What advice are oncologists and surgeons in the United Kingdom giving to breast cancer patients about physical activity?

Evidence has shown that physical activity may attenuate the negative physical, psychological and functional effects of treatment in women diagnosed with breast cancer. Physical activity levels also decline substantially during and after completion of treatment for cancer, highlighting the importance of strategies to promote participation in regular physical activity in this population. Oncologists and surgeons may serve as an influential source of motivation to be physically activity in cancer patients, by conveying the importance of a healthy lifestyle. The primary purpose of the present study was to investigate whether oncologists and surgeons routinely discuss physical activity with their breast cancer patients and to investigate the nature of any information/advice provided during consultations. A secondary aim was to examine whether physically active oncologists and surgeons were more likely to provide advice about physical activity to patients, than inactive oncologists and surgeons. A brief postal questionnaire was sent to 710 consultant breast cancer oncologists and surgeons throughout the UK and 102 responded (response rate = 14.4%). Of responders, most (55.9%) did not routinely discuss physical activity with their patients. Amongst oncologists/surgeons (clinicians) who did offer advice, most focussed on discussing the benefits of physical activity for physical and functional health gains and for facilitating weight control and maintenance. A number of clinicians indicated they advised patients that physical activity may decrease risk of recurrence and improve survival, despite the lack of evidence from RCTs to support this suggestion. There was no significant association between the physical activity status of oncologists/surgeons and the likelihood that they discussed physical activity with patients. Educational strategies aimed at encouraging clinicians to promote physical activity in consultations need to be targeted widely amongst the cancer clinician community

Meta-analysis of randomized phase II trials to inform subsequent phase III decisions

BACKGROUND: If multiple Phase II randomized trials exist then meta-analysis is favorable to increase statistical power and summarize the existing evidence about an intervention's effect in order to help inform Phase III decisions. We consider some statistical issues for meta-analysis of Phase II trials for this purpose, as motivated by a real example involving nine Phase II trials of bolus thrombolytic therapy in acute myocardial infarction with binary outcomes. METHODS: We propose that a Bayesian random effects logistic regression model is most suitable as it models the binomial distribution of the data, helps avoid continuity corrections, accounts for between-trial heterogeneity, and incorporates parameter uncertainty when making inferences. The model also allows predictions that inform Phase III decisions, and we show how to derive: (i) the probability that the intervention will be truly beneficial in a new trial, and (ii) the probability that, in a new trial with a given sample size, the 95% credible interval for the odds ratio will be entirely in favor of the intervention. As Phase II trials are potentially optimistic due to bias in design and reporting, we also discuss how skeptical prior distributions can reduce this optimism to make more realistic predictions. RESULTS: In the example, the model identifies heterogeneity in intervention effect missed by an I-squared of 0%. Prediction intervals accounting for this heterogeneity are shown to support subsequent Phase III trials. The probability of success in Phase III trials increases as the sample size increases, up to 0.82 for intracranial hemorrhage and 0.79 for reinfarction outcomes. CONCLUSIONS: The choice of meta-analysis methods can influence the decision about whether a trial should proceed to Phase III and thus need to be clearly documented and investigated whenever a Phase II meta-analysis is performed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1745-6215-15-346) contains supplementary material, which is available to authorized users

Dose Transition Pathways::The missing link between complex dose-finding designs and simple decision-making

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR

Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata

Background: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. // Methods: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon’s two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata. // Results: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events. // Conclusions: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. // Clinical Trial Registration: ISRCTN 6079133

Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial)

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09697-9

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity