Surgeon preference for treatment allocation in older people facing major gastrointestinal surgery: an application of the discrete choice experiment methodology

Aim: Variation in major gastrointestinal surgery rates in the older population suggests heterogeneity in surgical management. A higher prevalence of comorbidities, frailty and cognitive impairments in the older population may account for some variation. The aim of this study was to determine surgeon preference for major surgery versus conservative management in hypothetical patient scenarios based on key attributes.Method: A survey was designed according to the discrete choice methodology guided by a separate qualitative study. Questions were designed to test for associations between key attributes (age, comorbidity, urgency of presentation, pathology, functional and cognitive status) and treatment preference for major gastrointestinal surgery versus conservative management. The survey consisting of 18 hypothetical scenarios was disseminated electronically to UK gastrointestinal surgeons. Binomial logistic regression was used to identify associations between the attributes and treatment preference.Results: In total, 103 responses were received after 256 visits to the questionnaire site (response rate 40.2%). Participants answered 1847 out of the 1854 scenarios (99.6%). There was a preference for major surgery in 1112/1847 (60.2%) of all scenarios. Severe comorbidities (OR 0.001, 95% CI 0.000–0.030; P = 0.000), severe cognitive impairment (OR 0.001, 95% CI 0.000–0.033; P = 0.000) and age 85 years and above (OR 0.028, 95% CI 0.005–0.168; P = 0.000) were all significant in the decision not to offer major gastrointestinal surgery.Conclusion: This study has demonstrated variation in surgical treatment preference according to key attributes in hypothetical scenarios. The development of fitness-stratified guidelines may help to reduce variation in surgical practice in the older population

The decision-making process for senior cancer patients: treatment allocation of older women with operable breast cancer in the UK.

Objective: Up to 40% of women over 70 years with primary operable breast cancer in the UK are treated with primary endocrine therapy (PET) as an alternative to surgery. A variety of factors are important in determining treatment for older breast cancer patients. This study aimed to identify the patient and tumor factors associated with treatment allocation in this population. Methods: Prospectively collected data on treatment received (surgery vs. PET) were analysed with multivariable logistic regression using the variables age, modified Charlson Comorbidity Index (CCI), activities of daily living (ADL) score, Mini-Mental State Examination (MMSE) score, HER2 status, tumour size, grade and nodal status. Results: Data were available for 1,122 cancers in 1,098 patients recruited between February 2013 and June 2015 from 51 UK hospitals. About 78% of the population were treated surgically, with the remainder being treated with PET. Increasing patient age at diagnosis, increasing CCI score, large tumor size (5 cm or more) and dependence in one or more ADL categories were all strongly associated with non-surgical treatment (P<0.05). Conclusion: Increasing comorbidity, large tumor size and reduced functional ability are associated with reduced likelihood of surgical treatment of breast cancer in older patients. However, age itself remains a significant factor for non-surgical treatment; reinforcing the need for evidence-based guidelines

Senescence and cancer : a review of clinical implications of senescence and senotherapies

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues

Healthcare professional preferences in the health and fitness assessment and optimization of older patients facing colorectal cancer surgery

Abstract: Aim: There are few age‐ and fitness‐specific, evidence‐based guidelines for colorectal cancer surgery. The uptake of different assessment and optimization strategies is variable. The aim of this study was to explore healthcare professional opinion about these issues using a mixed methods design. Methods: Semi‐structured qualitative interviews were undertaken with healthcare professionals from a single UK region involved in the treatment, assessment and optimization of colorectal surgery patients. Interviews were analysed using the framework approach. An online questionnaire survey was subsequently designed and disseminated to UK surgeons to quantitatively assess the importance of interview themes. Descriptive statistics were used to analyse questionnaire data. Results: Thirty‐seven healthcare professionals out of 42 approached (response rate 88%) were interviewed across five hospitals in the south Yorkshire region. Three broad themes were developed: attitudes towards treatment of the older patient, methods of assessment of suitability and optimization strategies. The questionnaire was completed by 103 out of an estimated 256 surgeons (estimated response rate 40.2%). There was a difference in opinion regarding the role of major surgery in older patients, particularly when there is coexisting dementia. Assessment was not standardized. Access to optimization strategies was limited, particularly in the emergency setting. Conclusion: There is wide variation in the process of assessment and provision of optimization strategies in UK practice. Lack of evidence‐based guidelines, cost and time constraints restrict the development of services and pathways. Differences in opinion between surgeons towards patients with frailty or dementia may account for some of the variation in colorectal cancer outcomes

Understanding older women's decision making and coping in the context of breast cancer treatment

Background: Primary endocrine therapy (PET) is a recognised alternative to surgery followed by endocrine therapy for a subset of older, frailer women with breast cancer. Choice of treatment is preference-sensitive and may require decision support. Older patients are often conceptualised as passive decision-makers. The present study used the Coping in Deliberation (CODE) framework to gain insight into decision making and coping processes in a group of older women who have faced breast cancer treatment decisions, and to inform the development of a decision support intervention (DSI). Methods: Semi-structured interviews were carried out with older women who had been offered a choice of PET or surgery from five UK hospital clinics. Women's information and support needs, their breast cancer diagnosis and treatment decisions were explored. A secondary analysis of these interviews was conducted using the CODE framework to examine women's appraisals of health threat and coping throughout the deliberation process. Results: Interviews with 35 women aged 75-98 years were analysed. Appraisals of breast cancer and treatment options were sometimes only partial, with most women forming a preference for treatment relatively quickly. However, a number of considerations which women made throughout the deliberation process were identified, including: past experiences of cancer and its treatment; scope for choice; risks, benefits and consequences of treatment; instincts about treatment choice; and healthcare professionals' recommendations. Women also described various strategies to cope with breast cancer and their treatment decisions. These included seeking information, obtaining practical and emotional support from healthcare professionals, friends and relatives, and relying on personal faith. Based on these findings, key questions were identified that women may ask during deliberation. Conclusions: Many older women with breast cancer may be considered involved rather than passive decision-makers, and may benefit from DSIs designed to support decision making and coping within and beyond the clinic setting

Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies

Differences in treatment and survival of older patients with operable breast cancer between the United Kingdom and the Netherlands – a comparison of two national prospective longitudinal multi-centre cohort studies

Background Previous studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has been hypothesised that these differences in survival outcomes could be related to treatment variation. Objectives We aimed to compare patient and tumour characteristics, treatment selection and survival outcomes between two large prospective cohorts of older patients with operable breast cancer from the United Kingdom (UK) and The Netherlands. Methods Women diagnosed with operable breast cancer aged ≥70 years were included. A baseline comprehensive geriatric assessment was performed in both cohorts, with data collected on age, comorbidities, cognition, nutritional and functional status. Baseline tumour characteristics and treatment type were collected. Univariable and multivariable Cox regression models were used to compare overall survival between the cohorts. Results 3262 patients from the UK Age Gap cohort and 618 patients from the Dutch Climb cohort were included, with median ages of 77.0 (IQR: 72.0–81.0) and 75.0 (IQR: 72.0–81.0) years, respectively. The cohorts were generally comparable, with slight differences in rates of comorbidity and frailty. Median follow-up for overall survival was 4.1 years (IQR 2.9–5.4) in Age Gap and 4.3 years (IQR 2.9–5.5) in Climb. In Age Gap, both the rates of primary endocrine therapy and adjuvant hormonal therapy after surgery were approximately twice those in Climb (16.6% versus 7.3%, p < 0.001 for primary endocrine therapy, and 62.2% versus 38.8%, p < 0.001 for adjuvant hormonal therapy). There was no evidence of a difference in overall survival between the cohorts (adjusted HR 0.94, 95% CI 0.74–1.17, p = 0.568). Conclusions In contrast to previous studies, this comparison of two large national prospective longitudinal multi-centre cohort studies demonstrated comparable survival outcomes between older patients with breast cancer treated in the UK and The Netherlands, despite differences in treatment allocation

Cost-Effectiveness Modeling of Surgery Plus Adjuvant Endocrine Therapy Versus Primary Endocrine Therapy Alone in UK Women Aged 70 and Over With Early Breast Cancer

Objectives: Approximately 20% of UK women aged 70+ with early breast cancer receive primary endocrine therapy (PET) instead of surgery. PET reduces surgical morbidity but with some survival decrement. To complement and utilize a treatment dependent prognostic model, we investigated the cost-effectiveness of surgery plus adjuvant therapies versus PET for women with varying health and fitness, identifying subgroups for which each treatment is cost-effective. Methods: Survival outcomes from a statistical model, and published data on recurrence, were combined with data from a large, multicenter, prospective cohort study of over 3400 UK women aged 70+ with early breast cancer and median 52-month follow-up, to populate a probabilistic economic model. This model evaluated the cost-effectiveness of surgery plus adjuvant therapies relative to PET for 24 illustrative subgroups: Age {70, 80, 90} × Nodal status {FALSE (F), TRUE (T)} × Comorbidity score {0, 1, 2, 3+}. Results: For a 70-year-old with no lymph node involvement and no comorbidities (70, F, 0), surgery plus adjuvant therapies was cheaper and more effective than PET. For other subgroups, surgery plus adjuvant therapies was more effective but more expensive. Surgery plus adjuvant therapies was not cost-effective for 4 of the 24 subgroups: (90, F, 2), (90, F, 3), (90, T, 2), (90, T, 3). Conclusion: From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy

Purpose Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. Methods The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. Results Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. Conclusions In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques

Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life

Background Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. Methods Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. Findings A total of 3416 women (median age 77, range 69–102) were recruited from 56 breast units—2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23–0.33, P < 0.001). Unmatched breast cancer–specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29–0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53–0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40–1.37, P = 0.34) although at 4–5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance. Interpretation For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4–5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). Trial registration number ISRCTN: 46099296