Citation: Bone Marrow Transplantation. 2019
Author: Wiktor-Jedrzejczak W. (wieslaw.jedrzejczak@wum.edu.pl); Drozd-Sokolowska J.; Eikema D.J.; Hoek J.; van Biezen A.; Potter M.; Wulf G.; Sellner L.; Dreger P.; Ljungman P.; Chevallier P.; Volin L.; Koc Y.; Martin S.; Bunjes D.; Rovira M.; Itala-Remes M.; Foa R.; Deconinck E.; Gedde-Dahl T.; Cornelissen J.; Collin M.; Brecht A.; Patel A.; de Groot M.; Remenyi P.; Nagler A.; Finke J.; Turlure P.; Iacobelli S.; Schetelig J.; Kroger N.
Abstract: Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in Tprolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.
Copyright © 2019, Springer Nature Limited.
Wednesday 24 July 2019
CCC publication: Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer
Citation: OncoImmunology. 2019, 8(6)
Author: Hardy-Werbin M.; Arpi O.; Rovira A.; Albanell J.; Arriola E. (earriola@parcdesalutmar.cat); Rocha P.; Taus A.; Villanueva X.; Nonell L.; Duran X.; Joseph-Pietras D.; Ottensmeier C.; Nolan L.; Danson S.; Griffiths R.; Lopez- Botet M.
Abstract: Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival. Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC.
Copyright © 2019, © 2019 Taylor & Francis Group, LLC.
Author: Hardy-Werbin M.; Arpi O.; Rovira A.; Albanell J.; Arriola E. (earriola@parcdesalutmar.cat); Rocha P.; Taus A.; Villanueva X.; Nonell L.; Duran X.; Joseph-Pietras D.; Ottensmeier C.; Nolan L.; Danson S.; Griffiths R.; Lopez- Botet M.
Abstract: Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival. Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC.
Copyright © 2019, © 2019 Taylor & Francis Group, LLC.
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: A systematic review comparing radiation toxicity after various endorectal techniques
Citation: Brachytherapy. 2019, 18(1), 71
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.; Sun Myint A.
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(s): 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
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.; Sun Myint A.
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(s): 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
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: 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.
Copyright © 2019 American Brachytherapy Society
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: 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.
Copyright © 2019 American Brachytherapy Society
CCC publication: Development of the GEC ESTRO/ABS Guidelines for Rectal Brachytherapy
Citation: Brachytherapy. 2019, 18(3)
Author: Stewart A.J.; Myint A.S.
Abstract: Purpose: The use of rectal brachytherapy is increasing. Two forms of rectal brachytherapy are available; contact brachytherapy using low energy X-Rays (CXB)and high dose rate brachytherapy (HDR-B). The use of a contact brachytherapy boost has been shown in medically inoperable patients to Result in a significantly lower rate of colostomy formation. In the UK approval has been granted by the National Institute of Clinical Excellence (NICE)for its use for primary rectal cancer control, particularly in elderly patients. In Europe, a randomized trial is recruiting comparing contact brachytherapy with an external beam radiotherapy boost. Phase two results of HDR-B in the pre-operative setting in place of external beam radiotherapy to the pelvis show low rates of locoregional
recurrence and a phase 3 study in North America is currently examining this in a randomized setting. The use of HDR-B in the palliative setting in surgically inoperable patients is also increasing and it appears to provide good palliation with acceptable rates of toxicity. Material(s) and Method(s): A multi-disciplinary group of ESTRO and ABS members was convened to develop consensus guidelines based on randomized trial data and clinical experience. Since there was greater variation in practice for HDR-B than CXB, an international survey was circulated regarding current practice and future expectations for clinical and dosimetry standards and reporting for HDR-B. Result(s): The GEC ESTRO/ABS consensus guidelines recommend the use of CXB for patients who are elderly
or surgically unfit or in selected patients with early stage low rectal tumours who wish to avoid colostomy formation. For palliative treatment, the use of HDR-B is recommended for symptomatic relief and disease control in surgically unfit or inoperable patients or those in whom radiotherapy is preferred to surgery. The use of rectal HDR-B is recommended within the setting of a clinical trial or registry for preoperative treatment or in an organ-preservation setting in surgically fit patients. HDR-B for palliation is recommended and dose fractionation schemes are given with recommendations for dosimetry and reporting in both the routine and the research setting.
Conclusion(s): The GEC ESTRO/ABS recommendations for rectal brachytherapy have been developed. Practitioners are encouraged to follow these guidelines and to develop further clinical trials to examine this treatment modality and increase the evidence base for its use. The routine collection of outcomes both clinical and patient-reported is also encouraged.
Copyright © 2019
Author: Stewart A.J.; Myint A.S.
Abstract: Purpose: The use of rectal brachytherapy is increasing. Two forms of rectal brachytherapy are available; contact brachytherapy using low energy X-Rays (CXB)and high dose rate brachytherapy (HDR-B). The use of a contact brachytherapy boost has been shown in medically inoperable patients to Result in a significantly lower rate of colostomy formation. In the UK approval has been granted by the National Institute of Clinical Excellence (NICE)for its use for primary rectal cancer control, particularly in elderly patients. In Europe, a randomized trial is recruiting comparing contact brachytherapy with an external beam radiotherapy boost. Phase two results of HDR-B in the pre-operative setting in place of external beam radiotherapy to the pelvis show low rates of locoregional
recurrence and a phase 3 study in North America is currently examining this in a randomized setting. The use of HDR-B in the palliative setting in surgically inoperable patients is also increasing and it appears to provide good palliation with acceptable rates of toxicity. Material(s) and Method(s): A multi-disciplinary group of ESTRO and ABS members was convened to develop consensus guidelines based on randomized trial data and clinical experience. Since there was greater variation in practice for HDR-B than CXB, an international survey was circulated regarding current practice and future expectations for clinical and dosimetry standards and reporting for HDR-B. Result(s): The GEC ESTRO/ABS consensus guidelines recommend the use of CXB for patients who are elderly
or surgically unfit or in selected patients with early stage low rectal tumours who wish to avoid colostomy formation. For palliative treatment, the use of HDR-B is recommended for symptomatic relief and disease control in surgically unfit or inoperable patients or those in whom radiotherapy is preferred to surgery. The use of rectal HDR-B is recommended within the setting of a clinical trial or registry for preoperative treatment or in an organ-preservation setting in surgically fit patients. HDR-B for palliation is recommended and dose fractionation schemes are given with recommendations for dosimetry and reporting in both the routine and the research setting.
Conclusion(s): The GEC ESTRO/ABS recommendations for rectal brachytherapy have been developed. Practitioners are encouraged to follow these guidelines and to develop further clinical trials to examine this treatment modality and increase the evidence base for its use. The routine collection of outcomes both clinical and patient-reported is also encouraged.
Copyright © 2019
CCC publication: Evaluation of seminal vesicle volume variability in patients receiving radiotherapy to the prostate
Citation: Journal of Radiotherapy in Practice. 2020, 19(1), 20-24
Author: Bairstow R.; Bridge P. (pete.bridge@liverpool.ac.uk); Cain M.; Reynolds P.
Abstract: Introduction:Prostate positional variability has been widely explored with seminal vesicle (SV) variability, coming into the forefront only in recent years. While planning target volume (PTV) margins and preparation protocols ameliorate the effects of bladder and rectum volume changes on prostate, studies on SV variation have looked at only position, not volume variability.
Aim(s):The aim of this study was to investigate whether the inter-fraction volume variability of the VSs can exist in patients receiving radiotherapy to the prostate.
Method(s):SV variability was investigated by comparing four on-treatment cone beam computer tomography scans to a planning computer tomography (CT) image for two patients receiving prostate radiotherapy. For each case, variation in volumes (cm3) was compared with intra-observer variation.
Result(s):SV volume variability was seen in both patients, with the largest change in volume being 78.38%. This variance was considerably (between 2 and 10 times) larger than the measured intra-observer variance.
Conclusion(s):This study identified the potential for daily SV volume variability in patients receiving prostate radiotherapy. Future large-scale studies are warranted to identify the extent of this motion and potential clinical impact. Evidence-informed PTV margins and possible SV volume control protocols may need to be adopted.
Copyright © Cambridge University Press 2019.
Author: Bairstow R.; Bridge P. (pete.bridge@liverpool.ac.uk); Cain M.; Reynolds P.
Abstract: Introduction:Prostate positional variability has been widely explored with seminal vesicle (SV) variability, coming into the forefront only in recent years. While planning target volume (PTV) margins and preparation protocols ameliorate the effects of bladder and rectum volume changes on prostate, studies on SV variation have looked at only position, not volume variability.
Aim(s):The aim of this study was to investigate whether the inter-fraction volume variability of the VSs can exist in patients receiving radiotherapy to the prostate.
Method(s):SV variability was investigated by comparing four on-treatment cone beam computer tomography scans to a planning computer tomography (CT) image for two patients receiving prostate radiotherapy. For each case, variation in volumes (cm3) was compared with intra-observer variation.
Result(s):SV volume variability was seen in both patients, with the largest change in volume being 78.38%. This variance was considerably (between 2 and 10 times) larger than the measured intra-observer variance.
Conclusion(s):This study identified the potential for daily SV volume variability in patients receiving prostate radiotherapy. Future large-scale studies are warranted to identify the extent of this motion and potential clinical impact. Evidence-informed PTV margins and possible SV volume control protocols may need to be adopted.
Copyright © Cambridge University Press 2019.
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.; 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.; 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: The emergency treatment of neutropenic sepsis in the UK-are we getting any better?
Citation: Supportive Care in Cancer. 2019, 27(1)
Author: Forde C.; Marshall E.; Cooksley T.; Young A.; Jones P.; Clarke M.; Wilson R.H.; Coyle V.
Abstract: Introduction Following concerns regarding the management of neutropenic sepsis (NS), the National Institute for Health and Care Excellence (NICE) published the UK's first consensus clinical guideline in 2012. It provides clear recommendations for the emergency treatment and assessment of patients with suspected NS. Methods 53 local adult NS policies from across the UK were reviewed for adoption of key NICE recommendations, along with 217 responses from an electronic survey of clinicians' standard clinical practice. Results 94% of policies highlight NS as a medical emergency, with 98% defining a target 'door to needle' time for first dose antibiotics or stating antibiotics must be given immediately. 98% of clinicians also aim for 60 minutes or less to first dose antibiotics, with 47% reporting this is easy to achieve. Diagnostic criteria used in policies and by clinicians continue to vary; although 76% of clinicians report making a diagnosis is easy. Most policies encourage peripheral and central blood cultures (92%) and that several routine blood tests are checked (79%). 100% highlight that central lines do not need removed routinely and 64% that chest x-rays are not required unless clinically indicated. 85% of policies promote initial beta lactam antibioticmonotherapy (compared with 36% prior to NICE guidance), with significant reductions in empirical aminoglycosides and glycopeptides.
Conclusions Although definitions and diagnostic criteria vary this work demonstrates a consistent approach to emergency NS management across the UK. Local policies and clinicians reported practice confirms the prioritising of NS as a medical emergency and reflects natonally recommended initial investigations and antibiotic regimens.
Author: Forde C.; Marshall E.; Cooksley T.; Young A.; Jones P.; Clarke M.; Wilson R.H.; Coyle V.
Abstract: Introduction Following concerns regarding the management of neutropenic sepsis (NS), the National Institute for Health and Care Excellence (NICE) published the UK's first consensus clinical guideline in 2012. It provides clear recommendations for the emergency treatment and assessment of patients with suspected NS. Methods 53 local adult NS policies from across the UK were reviewed for adoption of key NICE recommendations, along with 217 responses from an electronic survey of clinicians' standard clinical practice. Results 94% of policies highlight NS as a medical emergency, with 98% defining a target 'door to needle' time for first dose antibiotics or stating antibiotics must be given immediately. 98% of clinicians also aim for 60 minutes or less to first dose antibiotics, with 47% reporting this is easy to achieve. Diagnostic criteria used in policies and by clinicians continue to vary; although 76% of clinicians report making a diagnosis is easy. Most policies encourage peripheral and central blood cultures (92%) and that several routine blood tests are checked (79%). 100% highlight that central lines do not need removed routinely and 64% that chest x-rays are not required unless clinically indicated. 85% of policies promote initial beta lactam antibioticmonotherapy (compared with 36% prior to NICE guidance), with significant reductions in empirical aminoglycosides and glycopeptides.
Conclusions Although definitions and diagnostic criteria vary this work demonstrates a consistent approach to emergency NS management across the UK. Local policies and clinicians reported practice confirms the prioritising of NS as a medical emergency and reflects natonally recommended initial investigations and antibiotic regimens.
CCC publication: Routine risk stratification of patients presenting with neutropenic sepsis-an assessment of standard clinical practice in the UK
Citation: Supportive Care in Cancer. 2019, 27(1)
Author: Forde C.; Marshall E.; Cooksley T.; Young A.; Jones P.; Clarke M.; Wilson R.H.; Coyle V.
Abstract: Introduction For patients presenting with neutropenic sepsis (NS) clinicians are encouraged to assess their risk of septic complications using a validated tool. This approach is promoted by national UK NS guidelines (NICE), and international organisations such as MASCC, ASCO and ESMO. Methods 53 local adult NS policies from across the UK were reviewed for approaches to risk stratification, along with 217 responses from an electronic survey of clinicians' standard clinical practice. Results 53% of policies encourage identification of 'low risk' patients within 24 hours of presentation and consider discharge on oral antibiotics prior to 48 hours in hospital (45% calculate a MASCC score, 8% their own criteria). This compares with approximately a third of policies when practice was reviewed in 2012. 40% of clinicians routinely risk stratify patients within 24 hours (70% MASCC tool, 30% institution's own risk scoring system, Modified Early Warning Score or Clinical Index of Stable Febrile Neutropenia). Awide range of approaches to early oral antibiotics, discharge and ambulatory care are described in policies and by clinicians. There is limited evidence of empirical oral antibiotics for low risk patients (9% policies, 5% clinicians) but a preference for initial intravenous antibiotics for all patients.
Conclusions There has been some enhanced uptake of routine risk assessment and consideration of early outpatient oral antibiotics for low risk patients. However this does not appear to be widespread standard practice. Further efforts are therefore required to improve the usability and performance of currently validated tools and optimise and promote low risk management care pathways.
Author: Forde C.; Marshall E.; Cooksley T.; Young A.; Jones P.; Clarke M.; Wilson R.H.; Coyle V.
Abstract: Introduction For patients presenting with neutropenic sepsis (NS) clinicians are encouraged to assess their risk of septic complications using a validated tool. This approach is promoted by national UK NS guidelines (NICE), and international organisations such as MASCC, ASCO and ESMO. Methods 53 local adult NS policies from across the UK were reviewed for approaches to risk stratification, along with 217 responses from an electronic survey of clinicians' standard clinical practice. Results 53% of policies encourage identification of 'low risk' patients within 24 hours of presentation and consider discharge on oral antibiotics prior to 48 hours in hospital (45% calculate a MASCC score, 8% their own criteria). This compares with approximately a third of policies when practice was reviewed in 2012. 40% of clinicians routinely risk stratify patients within 24 hours (70% MASCC tool, 30% institution's own risk scoring system, Modified Early Warning Score or Clinical Index of Stable Febrile Neutropenia). Awide range of approaches to early oral antibiotics, discharge and ambulatory care are described in policies and by clinicians. There is limited evidence of empirical oral antibiotics for low risk patients (9% policies, 5% clinicians) but a preference for initial intravenous antibiotics for all patients.
Conclusions There has been some enhanced uptake of routine risk assessment and consideration of early outpatient oral antibiotics for low risk patients. However this does not appear to be widespread standard practice. Further efforts are therefore required to improve the usability and performance of currently validated tools and optimise and promote low risk management care pathways.
CCC publication: Surgery for epilepsy
Citation: Cochrane Database of Systematic Reviews. 2019, (6)
Author: West S. (siobhan.west@cmft.nhs.uk); Sudan A.; Newton R.; Nevitt S.J.; Cotton J.; Gandhi S.; Weston J.; Ramirez R.
Abstract: Background This is an updated version of the original Cochrane review, published in 2015. Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary between at least 20% and up to 70%. If the epileptogenic zone can be located, surgical resection offers the chance of a cure with a corresponding increase in quality of life. Objectives The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials. Secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence, and to identify the factors that correlate with remission of seizures postoperatively. Search methods For the latest update, we searched the following databases on 11 March 2019: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to March 08, 2019), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Selection criteria Eligible
studies were randomised controlled trials (RCTs) that included at least 30 participants in a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), with an MRI performed in at least 90% of cases and an expected duration of followup of at least one year, and reporting an outcome related to postoperative seizure control. Cohort studies or case series were included in the previous version of this review. Data collection and analysis Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportions of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RRs) and 95% confidence intervals (95% CIs). Main results We identified 182 studies with a total of 16,855 included participants investigating outcomes of surgery for epilepsy. Nine studies were RCTs (including two that randomised participants to surgery or medical treatment (99 participants included in the two trials received medical treatment)). Risk of bias in these RCTs was unclear or high. Most of the remaining 173 non-randomised studies followed a retrospective design. We assessed study quality using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses, we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across domains. In terms of freedom from seizures, two RCTs found surgery (n = 97) to be superior to medical treatment (n = 99); four found no statistically significant differences between anterior temporal lobectomy (ATL) with or without corpus callosotomy (n = 60), between subtemporal or transsylvian approach to selective amygdalohippocampectomy (SAH) (n = 47); between ATL, SAH and
parahippocampectomy (n = 43) or between 2.5 cm and 3.5 cm ATL resection (n = 207). One RCT found total hippocampectomy to be superior to partial hippocampectomy (n = 70) and one found ATL to be superior to stereotactic radiosurgery (n = 58); and another provided data to show that for Lennox-Gastaut syndrome, no significant differences in seizure outcomes were evident between those treated with resection of the epileptogenic zone and those treated with resection of the epileptogenic zone plus corpus callosotomy (n = 43). We judged evidence from the nine RCTs to be of moderate to very low quality due to lack of information reported about the randomised trial design and the restricted study populations. Of the 16,756 participants included in this review who underwent a surgical procedure, 10,696 (64%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to recording of adverse events to be very poor. In total, 120 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better postsurgical seizure outcome: abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical
resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography, history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection, and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation, and presence of postoperative discharges were prognostic factors of outcome.Twenty-nine studies reported multivariable models of prognostic factors, and showed that the direction of association of factors with outcomes was generally the same as that found in univariate analyses. We observed variability in many of our analyses, likely due to small study sizes with unbalanced group sizes and variation in the definition of seizure outcome, the definition of prognostic factors, and the influence of the site of surgery Authors' conclusions Study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcomes. Future research should be of high quality, follow a prospective design, be appropriately powered, and focus on specific issues related to diagnostic tools, the site-specific surgical approach, and other issues such as extent of resection. Researchers should investigate prognostic factors related to the outcome of surgery via multi-variable statistical regression modelling, where variables are selected for modelling according to clinical relevance, and all numerical results of the prognostic models are fully reported. Journal editors should not accept papers for which study authors did not record adverse events from a medical intervention. Researchers have achieved improvements in cancer care over the past three to four decades by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Author: West S. (siobhan.west@cmft.nhs.uk); Sudan A.; Newton R.; Nevitt S.J.; Cotton J.; Gandhi S.; Weston J.; Ramirez R.
Abstract: Background This is an updated version of the original Cochrane review, published in 2015. Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary between at least 20% and up to 70%. If the epileptogenic zone can be located, surgical resection offers the chance of a cure with a corresponding increase in quality of life. Objectives The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials. Secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence, and to identify the factors that correlate with remission of seizures postoperatively. Search methods For the latest update, we searched the following databases on 11 March 2019: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to March 08, 2019), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Selection criteria Eligible
studies were randomised controlled trials (RCTs) that included at least 30 participants in a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), with an MRI performed in at least 90% of cases and an expected duration of followup of at least one year, and reporting an outcome related to postoperative seizure control. Cohort studies or case series were included in the previous version of this review. Data collection and analysis Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportions of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RRs) and 95% confidence intervals (95% CIs). Main results We identified 182 studies with a total of 16,855 included participants investigating outcomes of surgery for epilepsy. Nine studies were RCTs (including two that randomised participants to surgery or medical treatment (99 participants included in the two trials received medical treatment)). Risk of bias in these RCTs was unclear or high. Most of the remaining 173 non-randomised studies followed a retrospective design. We assessed study quality using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses, we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across domains. In terms of freedom from seizures, two RCTs found surgery (n = 97) to be superior to medical treatment (n = 99); four found no statistically significant differences between anterior temporal lobectomy (ATL) with or without corpus callosotomy (n = 60), between subtemporal or transsylvian approach to selective amygdalohippocampectomy (SAH) (n = 47); between ATL, SAH and
parahippocampectomy (n = 43) or between 2.5 cm and 3.5 cm ATL resection (n = 207). One RCT found total hippocampectomy to be superior to partial hippocampectomy (n = 70) and one found ATL to be superior to stereotactic radiosurgery (n = 58); and another provided data to show that for Lennox-Gastaut syndrome, no significant differences in seizure outcomes were evident between those treated with resection of the epileptogenic zone and those treated with resection of the epileptogenic zone plus corpus callosotomy (n = 43). We judged evidence from the nine RCTs to be of moderate to very low quality due to lack of information reported about the randomised trial design and the restricted study populations. Of the 16,756 participants included in this review who underwent a surgical procedure, 10,696 (64%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to recording of adverse events to be very poor. In total, 120 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better postsurgical seizure outcome: abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical
resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography, history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection, and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation, and presence of postoperative discharges were prognostic factors of outcome.Twenty-nine studies reported multivariable models of prognostic factors, and showed that the direction of association of factors with outcomes was generally the same as that found in univariate analyses. We observed variability in many of our analyses, likely due to small study sizes with unbalanced group sizes and variation in the definition of seizure outcome, the definition of prognostic factors, and the influence of the site of surgery Authors' conclusions Study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcomes. Future research should be of high quality, follow a prospective design, be appropriately powered, and focus on specific issues related to diagnostic tools, the site-specific surgical approach, and other issues such as extent of resection. Researchers should investigate prognostic factors related to the outcome of surgery via multi-variable statistical regression modelling, where variables are selected for modelling according to clinical relevance, and all numerical results of the prognostic models are fully reported. Journal editors should not accept papers for which study authors did not record adverse events from a medical intervention. Researchers have achieved improvements in cancer care over the past three to four decades by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CCC publication: Reply
Citation: Journal of Vascular Surgery. 2019, 70(2), 660-61
Author: Wee I.J.Y.; Mohamed I.H.; Patel A.; Choong A.M.T.L.
Author: Wee I.J.Y.; Mohamed I.H.; Patel A.; Choong A.M.T.L.
CCC publication: Long term follow-up of FoRT: a phase III multi-centre 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 Lenalidomide in patients with relapsed or refractory diffuse large B-Cell Lymphoma (L-MIND)
Citation: Hematological Oncology. 2019, 37, 173-74
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: 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, 14(7), 1255-65
Author: Cho, Byoung Chul; Obermannova, Radka; Bearz, Alessandra; McKeage, Mark; Kim, Dong-Wang; Batra, Ullas; Borra, Gloria; Orlov, Sergey; Kim, Sang-We; Geater, Sarayut L.; Postmus, Pieter E.; Laurie, Scott A.; Park, Keunchil; Yang, Cheng-Ta; Ardizzoni, Andrea; Bettini, Anna C.; de Castro, Gilberto; Kiertsman, Flavia; Chen, Zhe; Lau, Yvonne Y
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: Cho, Byoung Chul; Obermannova, Radka; Bearz, Alessandra; McKeage, Mark; Kim, Dong-Wang; Batra, Ullas; Borra, Gloria; Orlov, Sergey; Kim, Sang-We; Geater, Sarayut L.; Postmus, Pieter E.; Laurie, Scott A.; Park, Keunchil; Yang, Cheng-Ta; Ardizzoni, Andrea; Bettini, Anna C.; de Castro, Gilberto; Kiertsman, Flavia; Chen, Zhe; Lau, Yvonne Y
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
CCC publication: Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome
Citation: Pigment cell & melanoma research. 2019, 32(4), 564-75
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; metastasis
Link to PubMed record
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; metastasis
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, Flach KD, Opdam M, Palmieri C, Linn SC, Wesseling J, Ali S, Bliss JM, Cheang MCU, Zwart W, Coombes RC
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, Flach KD, Opdam M, Palmieri C, Linn SC, Wesseling J, Ali S, Bliss JM, Cheang MCU, Zwart W, Coombes RC
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: A cohort study of local excision followed by adjuvant therapy incorporating a contact X-ray brachytherapy boost instead of radical resection in 180 patients with rectal cancer
Citation: Colorectal Disease. 2019, 21(6), 663-70
Author: Smith FM, Pritchard DM, Wong H, Whitmarsh K, Hershman MJ, Sun Myint A
Abstract: AIM: Recent data have suggested near-equivalent oncological results when treating early rectal cancer by local excision followed by radio- ± chemotherapy rather than salvage radical surgery. The aim of this retrospective study was to assess the use of contact X-ray brachytherapy within this paradigm.
METHOD: All patients had undergone local excision and were referred to our radiotherapy centre for treatment with contact X-ray brachytherapy. Postoperative (chemo)radiotherapy was also given in their local hospital in most cases. Variables assessed were local excision method, postoperative therapy received, follow-up duration, disease-free survival, salvage surgery and stoma-free survival.
RESULTS: In total, 180 patients with a median age of 70 (range 36-99) years were assessed. Following local excision, pT stages were pT1 = 131 (72%), pT2 = 44 (26%), pT3 = 5 (2%). All patients received contact X-ray brachytherapy boosting at our centre and, in addition, 110 received chemoradiotherapy and 60 received radiotherapy alone. After a median follow-up of 36 months (range 6-48), 169 patients (94%) remained free of local recurrence. Of the 11 patients with local recurrence (three isolated nodal), five underwent salvage abdominoperineal excision. Eight patients developed distant disease, of whom five underwent metastasis surgery. At last included follow-up 173 (96%) patients were free of all disease and 170 (94%) were stoma free.
CONCLUSIONS: Contact therapy can be offered in addition to external beam radio (±chemo) therapy instead of radical surgery as follow-on treatment after local excision of early rectal cancer. This combination can provide equivalent outcomes to radical surgery. The added value of contact therapy should be formally assessed in a clinical trial.
Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.
KEYWORDS: Rectal cancer; chemotherapy; local excision; radiotherapy; ‘watch and wait’
Link to PubMed record
Author: Smith FM, Pritchard DM, Wong H, Whitmarsh K, Hershman MJ, Sun Myint A
Abstract: AIM: Recent data have suggested near-equivalent oncological results when treating early rectal cancer by local excision followed by radio- ± chemotherapy rather than salvage radical surgery. The aim of this retrospective study was to assess the use of contact X-ray brachytherapy within this paradigm.
METHOD: All patients had undergone local excision and were referred to our radiotherapy centre for treatment with contact X-ray brachytherapy. Postoperative (chemo)radiotherapy was also given in their local hospital in most cases. Variables assessed were local excision method, postoperative therapy received, follow-up duration, disease-free survival, salvage surgery and stoma-free survival.
RESULTS: In total, 180 patients with a median age of 70 (range 36-99) years were assessed. Following local excision, pT stages were pT1 = 131 (72%), pT2 = 44 (26%), pT3 = 5 (2%). All patients received contact X-ray brachytherapy boosting at our centre and, in addition, 110 received chemoradiotherapy and 60 received radiotherapy alone. After a median follow-up of 36 months (range 6-48), 169 patients (94%) remained free of local recurrence. Of the 11 patients with local recurrence (three isolated nodal), five underwent salvage abdominoperineal excision. Eight patients developed distant disease, of whom five underwent metastasis surgery. At last included follow-up 173 (96%) patients were free of all disease and 170 (94%) were stoma free.
CONCLUSIONS: Contact therapy can be offered in addition to external beam radio (±chemo) therapy instead of radical surgery as follow-on treatment after local excision of early rectal cancer. This combination can provide equivalent outcomes to radical surgery. The added value of contact therapy should be formally assessed in a clinical trial.
Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.
KEYWORDS: Rectal cancer; chemotherapy; local excision; radiotherapy; ‘watch and wait’
Link to PubMed record
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 TA, Kirkwood AA, Gohill S, Follows G, Walewska R, Walter H, Cross M, Forconi F, Shah N, Chasty R, Hart A, Broom A, Marr H, Patten PEM, Dann A, Arumainathan A, Munir T, Shankara P, Bloor A, Johnston R, Orchard K, Schuh AH, et al
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
Link to PubMed record
Author: Eyre TA, Kirkwood AA, Gohill S, Follows G, Walewska R, Walter H, Cross M, Forconi F, Shah N, Chasty R, Hart A, Broom A, Marr H, Patten PEM, Dann A, Arumainathan A, Munir T, Shankara P, Bloor A, Johnston R, Orchard K, Schuh AH, et al
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
Link to PubMed record
CCC publication: Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage
Citation: International Journal of Radiation Oncology, Biology, Physics. 2019, 104(3), 656-65
Author: Carter RJ, Nickson CM, Thompson JM, Kacperek A, Hill MA, Parsons JL
Abstract: PURPOSE: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking.
METHODS AND MATERIALS: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay.
RESULTS: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA.
CONCLUSIONS: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved
Link to PubMed record
Author: Carter RJ, Nickson CM, Thompson JM, Kacperek A, Hill MA, Parsons JL
Abstract: PURPOSE: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking.
METHODS AND MATERIALS: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay.
RESULTS: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA.
CONCLUSIONS: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved
Link to PubMed record
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 JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, et al
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 JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, et al
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: Therapeutic Radiographers' perceptions of the barriers and enablers to effective smoking cessation support
Citation: Radiography. 2019, 25(2), 121-28
Author: Charlesworth L, Hutton D, Hussain H
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
Link to PubMed record
Author: Charlesworth L, Hutton D, Hussain H
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
Link to PubMed record
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), 541-48
Author: Gore M, Hackshaw A, Brady WE, Penson RT, Zaino R, McCluggage WG, Ganesan R, Wilkinson N, Perren T, Montes A, Summers J, Lord R, Dark G, Rustin G, Mackean M, Reed N, Kehoe S, Frumovitz M, Christensen H, Feeney A, Ledermann J, Gershenson DM
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
Link to PubMed record
Author: Gore M, Hackshaw A, Brady WE, Penson RT, Zaino R, McCluggage WG, Ganesan R, Wilkinson N, Perren T, Montes A, Summers J, Lord R, Dark G, Rustin G, Mackean M, Reed N, Kehoe S, Frumovitz M, Christensen H, Feeney A, Ledermann J, Gershenson DM
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
Link to PubMed record
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, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, Manoharan P, Palmer D, Bridgewater J, Valle JW
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
Link to PubMed record
Author: Lamarca A, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, Manoharan P, Palmer D, Bridgewater J, Valle JW
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
Link to PubMed record
CCC publication: Integration of Checkpoint Inhibitors into the Management of Locally Advanced Head and Neck Cancer - Future Perspectives
Citation: Clinical Oncology. 2019, 31(7), 424-31
Author: Brooker RC, Sacco JJ, Schache AG
Link to PubMed record
Author: Brooker RC, Sacco JJ, Schache AG
Link to PubMed record
CCC publication: Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer
Citation: Clinical Cancer Research. 2019 May 21 [Epub ahead of print]
Author: Slovin S, Hussain S, Saad F, Garcia J, Picus J, Ferraldeschi R, Crespo M, Flohr P, Riisnaes R, Lin C, Keer H, Oganesian A, Workman P, de Bono J
Abstract: Purpose: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P.Patients and Methods: Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous 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 (CTC) 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 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients 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.
©2019 American Association for Cancer Research.
Link to PubMed record
Author: Slovin S, Hussain S, Saad F, Garcia J, Picus J, Ferraldeschi R, Crespo M, Flohr P, Riisnaes R, Lin C, Keer H, Oganesian A, Workman P, de Bono J
Abstract: Purpose: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P.Patients and Methods: Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous 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 (CTC) 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 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients 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.
©2019 American Association for Cancer Research.
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: Gynecologic Oncology. 2019, 154(1), 29-37
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 Elsevier Inc. All rights reserved.
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 Elsevier Inc. All rights reserved.
KEYWORDS: Aromatase inhibitor; Clinical trial; Endometrial cancer; Quality of life
Link to PubMed record
CCC publication: Assembling the brain trust: the multidisciplinary imperative in neuro-oncology
Citation: Nature reviews. Clinical Oncology. 2019, 16(8), 521-22
Author: Ludmir EB, Mahajan A, Ahern V, Ajithkumar T, Alapetite C, Bernier-Chastagner V, Bindra RS, Bishop AJ, Bolle S, Brown PD, Carrie C, Chalmers AJ, Chang EL, Chung C, Dieckmann K, Esiashvili N, Gandola L, Ghia AJ, Gondi V, Grosshans DR, Harrabi SB, Horan G, et al
Link to PubMed record
Author: Ludmir EB, Mahajan A, Ahern V, Ajithkumar T, Alapetite C, Bernier-Chastagner V, Bindra RS, Bishop AJ, Bolle S, Brown PD, Carrie C, Chalmers AJ, Chang EL, Chung C, Dieckmann K, Esiashvili N, Gandola L, Ghia AJ, Gondi V, Grosshans DR, Harrabi SB, Horan G, et al
Link to PubMed record
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 [Epub ahead of print]
Author: Khoja L, Atenafu EG, Suciu S, Leyvraz S, Sato T, Marshall E, Keilholz U, Zimmer L, Patel SP, Piperno-Neumann S, Piulats J, Kivelä TT, Pfoehler C, Bhatia S, Huppert P, Van Iersel LBJ, De Vries IJM, Penel N, Vogl T, Cheng T, Fiorentini G, Mouriaux F, et al
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 EG, Suciu S, Leyvraz S, Sato T, Marshall E, Keilholz U, Zimmer L, Patel SP, Piperno-Neumann S, Piulats J, Kivelä TT, Pfoehler C, Bhatia S, Huppert P, Van Iersel LBJ, De Vries IJM, Penel N, Vogl T, Cheng T, Fiorentini G, Mouriaux F, et al
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: 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, 31(9), 611-20
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: AIM: Organ-preserving local excision by transanal endoscopic microsurgery (TEM) for early rectal cancer offers significantly lower morbidity as compared to formal rectal cancer resection with acceptable outcomes. This study presents our 6-year experience of TEM for rectal lesions referred to a specialist early rectal cancer centre in the UK.
METHOD: Data were collected for all patients referred for TEM of suspected early rectal cancer to a regional specialist early rectal cancer multidisciplinary team (MDT) over a 6-year period.
RESULTS: One hundred and forty-one patients who underwent full-thickness TEM for suspected or confirmed early rectal cancer were included. Thirty 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%), pT1 in 32 (51.7%), pT2 in 11 (18.0%) and pT3 in 1 (1.6%). Thirty-eight of 61 patients (62.3%) had one or more poor histological prognostic features and these patients were offered further treatment. Twenty-three of 61 (37.7%) patients with rectal adenocarcinoma required no further treatment following TEM. Forty-three cases of rectal adenocarcinoma were available for establishing recurrence rates. Two of 43 patients (4.7%) developed a recurrence at a median follow-up of 28.7 months (12.1-66.5 months). The overall estimated 5-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.
Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.
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: AIM: Organ-preserving local excision by transanal endoscopic microsurgery (TEM) for early rectal cancer offers significantly lower morbidity as compared to formal rectal cancer resection with acceptable outcomes. This study presents our 6-year experience of TEM for rectal lesions referred to a specialist early rectal cancer centre in the UK.
METHOD: Data were collected for all patients referred for TEM of suspected early rectal cancer to a regional specialist early rectal cancer multidisciplinary team (MDT) over a 6-year period.
RESULTS: One hundred and forty-one patients who underwent full-thickness TEM for suspected or confirmed early rectal cancer were included. Thirty 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%), pT1 in 32 (51.7%), pT2 in 11 (18.0%) and pT3 in 1 (1.6%). Thirty-eight of 61 patients (62.3%) had one or more poor histological prognostic features and these patients were offered further treatment. Twenty-three of 61 (37.7%) patients with rectal adenocarcinoma required no further treatment following TEM. Forty-three cases of rectal adenocarcinoma were available for establishing recurrence rates. Two of 43 patients (4.7%) developed a recurrence at a median follow-up of 28.7 months (12.1-66.5 months). The overall estimated 5-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.
Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.
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
CCC publication: Earlier identification of seriously ill patients: an implementation case series
Citation: BMJ supportive and palliative care. 2019 Jun 28 [Epub ahead of print]
Author: Lakin JR, Desai M, Engelman K, O'Connor N, Teuteberg WG, Coackley A, Kilpatrick LB, Gawande A, Fromme EK
Abstract: OBJECTIVE: To describe the strategies used by a collection of healthcare systems to apply different methods of identifying seriously ill patients for a targeted palliative care intervention to improve communication around goals and values.
METHODS: We present an implementation case series describing the experiences, challenges and best practices in applying patient selection strategies across multiple healthcare systems implementing the Serious Illness Care Program (SICP).
RESULTS: Five sites across the USA and England described their individual experiences implementing patient selection as part of the SICP. They employed a combination of clinician screens (such as the 'Surprise Question'), disease-specific criteria, existing registries or algorithms as a starting point. Notably, each describes adaptation and evolution of their patient selection methodology over time, with several sites moving towards using more advanced machine learning-based analytical approaches.
CONCLUSIONS: Involving clinical and programme staff to choose a simple initial method for patient identification is the ideal starting place for selecting patients for palliative care interventions. However, improving and refining methods over time is important and we need ongoing research into better patient selection methodologies that move beyond mortality prediction and instead focus on identifying seriously ill patients-those with poor quality of life, worsening functional status and medical care that is negatively impacting their families.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: advance care planning; palliative care; patient identification; patient selection; serious illness communication; triggers
Link to PubMed record
Author: Lakin JR, Desai M, Engelman K, O'Connor N, Teuteberg WG, Coackley A, Kilpatrick LB, Gawande A, Fromme EK
Abstract: OBJECTIVE: To describe the strategies used by a collection of healthcare systems to apply different methods of identifying seriously ill patients for a targeted palliative care intervention to improve communication around goals and values.
METHODS: We present an implementation case series describing the experiences, challenges and best practices in applying patient selection strategies across multiple healthcare systems implementing the Serious Illness Care Program (SICP).
RESULTS: Five sites across the USA and England described their individual experiences implementing patient selection as part of the SICP. They employed a combination of clinician screens (such as the 'Surprise Question'), disease-specific criteria, existing registries or algorithms as a starting point. Notably, each describes adaptation and evolution of their patient selection methodology over time, with several sites moving towards using more advanced machine learning-based analytical approaches.
CONCLUSIONS: Involving clinical and programme staff to choose a simple initial method for patient identification is the ideal starting place for selecting patients for palliative care interventions. However, improving and refining methods over time is important and we need ongoing research into better patient selection methodologies that move beyond mortality prediction and instead focus on identifying seriously ill patients-those with poor quality of life, worsening functional status and medical care that is negatively impacting their families.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: advance care planning; palliative care; patient identification; patient selection; serious illness communication; triggers
Link to PubMed record
CCC publication: Real-world experience with cabazitaxel in patients with metastatic castration-resistant prostate cancer: a final, pooled analysis of the compassionate use programme and early access programme
Citation: Oncotarget. 2019, 10(41), 4161-68
Author: Malik Z, Heidenreich A, Bracarda S, Ardavanis A, Parente P, Scholz HJ, Ozatilgan A, Ecstein-Fraisse E, Hitier S, Di Lorenzo G
Abstract: Background: Cabazitaxel is a second-generation taxane approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. Early access programmes were established to allow eligible patients with mCRPC access to cabazitaxel before regulatory approval.
Materials and Methods: The primary objective was to allow access to cabazitaxel before commercial availability for patients with mCRPC whose disease had progressed during or after chemotherapy with docetaxel; the secondary objective was overall safety. Patients received cabazitaxel 25 mg/m2 on Day 1 of a 21-day cycle, with daily oral 10 mg prednisone/prednisolone. G-CSF was administered per ASCO guidelines.
Results: In total, 1432 patients received cabazitaxel across 41 countries between 2010 and 2014 (median 6.0 treatment cycles [range 1-49]). The most frequently occurring treatment-emergent adverse events (TEAEs) possibly related to treatment were diarrhoea (33.3%), fatigue (25.4%) and anaemia (23.7%); the most frequently occurring possibly related Grade 3/4 TEAEs were neutropenia (18.7%) and febrile neutropenia (6.9%). G-CSF was administered in ≥ 1 cycle in 64% of patients (10.1% therapeutic use; 57.8% prophylactic use; 9.7% both uses).
Conclusion: The safety profile of cabazitaxel in this pooled analysis of two cabazitaxel early access programmes was manageable and consistent with previous Phase III trials (TROPIC, PROSELICA).
KEYWORDS: CUP; EAP; cabazitaxel; mCRPC; real-world
Link to PubMed record
Author: Malik Z, Heidenreich A, Bracarda S, Ardavanis A, Parente P, Scholz HJ, Ozatilgan A, Ecstein-Fraisse E, Hitier S, Di Lorenzo G
Abstract: Background: Cabazitaxel is a second-generation taxane approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. Early access programmes were established to allow eligible patients with mCRPC access to cabazitaxel before regulatory approval.
Materials and Methods: The primary objective was to allow access to cabazitaxel before commercial availability for patients with mCRPC whose disease had progressed during or after chemotherapy with docetaxel; the secondary objective was overall safety. Patients received cabazitaxel 25 mg/m2 on Day 1 of a 21-day cycle, with daily oral 10 mg prednisone/prednisolone. G-CSF was administered per ASCO guidelines.
Results: In total, 1432 patients received cabazitaxel across 41 countries between 2010 and 2014 (median 6.0 treatment cycles [range 1-49]). The most frequently occurring treatment-emergent adverse events (TEAEs) possibly related to treatment were diarrhoea (33.3%), fatigue (25.4%) and anaemia (23.7%); the most frequently occurring possibly related Grade 3/4 TEAEs were neutropenia (18.7%) and febrile neutropenia (6.9%). G-CSF was administered in ≥ 1 cycle in 64% of patients (10.1% therapeutic use; 57.8% prophylactic use; 9.7% both uses).
Conclusion: The safety profile of cabazitaxel in this pooled analysis of two cabazitaxel early access programmes was manageable and consistent with previous Phase III trials (TROPIC, PROSELICA).
KEYWORDS: CUP; EAP; cabazitaxel; mCRPC; real-world
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, Field JK, Davies MPA, Escriu C, Gruver A, Gosney JR
Abstract: OBJECTIVES: PD-L1 expression on tumour cells can guide the use of anti-PD-1/PD-L1 immune modulators to treat patients with non-small cell lung cancer (NSCLC). Heterogeneity of PD-L1 expression both within and between tumour sites is a well-documented phenomenon that compromises its predictive power. Our aim was to better characterise the pattern and extent of PD-L1 heterogeneity with a view to optimising tumour sampling and improve its accuracy as a biomarker.
MATERIALS AND METHODS:
Expression of PD-L1 was assessed by immunochemistry using the SP263 clone in 107 resected primary NSCLCs and their nodal metastases. Intra-tumoural heterogeneity, defined as 'small-scale' (mm²), 'medium-scale' (cm²) and 'large-scale' (between tumour blocks), was assessed by digital imaging using a novel 'squares method'. Inter-tumoural heterogeneity between the primary tumours and their nodal metastases and between N1 and N2 nodal stages was also assessed.
RESULTS: The majority of tumours demonstrated intra-tumoural heterogeneity (small-scale 78%, medium-scale 50%, large-scale 46%). Inter-tumoural heterogeneity between the primary and nodal metastases was present in 53% of cases and, in 17%, between N1 and N2 disease. These differences were occasionally sufficient to lead to discrepancy across the ≥1%, ≥25% and ≥50% cut-offs used to guide therapy.
CONCLUSION: Heterogeneity of PD-L1 expression is common, variable in scale and extent, and carries significant implications for its accuracy as a predictive biomarker. Extensive sampling reduces, but cannot eliminate, this inaccuracy.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
KEYWORDS: Heterogeneity; NSCLC; Nodal metastases; PD-L1; Programmed-death ligand-1
Link to PubMed record
Author: Haragan A, Field JK, Davies MPA, Escriu C, Gruver A, Gosney JR
Abstract: OBJECTIVES: PD-L1 expression on tumour cells can guide the use of anti-PD-1/PD-L1 immune modulators to treat patients with non-small cell lung cancer (NSCLC). Heterogeneity of PD-L1 expression both within and between tumour sites is a well-documented phenomenon that compromises its predictive power. Our aim was to better characterise the pattern and extent of PD-L1 heterogeneity with a view to optimising tumour sampling and improve its accuracy as a biomarker.
MATERIALS AND METHODS:
Expression of PD-L1 was assessed by immunochemistry using the SP263 clone in 107 resected primary NSCLCs and their nodal metastases. Intra-tumoural heterogeneity, defined as 'small-scale' (mm²), 'medium-scale' (cm²) and 'large-scale' (between tumour blocks), was assessed by digital imaging using a novel 'squares method'. Inter-tumoural heterogeneity between the primary tumours and their nodal metastases and between N1 and N2 nodal stages was also assessed.
RESULTS: The majority of tumours demonstrated intra-tumoural heterogeneity (small-scale 78%, medium-scale 50%, large-scale 46%). Inter-tumoural heterogeneity between the primary and nodal metastases was present in 53% of cases and, in 17%, between N1 and N2 disease. These differences were occasionally sufficient to lead to discrepancy across the ≥1%, ≥25% and ≥50% cut-offs used to guide therapy.
CONCLUSION: Heterogeneity of PD-L1 expression is common, variable in scale and extent, and carries significant implications for its accuracy as a predictive biomarker. Extensive sampling reduces, but cannot eliminate, this inaccuracy.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
KEYWORDS: Heterogeneity; NSCLC; Nodal metastases; PD-L1; Programmed-death ligand-1
Link to PubMed record
Monday 8 July 2019
WUTH publication: Anti-VEGF intervention in neovascular AMD: benefits and risks restated as natural frequencies
Citation: BMJ Open Ophthalmology. 2019, 4(1), e000257
Author: Clearkin L, Ramasamy B, Wason J, Tiew S
Abstract: OBJECTIVE: Clear information is essential to properly determine preference in medical intervention. In neovascular age-related macular degeneration, patients need to understand the balance of risk and benefit of anti-vascular endothelial growth factor (VEGF) treatment. This balance is altered by the number of injections administered.
METHODS: Natural frequencies, displayed as pictographically as icon arrays, are used to show material outcomes from the MARINA and HARBOR (12 months) trials. We also calculated the number needed to treat (NNT) and number needed to harm (NNH).
RESULTS: MARINA 24-month data show the absolute risk reduction is 37% and the NNT is 3; meaning for one patient to benefit three need to be treated.12 months' HARBOR data show that compared with as-needed treatment, scheduled monthly injection treatment increases the number of patients achieving a better visual outcome. The number of patients suffering harm is also increased by the additional injections.
CONCLUSION: Displaying MARINA and HARBOR trial data as natural frequencies, with numbers needed to treat and harm, communicates complimentary information on the positive and negative aspects of anti-VEGF treatment.
KEYWORDS: macula; neovascularisation
Link to PubMed record
Author: Clearkin L, Ramasamy B, Wason J, Tiew S
Abstract: OBJECTIVE: Clear information is essential to properly determine preference in medical intervention. In neovascular age-related macular degeneration, patients need to understand the balance of risk and benefit of anti-vascular endothelial growth factor (VEGF) treatment. This balance is altered by the number of injections administered.
METHODS: Natural frequencies, displayed as pictographically as icon arrays, are used to show material outcomes from the MARINA and HARBOR (12 months) trials. We also calculated the number needed to treat (NNT) and number needed to harm (NNH).
RESULTS: MARINA 24-month data show the absolute risk reduction is 37% and the NNT is 3; meaning for one patient to benefit three need to be treated.12 months' HARBOR data show that compared with as-needed treatment, scheduled monthly injection treatment increases the number of patients achieving a better visual outcome. The number of patients suffering harm is also increased by the additional injections.
CONCLUSION: Displaying MARINA and HARBOR trial data as natural frequencies, with numbers needed to treat and harm, communicates complimentary information on the positive and negative aspects of anti-VEGF treatment.
KEYWORDS: macula; neovascularisation
Link to PubMed record
Subscribe to:
Posts (Atom)