/127]; 2degreeMF, 32% [23/73]), with 69% (65/ 94) progressing to active treatment. In these 94 patients (including 29 with no active treatment at data collection), the median (IQR) time from diagnosis to active treatment (or data collection) was 409.0 (141.5-650.0) days (IPSS low: 280.5 [195.0-369.3] days [n = 4]; IPSS int-1: 284.5 [98.0-625.3] days [n = 24]; IPSS int-2 461.0 [259.5-737.3] days [n = 30]; IPSS high: 119.0 [60.3-277.0] days [n = 12]). Active treatment was started at diagnosis for 53% (106/200) of patients. A total of 409 management strategies (defined as any clinical decision on patient management) were observed. The commonest strategies were 'watch and wait' (26% [107/409]), ruxolitinib (25% [102/409]), hydroxycarbamide (17% [68/409]) and allogenic stem cell transplantation (3% [11/409]). The median treatment duration (during the observation period) was 378 (IQR 162.3-690.8) days for ruxolitinib and 336.5 (IQR 108.5-767.5) days for hydroxycarbamide. 47 (24%) patients died between diagnosis and data collection. The recorded causes of death were: MF-related (including progression 38% [18/47]), other malignancies (9% [4/47]), infection (9% [4/47]) and heart failure (6% [3/47]); cause unknown in 38% (18/ 47) cases. The results of this interim analysis suggest there are a broad range of management strategies for patients with MF, reflecting the symptomatic treatment of MF. Many of the patients were observed without active treatment following diagnosis, and the most common cause of death was MF-related.
Author: Mead A.; Butt N.; Nagi W.; Whiteway A.; Kirkpatrick S.; Rinaldi C.; Roughley C.; Ackroyd S.; Ewing J.; Neelakantan P.; Garg M.; Harrison C.; Tucker D.; Collington S.; Chiu G.; Hickey J.; Somervaille T.
Abstract: Current treatment options for myelofibrosis (MF) are diverse; typically active treatments manage MF-related symptoms and are not disease modifying. Patients who are initially asymptomatic and those at low risk for progression are often observed without active treatment ('watch and wait') until the appearance of symptoms or progression. There are limited real-world data on the management of patients with MF in the United Kingdom (UK). The REALISM UK study aims to document the early management pathways for patients with MF in routine clinical practice. REALISM UK is a multi-centre, retrospective, non-interventional study ongoing in 15 UK secondary care centres. Eligible patients were those aged >= 18 years at diagnosis of MF, with diagnosis > 6 months and <= 5 years prior to data collection and with >= 1 follow-up visits. Data on patient demographics, clinical characteristics MF management strategies and outcomes were collected from patients' medical records; the observation period was from the date of MF diagnosis until data collection. The primary endpoint was the time from diagnosis to active treatment. Herein we report results from an interim analysis. A total of 200 patients were recruited (64% [127/200] with primary MF (PMF), 36% [73/200] with secondary [2degree] MF). The median age at MF diagnosis was 69.7 (Interquartile range [IQR] 63.5-75.7) years and 63% (125/200) had a JAK2 mutation. 60% (119/200) of patients had International Prognostic Scoring System (IPSS) categories of intermediate-2 (int-2) or high at diagnosis. Common documented features of disease at diagnosis included an enlarged spleen (47%, 94/200), anaemia (44%, 88/200), and constitutional symptoms (e.g. night sweats, unexplained fever or weight loss, [30%, 60/200]). The median time from diagnosis to active treatment was 0.0 (IQR 0.0-369.3) days (n = 200). During the study observation period 'watch and wait' was the first management strategy for 47% (94/200) of patients (PMF, 56% [71/127]; 2degreeMF, 32% [23/73]), with 69% (65/ 94) progressing to active treatment. In these 94 patients (including 29 with no active treatment at data collection), the median (IQR) time from diagnosis to active treatment (or data collection) was 409.0 (141.5-650.0) days (IPSS low: 280.5 [195.0-369.3] days [n = 4]; IPSS int-1: 284.5 [98.0-625.3] days [n = 24]; IPSS int-2 461.0 [259.5-737.3] days [n = 30]; IPSS high: 119.0 [60.3-277.0] days [n = 12]). Active treatment was started at diagnosis for 53% (106/200) of patients. A total of 409 management strategies (defined as any clinical decision on patient management) were observed. The commonest strategies were 'watch and wait' (26% [107/409]), ruxolitinib (25% [102/409]), hydroxycarbamide (17% [68/409]) and allogenic stem cell transplantation (3% [11/409]). The median treatment duration (during the observation period) was 378 (IQR 162.3-690.8) days for ruxolitinib and 336.5 (IQR 108.5-767.5) days for hydroxycarbamide. 47 (24%) patients died between diagnosis and data collection. The recorded causes of death were: MF-related (including progression 38% [18/47]), other malignancies (9% [4/47]), infection (9% [4/47]) and heart failure (6% [3/47]); cause unknown in 38% (18/ 47) cases. The results of this interim analysis suggest there are a broad range of management strategies for patients with MF, reflecting the symptomatic treatment of MF. Many of the patients were observed without active treatment following diagnosis, and the most common cause of death was MF-related.
CCC publication: Regional experience of screening for JAK2 exon 12 mutations, independent of erythropoietin level stratification, during the investigation of JAK2 V617F negative erythrocytosis
Citation: British Journal of Haematology. 2019, 185, 58-9
Author: Lindsay K.R.; Butt N.M.; Miller K.
Abstract: The updated British Society for Haematology (BSH) guidelines on the diagnosis and management of polycythaemia vera (2018) recommend testing for JAK2 exon 12 mutations in patients with significant JAK2-unmutated erythrocytosis who have low or normal serum erythropoietin (EPO) levels. Our regional molecular genetics service perform JAK2 exon 12 mutation screening based on clinician request without the requirement of EPO-based stratification. In the light of the updated BSH guidance, we retrospectively reviewed a serial cohort of cases of polycythaemia referred for JAK2 mutation screening to determine if adopting an EPO-based algorithm for JAK2 exon 12 mutation screening would significantly alter the number of cases referred for testing. This could have implications on the clinical appropriateness of JAK2 exon 12 mutation screening and may contribute to cost savings. Our regional molecular genetics service provided details of 207 serial regional cases referred for JAK2 V617F testing between February 2018 and October 2018 with clinical details indicating suspected polycythaemia. Twenty-one of the 207 cases were positive for a JAK2 V617F mutation (10%). The majority of JAK2 V617F negative cases (122) did not have any further molecular testing performed, presumably due to the lack of suspicion of a primary polycythaemia. The remaining 64 JAK2 V617F negative cases went on to have JAK2 exon 12 mutation screening. None of these cases were identified to have JAK2 exon 12 mutations. To determine the role of a possible EPO-based stratification for JAK2 exon 12 mutation screening, EPO levels were sought for these 64 cases. Results were available for 51 of these cases. Seven cases had low EPO levels, 42 had levels in the normal range and the two remaining cases had high EPO levels. This confirms that at least two cases were tested for JAK2 exon 12 mutations which would not be indicated if based on the updated BSH guidelines. Assuming the same proportion of cases with high EPO levels (2/51) were found in the remaining 13 cases where EPO levels were not available, this equates to a further 0.51 cases. Based on 2.51 cases tested for JAK2 exon 12 mutations outside of the updated BSH guidelines, at the current cost of 150.00 per JAK2 exon 12 mutation screen, this equates to a cost saving of 376.50. Whilst any cost savings for unnecessary molecular tests are creditable, we do not currently believe that our regional molecular genetics service should withhold JAK2 exon 12 mutation screening in the absence of a EPO-based stratification given that the vast majority of cases will have normal or low results. Finally, a point of interest discovered in the process of this audit was that regardless of the EPO level there were no cases where an exon 12 mutation was detected. Indeed, when our regional molecular genetics service reviewed all requests for JAK2 exon 12 mutation screening since testing for this began in 2008, out of more than 500 cases tested only one mutation was identified, in 2016. Of note is that this patient had a serum EPO level in the normal range. Requests for exon 12 testing continue to increase annually with more than 100 cases tested in each of the last two calendar years. This confirms the high overall cost of screening for exon 12 mutations in suspected primary polycythaemia in JAK2 V617F negative cases given their very low prevalence.
Author: Lindsay K.R.; Butt N.M.; Miller K.
Abstract: The updated British Society for Haematology (BSH) guidelines on the diagnosis and management of polycythaemia vera (2018) recommend testing for JAK2 exon 12 mutations in patients with significant JAK2-unmutated erythrocytosis who have low or normal serum erythropoietin (EPO) levels. Our regional molecular genetics service perform JAK2 exon 12 mutation screening based on clinician request without the requirement of EPO-based stratification. In the light of the updated BSH guidance, we retrospectively reviewed a serial cohort of cases of polycythaemia referred for JAK2 mutation screening to determine if adopting an EPO-based algorithm for JAK2 exon 12 mutation screening would significantly alter the number of cases referred for testing. This could have implications on the clinical appropriateness of JAK2 exon 12 mutation screening and may contribute to cost savings. Our regional molecular genetics service provided details of 207 serial regional cases referred for JAK2 V617F testing between February 2018 and October 2018 with clinical details indicating suspected polycythaemia. Twenty-one of the 207 cases were positive for a JAK2 V617F mutation (10%). The majority of JAK2 V617F negative cases (122) did not have any further molecular testing performed, presumably due to the lack of suspicion of a primary polycythaemia. The remaining 64 JAK2 V617F negative cases went on to have JAK2 exon 12 mutation screening. None of these cases were identified to have JAK2 exon 12 mutations. To determine the role of a possible EPO-based stratification for JAK2 exon 12 mutation screening, EPO levels were sought for these 64 cases. Results were available for 51 of these cases. Seven cases had low EPO levels, 42 had levels in the normal range and the two remaining cases had high EPO levels. This confirms that at least two cases were tested for JAK2 exon 12 mutations which would not be indicated if based on the updated BSH guidelines. Assuming the same proportion of cases with high EPO levels (2/51) were found in the remaining 13 cases where EPO levels were not available, this equates to a further 0.51 cases. Based on 2.51 cases tested for JAK2 exon 12 mutations outside of the updated BSH guidelines, at the current cost of 150.00 per JAK2 exon 12 mutation screen, this equates to a cost saving of 376.50. Whilst any cost savings for unnecessary molecular tests are creditable, we do not currently believe that our regional molecular genetics service should withhold JAK2 exon 12 mutation screening in the absence of a EPO-based stratification given that the vast majority of cases will have normal or low results. Finally, a point of interest discovered in the process of this audit was that regardless of the EPO level there were no cases where an exon 12 mutation was detected. Indeed, when our regional molecular genetics service reviewed all requests for JAK2 exon 12 mutation screening since testing for this began in 2008, out of more than 500 cases tested only one mutation was identified, in 2016. Of note is that this patient had a serum EPO level in the normal range. Requests for exon 12 testing continue to increase annually with more than 100 cases tested in each of the last two calendar years. This confirms the high overall cost of screening for exon 12 mutations in suspected primary polycythaemia in JAK2 V617F negative cases given their very low prevalence.
CCC publication: Results of the First Completed Clinical Trial of an iPSC-Derived Product: CYP-001 in Steroid-Resistant Acute GvHD,
Citation: Biology of Blood and Marrow Transplantation. 2019, 25(3), S255-S256
Author: John E.J. Rasko, Amit Patel, James E. Griffin, Maria H. Gilleece, Rohini Radia, David T. Yeung, Igor Slukvin, Kilian Kelly, Adrian J Bloor,
Abstract: Mesenchymal stem cells (MSCs) have been widely investigated as a treatment for graft versus host disease (GvHD), but with mixed results. Factors such as MSC donor variability and the effects of prolonged culture expansion may have contributed to disappointing outcomes. The novel Cymerus™ manufacturing process facilitates virtually limitless production of well-defined and consistent MSCs from a single iPSC bank, using proprietary clonogenic progenitor-based technology. This avoids both inter-donor variability and the need for excessive culture expansion once MSCs are formed. This is a multi-center, open label study of Cymerus MSCs (CYP-001) in adults with steroid-resistant acute GvHD, following allogeneic hematopoietic stem cell transplantation (NCT02923375). Prior to enrolment, all subjects had failed to respond to at least three days of steroid treatment (≥1 mg/kg/day), administered in accordance with standard management at each center. Subjects received two intravenous infusions of CYP-001 one week apart, at a dose of 1 × 106 cells/kg (Cohort A) or 2 × 106 cells/kg (Cohort B), in addition to standard of care medications. The study involves follow-up over two years, with primary evaluation at 100 days. GvHD was staged and graded according to the 1994 Consensus Conference on Acute GvHD Grading. An Overall Response (OR) was defined as at least a one-grade improvement in GvHD severity, while a Complete Response (CR) was defined as the absence of any GvHD signs or symptoms. The primary objective was assessment of safety and tolerability, while the secondary objective was efficacy, based on overall survival (OS) and best responses by Day 28/Day 100. Eight subjects were enrolled per cohort, but one subject in Cohort B withdrew prior to the initiation of CYP-001 treatment. All subjects had Grade II or III GvHD at baseline. The treatment was well tolerated in all cases, and there were no treatment-related Serious Adverse Events (SAEs) reported. One patient in Cohort A died after developing pneumonia, which was not considered to be CYP-001 treatment-related. One patient in Cohort B did not show a response to CYP-001 treatment, and withdrew from the trial on Day 22 to commence palliative care. All other patients showed an OR and remained alive at Day 100. Overall, outcomes by Day 100 were similar in both cohorts, but Day 28 data suggest a faster response to the higher dose level used in Cohort B (see Table 1 and Figure 1). In conclusion, CYP-001 infusions were found to be safe and well tolerated in this study, and we believe the encouraging treatment response and overall survival rates support progression to a Phase II trial.
Author: John E.J. Rasko, Amit Patel, James E. Griffin, Maria H. Gilleece, Rohini Radia, David T. Yeung, Igor Slukvin, Kilian Kelly, Adrian J Bloor,
Abstract: Mesenchymal stem cells (MSCs) have been widely investigated as a treatment for graft versus host disease (GvHD), but with mixed results. Factors such as MSC donor variability and the effects of prolonged culture expansion may have contributed to disappointing outcomes. The novel Cymerus™ manufacturing process facilitates virtually limitless production of well-defined and consistent MSCs from a single iPSC bank, using proprietary clonogenic progenitor-based technology. This avoids both inter-donor variability and the need for excessive culture expansion once MSCs are formed. This is a multi-center, open label study of Cymerus MSCs (CYP-001) in adults with steroid-resistant acute GvHD, following allogeneic hematopoietic stem cell transplantation (NCT02923375). Prior to enrolment, all subjects had failed to respond to at least three days of steroid treatment (≥1 mg/kg/day), administered in accordance with standard management at each center. Subjects received two intravenous infusions of CYP-001 one week apart, at a dose of 1 × 106 cells/kg (Cohort A) or 2 × 106 cells/kg (Cohort B), in addition to standard of care medications. The study involves follow-up over two years, with primary evaluation at 100 days. GvHD was staged and graded according to the 1994 Consensus Conference on Acute GvHD Grading. An Overall Response (OR) was defined as at least a one-grade improvement in GvHD severity, while a Complete Response (CR) was defined as the absence of any GvHD signs or symptoms. The primary objective was assessment of safety and tolerability, while the secondary objective was efficacy, based on overall survival (OS) and best responses by Day 28/Day 100. Eight subjects were enrolled per cohort, but one subject in Cohort B withdrew prior to the initiation of CYP-001 treatment. All subjects had Grade II or III GvHD at baseline. The treatment was well tolerated in all cases, and there were no treatment-related Serious Adverse Events (SAEs) reported. One patient in Cohort A died after developing pneumonia, which was not considered to be CYP-001 treatment-related. One patient in Cohort B did not show a response to CYP-001 treatment, and withdrew from the trial on Day 22 to commence palliative care. All other patients showed an OR and remained alive at Day 100. Overall, outcomes by Day 100 were similar in both cohorts, but Day 28 data suggest a faster response to the higher dose level used in Cohort B (see Table 1 and Figure 1). In conclusion, CYP-001 infusions were found to be safe and well tolerated in this study, and we believe the encouraging treatment response and overall survival rates support progression to a Phase II trial.
CCC publication: Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group
Citation: The Lancet Oncology. 2019, 20(3), e155-6
Author: Hoeben B.A. (b.hoeben@radboudumc.nl); Carrie C.; Timmermann B.; Mandeville H.C.; Gandola L.; Dieckmann K.; Ramos Albiac M.; Magelssen H.; Lassen-Ramshad Y.; Seiersen K.; Ondrova B.; Ajithkumar T.; Alapetite C.; Balgobind B.V.; Bolle S.; Cameron A.L.; Davila Fajardo R.; Seravalli E.; Janssens G.O.; van den Heuvel-Eibrink M.M.; Dietzsch S.; Kortmann R.D.; Dumont Lecomte D.; Laprie A.; Melchior P.; Padovani L.; Rombi B.; Scarzello G.; Schwarz R.; Thorp N.; Whitfield G.A.; Boterberg T.
Abstract: Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.
Copyright © 2019 Elsevier Ltd. All rights reserved
Link to PubMed record
Author: Hoeben B.A. (b.hoeben@radboudumc.nl); Carrie C.; Timmermann B.; Mandeville H.C.; Gandola L.; Dieckmann K.; Ramos Albiac M.; Magelssen H.; Lassen-Ramshad Y.; Seiersen K.; Ondrova B.; Ajithkumar T.; Alapetite C.; Balgobind B.V.; Bolle S.; Cameron A.L.; Davila Fajardo R.; Seravalli E.; Janssens G.O.; van den Heuvel-Eibrink M.M.; Dietzsch S.; Kortmann R.D.; Dumont Lecomte D.; Laprie A.; Melchior P.; Padovani L.; Rombi B.; Scarzello G.; Schwarz R.; Thorp N.; Whitfield G.A.; Boterberg T.
Abstract: Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.
Copyright © 2019 Elsevier Ltd. All rights reserved
Link to PubMed record
CCC publication: Pretrial outlining quality assurance in PIVITOLBoost
Citation: Journal of Clinical Oncology. 2019, 37
Author: Evans E.; Mayles H.; Naismith O.F.; Hall E.; Tree A.; Staffurth J.; Syndikus I.
Abstract: Background: PIVOTALBoost is a Phase III randomised controlled trial (CRUK/16/018) of radiotherapy to prostate and pelvic nodes versus prostate alone with or without prostate boost. To minimise impact of target volume delineation (TVD) variation on trial outcome, pre-trial radiotherapy quality assurance (RTQA) was implemented to identify and correct potential variations. <br/>Method(s): Participating centres offering a prostate boost submitted two pre-accrual outlining benchmark cases: one with a central zone boost (GTVpb) only and another with GTVpb (peripheral zone), CTVp/psv and CTVn. A detailed outlining protocol and diagnostic information were provided to centres. Submitted outlines were compared to consensus volumes created by the trial management group (TMG). The TMG deemed the volumes acceptable or as having acceptable or unacceptable variation. Detailed feedback was provided for each submission. Unacceptable variations required resubmission. <br/>Result(s): 32 investigators submitted pretrial outlines. GTVpb was the most incorrectly outlined volume; 22 (69%) outliners had unacceptable errors for case 2 GTVpb, 17 (53%) for case 1 GTVpb. Most common GTVpb error was inferior extent of lesion followed by incorrect lesion outlined. 12 (38%) of outliners had unacceptable errors for CTVp/psv, most commonly due to delineation at the prostate apex. 8 (25%) outliners had unacceptable CTVn mostly due to incorrect vessel delineation. Of 26 (81%) outliners required to resubmit at least 1 case, 3(12%) required a second resubmission due to unacceptable errors on first resubmission. <br/>Conclusion(s): The majority of pretrial outlining submissions had unacceptable errors requiring resubmission of at least one case. This was predominantly due to boost delineation error which is a relatively new skill for prostate clinical oncologists in the UK. This suggests robust on-trial RTQA is imperative to minimise further variation.
Author: Evans E.; Mayles H.; Naismith O.F.; Hall E.; Tree A.; Staffurth J.; Syndikus I.
Abstract: Background: PIVOTALBoost is a Phase III randomised controlled trial (CRUK/16/018) of radiotherapy to prostate and pelvic nodes versus prostate alone with or without prostate boost. To minimise impact of target volume delineation (TVD) variation on trial outcome, pre-trial radiotherapy quality assurance (RTQA) was implemented to identify and correct potential variations. <br/>Method(s): Participating centres offering a prostate boost submitted two pre-accrual outlining benchmark cases: one with a central zone boost (GTVpb) only and another with GTVpb (peripheral zone), CTVp/psv and CTVn. A detailed outlining protocol and diagnostic information were provided to centres. Submitted outlines were compared to consensus volumes created by the trial management group (TMG). The TMG deemed the volumes acceptable or as having acceptable or unacceptable variation. Detailed feedback was provided for each submission. Unacceptable variations required resubmission. <br/>Result(s): 32 investigators submitted pretrial outlines. GTVpb was the most incorrectly outlined volume; 22 (69%) outliners had unacceptable errors for case 2 GTVpb, 17 (53%) for case 1 GTVpb. Most common GTVpb error was inferior extent of lesion followed by incorrect lesion outlined. 12 (38%) of outliners had unacceptable errors for CTVp/psv, most commonly due to delineation at the prostate apex. 8 (25%) outliners had unacceptable CTVn mostly due to incorrect vessel delineation. Of 26 (81%) outliners required to resubmit at least 1 case, 3(12%) required a second resubmission due to unacceptable errors on first resubmission. <br/>Conclusion(s): The majority of pretrial outlining submissions had unacceptable errors requiring resubmission of at least one case. This was predominantly due to boost delineation error which is a relatively new skill for prostate clinical oncologists in the UK. This suggests robust on-trial RTQA is imperative to minimise further variation.
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