Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial.

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 130 mg/m2 on day 1, capecitabine 625 mg/m2 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. Trial Registration: isrctn.org Identifier: ISRCTN44687907.

Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group.

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® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® 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® (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.

Essential Research Priorities in Renal Cancer: A Modified Delphi Consensus Statement.

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.

Setting Research Priorities in Partnership with Patients to Provide Patient-centred Urological Cancer Care.

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.

Comprehensive geriatric assessment and decision-making in older men with incurable but manageable (chronic) cancer.

PURPOSE: In older cancer patients, treatment decision-making is often complex. A comprehensive geriatric assessment (CGA) is an established tool used in geriatric medicine to identify unmet need requiring intervention. This study aimed to assess whether using a CGA in older male cancer patients with incurable but manageable disease provides information that would alter a cancer clinician's intended management plan. Acceptability and feasibility were secondary aims. METHODS: Elderly men with incurable but manageable malignancies (advanced prostate cancer and multiple myeloma) who had previously received at least one line of treatment were recruited from hospital outpatient clinics. A CGA was undertaken. Additional parameters measuring pain, fatigue and disease-specific concerns were also recorded, at the recommendation of patient involvement groups. Results were made available to clinicians. Patient and clinician acceptability and changes in subsequent management were recorded. RESULTS: Forty-eight patients completed the study. The median ages were 70.8 years and 74 years for myeloma and prostate respectively. Most identified concerns are related to disease-specific concerns (93%), pain (91%), frailty (57%) and nutrition (52%). Results altered the clinician's oncological management plan in nine cases only. Patients found the format and content of CGA acceptable. CONCLUSIONS: Many unmet needs were identified in this population of elderly men with manageable but non curable cancer which led to supportive care referrals and interventions. The CGA, however, did not result in significant changes in clinical oncology treatment plans for the majority of patients. The application of the CGA and other assessments was viewed positively by participants and can feasibly be undertaken in the outpatient oncology setting.

Cancer Treatment and Bone Health.

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 Glasgow Prognostic Score at the Time of Palliative Esophageal Stent Insertion is a Predictive Factor of 30-Day Mortality and Overall Survival.

BACKGROUND: Optimizing the timing of esophageal stent insertion is a challenge, partly due to difficulty predicting survival in advanced malignancy. The Glasgow prognostic score (GPS) is a validated tool for predicting survival in a number of cancers. GOALS: To assess the utility of the GPS in predicting 30-day mortality and overall survival postesophageal stent insertion. STUDY: Patients at a tertiary referral center who had received an esophageal stent for palliation of dysphagia were included if they had a measurement of albumin and C-reactive protein (CRP) in the week preceding the procedure (n=209). Patients with both an elevated CRP (>10 mg/L) and hypoalbuminemia (<35 g/L) were given a GPS score of 2 (GPS2). Patients with only one of these abnormalities were assigned as GPS1 and those with normal CRP and albumin were assigned as GPS0. Clinical and pathologic parameters were also collected to assess for potential confounding factors in the survival analysis. RESULTS: Increasing GPS was associated with 30-day mortality; for patients with GPS0, 30-day mortality was 5% (2/43), for GPS1 it was 23% (26/114), and for GPS2 it was 33% (17/52). The adjusted hazard ratio for overall poststent mortality was 1.6 (95% confidence interval, 1.1-2.4; P=0.02) for GPS1 and 2.4 (95% confidence interval, 1.5-3.8; P<0.001) for GPS2 patients compared with GPS0. CONCLUSIONS: GPS is an independent prognostic factor of 30-day mortality and overall survival after esophageal stent insertion. It is a potential adjunct to clinical assessment in identifying those patients at high-risk of short-term mortality poststent.

Variation in the measurement of DNA damage by comet assay measured by the ECVAG inter-laboratory validation trial.

The comet assay has become a popular method for the assessment of DNA damage in biomonitoring studies and genetic toxicology. However, few studies have addressed the issue of the noted inter-laboratory variability of DNA damage measured by the comet assay. In this study, 12 laboratories analysed the level of DNA damage in monocyte-derived THP-1 cells by either visual classification or computer-aided image analysis of pre-made slides, coded cryopreserved samples of cells and reference standard cells (calibration curve samples). The reference standard samples were irradiated with ionizing radiation (0-10 Gy) and used to construct a calibration curve to calculate the number of lesions per 10(6) base pair. All laboratories detected dose-response relationships in the coded samples irradiated with ionizing radiation (1.5-7 Gy), but there were overt differences in the level of DNA damage reported by the different laboratories as evidenced by an inter-laboratory coefficient of variation (CV) of 47%. Adjustment of the primary comet assay end points by a calibration curve prepared in each laboratory reduced the CV to 28%, a statistically significant reduction (P < 0.05, Levene's test). A large fraction of the inter-laboratory variation originated from differences in image analysis, whereas the intra-laboratory variation was considerably smaller than the variation between laboratories. In summary, adjustment of primary comet assay results by reference standards reduces inter-laboratory variation in the level of DNA damage measured by the alkaline version of the comet assay.