Phantom calibration is currently the gold standard for calibrating CT scans and for calculating material properties of dense tissues for computational models. However, in Oncology departments and low-resource settings, it is not routine to include a calibration phantom within the scanning protocol. Therefore, retrospective scan datasets are challenging to calibrate for biomechanical investigations, precluding detailed measurements of material and mechanical properties. In this study, we compared the results from a phantomless calibration technique, where the density within each scan was independently calibrated based on known tissue densities captured within each scan (e.g., air), with those from a traditional inline phantom calibration. To do so we used scans from a cohort of healthy volunteers from the control arm of a clinical trial dataset (ANTELOPE) in which inline calibration phantoms were included. We found that, when selecting air and the aorta as regions for calibration within individual CT scans, a strong individual-specific correlation existed between bone mineral density measured in the phantomless and phantom calibrations. This indicates that the phantomless calibration method can be a useful and reliable tool for quantifying the densitometric material properties of healthy human vertebrae, and provides the opportunity for further analysis of spinal CT scans in either retrospective datasets or in low-resource clinical settings.

Androgen deprivation therapy (ADT) for localised and metastatic prostate cancer (PCa) is known to improve survival in patients but has been associated with negative long-term impacts on the skeleton, including decreased bone mineral density (BMD) and increased fracture risk. Generally, dual-enery X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) of vertebrae are used clinically to assess bone health. However, a prediction of vertebral bone strength requires information that aBMD cannot provide, such as geometry and volumetric BMD (vBMD). This study aims to investigate the effect of ADT on the densitometric (aBMD, trabecular vBMD, integral vBMD) and mechanical integrity (failure load and failure strength) of vertebrae, using a combination of DXA, quantitative computed tomography (QCT) and finite element (FE) modelling. For the FE analyses, 3D models were reconstructed from QCT images of 26 ADT treated patients, and their matched controls, collected as part of the ANTELOPE clinical trial. The ADT treated group experienced significantly decreased trabecular and integral vBMD (trabecular vBMD: -18 %, p < 0.001, integral vBMD: -11 %, p < 0.001) compared to control patients that showed no significant temporal changes (trabecular vBMD p = 0.037, integral vBMD p = 0.56). A similar trend was seen in the ADT treated group for the failure load and failure strength, where a decrease of 14 % was observed (p < 0.001). When comparing the proficiency in predicting the mechanical properties from densitometric properties, the integral vBMD performed best in the pooled data (r = 0.86-0.87, p < 0.001) closely followed by trabecular vBMD (r = 0.73-0.75, p < 0.001) with aBMD having a much weaker predictive ability (r = 0.19-0.21, p < 0.01). In conclusion, ADT significantly reduced both the densitometric properties and the mechanical strength of vertebrae. A stronger relationship between both trabecular vBMD and integral vBMD with the mechanical properties than the aBMD was observed, suggesting that such clinical measurements could improve predictions of fracture risk in prostate cancer patients treated with ADT.

Introduction: Androgen Deprivation Therapy (ADT) for prostate cancer (PC) has substantial negative impacts on the musculoskeletal system and body composition. Many studies have focused on the effects of ADT on areal bone mineral density (aBMD), but aBMD does not capture key determinants of bone strength and fracture risk, for example volumetric bone density (vBMD), geometry, cortical thickness and porosity, trabecular parameters and rate of remodelling. More specialist imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) have become available to evaluate these parameters. Although it has previously been demonstrated that bone microarchitectural deterioration occurs in men undergoing ADT, the aim of the ANTELOPE study was to examine longitudinal changes in bone microstructure alongside a range of musculoskeletal parameters and frailty, comparing men with PC receiving ADT alone or ADT plus chemotherapy for metastatic disease, with a healthy age-matched population. Methods: We used HR-pQCT to investigate effects of 12 months of ADT on vBMD and microstructural parameters, complemented by assessment of changes in aBMD, serum bone turnover markers, sex hormones, body composition, grip strength, physical and muscle function, frailty and fracture risk. We studied three groups: Group A - men with localised/locally advanced PC due to commence ADT; Group B - men with newly diagnosed hormone-sensitive, metastatic PC, starting ADT alongside docetaxel chemotherapy and steroids; Group C - healthy, age-matched men. The primary endpoint was change in vBMD (Group A vs Group C) at the distal radius. Results: Ninety-nine participants underwent baseline study assessments (Group A: n = 38, Group B: n = 30 and Group C: n = 31). Seventy-five participants completed all study assessments (Group A (29), Group B (18), Group C (28). At baseline, there were no significant differences between Groups A and C in any of the BMD or bone microstructure outcomes of interest. After 12 months of ADT treatment, there was a significantly greater decrease in vBMD (p < 0.001) in Group A (mean 12-month change = -13.7 mg HA/cm(3), -4.1 %) compared to Group C (mean 12-month change = -1.3 mg HA/cm(3), -0.4 %), demonstrating achievement of primary outcome. Similar effects were observed when comparing the change in vBMD between Group B (mean 12-month change = -13.5 mg HA/cm(3), -4.3 %) and Group C. These changes were mirrored in aBMD. ADT resulted in microstructural deterioration, a reduction in estimated bone strength and an increase in bone turnover. There was evidence of increase in total fat mass and trunkal fat mass in ADT-treated patients, with marked loss in upper limb mass, along with BMI gain. Frailty increased and physical performance and strength deteriorated in both ADT groups, relative to the healthy control group. Conclusion: The study showed that ADT has profound effects on vBMD, aBMD, bone microstructure and strength and body composition, and important impacts on frailty and physical performance. Whilst DXA remains a valuable tool (changes in aBMD are of the same magnitude as those observed for vBMD), HR-pQCT should be considered for assessing the effects of anti-androgens and other newer PC therapies on bone, as well as potential mitigation by bone-targeted agents.

Background There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods Participants Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and −0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat −0.05 (−0.15 to 0.05); per-protocol 0.04 (−0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ −0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians’ perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

IMPORTANCE Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. OBJECTIVE The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. DESIGN, SETTING, AND PARTICIPANTS This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. INTERVENTIONS There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130mg/m(2) on day 1, capecitabine 625mg/m(2) twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. MAIN OUTCOMES AND MEASURES First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. RESULTS A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. CONCLUSIONS AND RELEVANCE This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment.

Context and objective: Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management. Methods: Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies. Summary of guidance: All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX (R) tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX (R) alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX (R) (including BMD) repeated after 12-18 months. Patient summary: Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient's bones with risk of fracture and it is therefore important to monitor patients' bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.

There is a well-documented discrepancy in prioritisation of research agendas between patients and researchers. Patient involvement in urological research from the outset is critical for well-prioritised research.

BACKGROUND:Identification of clear and focused research priorities is crucial to drive research forward. OBJECTIVE:To identify research priorities in renal cell carcinoma (RCC) through a multidisciplinary collaboration between clinicians, researchers, and patients. DESIGN, SETTING, AND PARTICIPANTS:In phase I, 44 RCC experts provided 24 literature reviews within their field, summarising research gaps (RGs). Three expert discussion meetings and patient interviews were performed, and 39 potential RGs were identified. In phase II, experts (N=82) scored these gaps on a nine-point scale (1-3: not important; 4-6: important; 7-9: critical) through a multistep Delphi process involving three online surveys and two further consensus meetings. The surveys aimed to reach a consensus, defined as ≥70% agreement by experts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Three iterations of the Delphi survey were performed. The results obtained after the third Delphi survey were distributed amongst the RCC experts and patient representatives for final feedback. RESULTS AND LIMITATIONS:In the first Delphi survey, the response rate was 56% (46/82), increasing to 67% (55/82) and 71% (58/82) in the second and third iterations, respectively. Survey respondents included 45.7% urologists, 37.0% oncologists, 8.7% radiologists, and 8.6% other specialists (pathologists, health economists, geneticist, and scientists). The process resulted in the identification of 14 crucial RGs, across a broad range of RCC themes. Key themes included further research into systemic therapies for RCC and management strategies that maximise quality of life, especially in patient groups that are "difficult to treat" and have rarer RCC subtypes. Two crucial RGs relate to biomarkers and novel imaging approaches for both localised and metastatic disease, to enable prognostic risk stratification and individualise patient management. Study participants were from a UK and European setting; therefore, we acknowledge that the RGs identified represent European priorities. CONCLUSIONS:These RGs will facilitate international collaboration towards a concerted attempt to improve patients' survival and quality of life. PATIENT SUMMARY:We formed a collaboration between researchers, clinicians, and patients to identify research priorities in kidney cancer. We identified 14 priorities that will improve patient outcomes by focusing on research efforts.

Considerable advances in oncology over recent decades have led to improved survival, while raising concerns about long-term consequences of anticancer treatments. In patients with breast or prostate malignancies, bone health is a major issue due to the high risk of bone metastases and the frequent prolonged use of hormone therapies that alter physiological bone turnover, leading to increased fracture risk. Thus, the onset of cancer treatment-induced bone loss (CTIBL) should be considered by clinicians and recent guidelines should be routinely applied to these patients. In particular, baseline and periodic follow-up evaluations of bone health parameters enable the identification of patients at high risk of osteoporosis and fractures, which can be prevented by the use of bone-targeting agents (BTAs), calcium and vitamin D supplementation and modifications of lifestyle. This review will focus upon the pathophysiology of breast and prostate cancer treatment-induced bone loss and the most recent evidence about effective preventive and therapeutic strategies.

The presence of metastatic bone disease is a devastating complication that has signiicant impact on morbidity and mortality in cancer patients. Although the type, incidence, and consequences of bone metastases (BM) may vary between primary cancer sites, all patients with BM require consideration as to how both their primary tumour and their bone disease should be managed in terms of avoiding complications and maximizing both quality of life and survival. This chapter will describe normal bone turnover, the pathophysiology of BM, and the most common clinical sequelae. We will then explain the current evidence for the prevention and treatment of BM for the most osteotropic tumours (breast, prostate, lung, and renal).