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
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Wednesday, 24 July 2019
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
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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
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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
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