Ageing-related considerations for medication used in supportive care in cancer.

Both randomized controlled trials (RCTs) and retrospective studies have shown that a comprehensive geriatric assessment (CGA) prior to a patient commencing systemic anti-cancer therapy (SACT) results in improved quality of life outcomes and is associated with a decreased risk of grade 3-5 toxicity; however, data are lacking in relation to adverse drug events (ADE) associated with supportive care medications. Supportive care medications are prescribed as prophylactic agents in a SACT regimen, for management of treatment related toxicity and for symptoms caused by the disease itself. While necessary, the commencement of SACT and supportive medications may cause, or exacerbate, a significant drug burden in older patients, some of whom may have existing comorbidities. For many medications, older adults are underrepresented in pharmacokinetic and pharmacodynamic modelling studies. In this article we will review ageing-related changes in pharmacokinetics and pharmacodynamics, as well as how these changes may impact supportive care medications. Additional considerations for prescribing these medications in older adults with cancer, such as polypharmacy, potentially inappropriate medications, drug-drug interactions, and anticholinergic burden, as well as ageing-related considerations and recommendations for supportive care medications commonly used in older adults with cancer are also reviewed.

Statin use in older adults with cancer - Experience from a dedicated geriatric oncology service.

INTRODUCTION: The increase in statin use, since their introduction, has been rapid and the broadening of indications has occurred seemingly without restriction. Once established on statin therapy, there is sparse research on discontinuation. Trials do not often address benefit in later life, or the impact of a life-limiting diagnosis. Data on primary prevention suggest that 100 patients need treatment for 2.5 years to prevent one major adverse cardiovascular event. Acknowledging this, we sought to determine the use of statins in a cohort of older adults with cancer, to highlight prevalence, and suggest a role for deprescribing. MATERIALS AND METHODS: Data were retrospectively collected from a prospectively maintained database of patients attending a single centre Geriatric Oncology clinic. Data collected included sex, age, cancer type and stage, systemic anti-cancer therapy (SACT) recommendation, comorbidities, non-SACT medications, and overall survival. For those receiving statin therapy, data were separated into primary prevention and stage IV cancer. RESULTS: In the group studied (n = 230), 135 (59%) were prescribed a statin, with 79 (58%) for primary prevention. Ninety-three (40%) had stage IV cancer. Of the 230 patients, 134 (58%) were recommended SACT. Within the primary prevention group, the median age was 79 years. Twenty-seven patients (34%) had stage III disease, while 36 (46%) had stage IV disease. Thirteen (16%) had diabetes mellitus. The median number of medications was seven (Interquartile range 5). Fifty patients (63%) were recommended SACT. In terms of survival, 31 (50%) were alive at one year, 18 (29%) alive at two years, and 14 (23%) alive beyond two and a half years. Within the stage IV disease group, 59 out of 93 (63%) were receiving statin therapy; 35 (59%) for primary prevention and seven (8%) for diabetes mellitus. Fifty-eight (63%) were recommended SACT. Twenty-four (29%) were alive at one year, 17 (21%) alive at two years, and 13 (16%) alive beyond two and a half years. DISCUSSION: Statin therapy is prevalent and continues into older age. Available data regarding statin therapy in older adults and survival seen in this study support deprescribing in primary prevention and life-limiting illness, such as stage IV cancer.

Hospitalization due to adverse drug events in older adults with cancer: A retrospective analysis.

INTRODUCTION: Geriatric oncology is a rapidly evolving field of practice, where comprehensive geriatric assessments (CGA) and multidisciplinary team (MDT) input have the potential to improve patient outcomes. Polypharmacy and potential drug interactions (PDI) have been associated with an increased risk of adverse outcomes in older adults with cancer, receiving systemic anti-cancer therapy (SACT). Our aim was to assess the incidence of unplanned hospitalization in older adults with cancer attending medical oncology outpatient clinics and to determine whether an unplanned hospitalization was potentially due to an adverse drug event (ADE). MATERIALS AND METHODS: We identified patients who attended a medical oncology outpatient appointment from January 1 to March 31, 2018. Medical records were examined to identify any unplanned hospital admissions between the clinic visit date and three and six months after initial clinic visit. Incidences of unplanned hospitalization were assessed to determine if an ADE potentially occurred. RESULTS: Data collected from 174 patients were analyzed. Over half (57%) were female, median age was 75 years and 53% had a favorable performance status. The most common malignancies were gastrointestinal (GI) at 31% (n = 54), breast 29% (n = 51), and genitourinary 22% (n = 37). Seventy-two percent had advanced disease (stage III/IV) and 61% had systemic therapy (SACT and hormonal therapy). Polypharmacy (≥5 medications) was observed in 77% of patients. The total number of admissions at six months was 99, with 55% of these potentially due to an ADE. On multivariate analysis breast cancer (p ≤0.001), lung cancer (p = 0.034), performance status (p ≤0.001), monochemotherapy (p = 0.012), polychemotherapy (p ≤0.001), and radiotherapy (p = 0.048) were independent predictors of unplanned hospitalization. Breast cancer (p = 0.008), GI cancer (p = 0.019), monochemotherapy (p = 0.039), and polychemotherapy (p ≤0.001) were independent predictors of unplanned hospitalization due to ADE on multivariate analysis. DISCUSSION: We observed that older adults with cancer have a high risk of unplanned hospitalization due to ADE. Medication review as part of a CGA in newly diagnosed older adults with cancer by a clinical pharmacist is recommended. This may identify opportunities to avoid medications that could potentially lead to unplanned hospitalization.

Pharmacological strategies to reduce anthracycline-associated cardiotoxicity in cancer patients.

INTRODUCTION: Anthracycline chemotherapeutic agents are widely used in the treatment of hematological and solid tumors, working principally through DNA intercalation and topoisomerase II inhibition. However, they are also well known to have cardiotoxic sequelae, commonly denoted as a reduction in ejection fraction. Drug-associated cardiotoxicity remains a significant limiting factor in the use of anthracyclines. AREAS COVERED: In this review, we explore the potential mechanisms of anthracycline-associated cardiotoxicity, identifying high-risk cohorts and approaches to cardiovascular monitoring. The mechanisms through which cardiotoxicity occurs are complex and diverse, ultimately leading to increased oxidative stress, mitochondrial dysfunction, and subsequent cellular apoptosis. Many of the cardiotoxic effects of anthracyclines exhibit a dose-dependent cumulative relationship and are more apparent in patients with previously existing cardiovascular risk factors. Long-term cardiovascular monitoring and optimization of risk factors, prior to commencing treatment as well as beyond the time of treatment, is therefore essential. EXPERT OPINION: We discuss some of the pharmacological strategies proposed to mitigate anthracycline-associated cardiotoxicity as well as prevention strategies to reduce the burden of coexisting cardiovascular risk factors. We highlight methods of early detection of patient cohorts who are at increased risk of developing anthracycline-associated cardiotoxicity and identify potential avenues for further research.

Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval.

Over the past 20 years, the management of gastrointestinal stromal tumors has acted as an important model in the advancement of molecularly targeted therapies for solid tumors. The success of imatinib has established it as a lasting therapy in the management of early-stage and advanced disease in the first-line setting. Imatinib resistance inevitably develops, resulting in the need for further lines of therapy. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor, specifically developed to target both primary and secondary KIT and PDGFRα resistance mutations. Herein, the authors discuss the molecular rationale, the preclinical evidence and the clinical use of ripretinib in the treatment of gastrointestinal stromal tumors in the advanced stages of disease.

Metastatic gastroesophageal cancer in older patients - is this patient cohort represented in clinical trials?

BACKGROUND: Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer. METHODS: A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model. RESULTS: Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18-94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65-80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%). CONCLUSIONS: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.

TGFß drives NK cell metabolic dysfunction in human metastatic breast cancer.

BACKGROUND: Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output. METHODS: Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controls RESULTS: In addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-ß (TGFß) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFß processing pathway, was increased on NK cells from some patients. Blocking the GARP-TGFß axis recapitulated the effects of TGFß neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time. CONCLUSIONS: TGFß contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFß and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.