To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors.
An Expert Panel ...conducted targeted systematic literature reviews to identify new studies.
The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update.
The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited.Additional information is available at www.asco.org/survivorship-guidelines.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity, negatively affecting both quality of life and disease outcomes. To date, there is no proven preventative ...strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.
Introduction: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. Validated prognostic and predictive biomarkers ...are needed to guide treatment decisions and prognostication.
Areas covered: In this review, we discuss established and developing prognostic and predictive biomarkers in TNBC and associated emerging and approved therapies. Biomarkers reviewed include epidermal growth factor receptor (EGFR), vascular endothelial growth factors (VEGF), fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), androgen receptor, NOTCH signaling, oxidative stress/redox signaling, microRNAs, TP53 mutation, breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutation/homologous recombination deficiency (HRD), NTRK gene fusion, PI3K/AKT/mTOR, immune biomarkers (programmed death-ligand 1 (PDL1), tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), neoantigens, defects in DNA mismatch repair proteins (dMMR)/microsatellite instability-high (MSI-H)), circulating tumor cells/cell-free DNA, novel targets of antibody-drug conjugates, and residual disease.
Expert opinion: Biomarker-driven care in the management of TNBC is increasing and has helped expand options for patients diagnosed with this subtype of breast cancer. Research efforts are ongoing to identify additional biomarkers and targeted treatment options with the ultimate goal of improving clinical outcomes and survivorship.
To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors.
A systematic ...literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life.
A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms.
On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted.
Abstract
Aims
The national incidence, risk factors, and associated mortality of atrial fibrillation (AF) in breast cancer patients are unknown.
Methods and results
Using the Surveillance, ...Epidemiology, and End Results-Medicare-linked database, we identified females, ≥66 years old, with a new primary diagnosis of breast cancer from 2007 through 2014. These patients were individually matched 1:1 to Medicare enrolees without cancer, and each pair was followed for 1 year to identify a primary outcome of AF. Cumulative incidence was calculated using competing risk survival statistics. Following this, identifying risk factors of AF among breast cancer patients was conducted using the adjusted Cox proportional hazards model. Finally, Kaplan–Meier methods and adjusted Cox proportional hazards modelling were performed to estimate mortality in breast cancer patients with incident and prevalent AF. This study included 85 423 breast cancer patients. Among these 9425 (11.0%) had AF diagnosis prior to the breast cancer diagnosis. New-onset AF was diagnosed in 2993 (3.9%) patients in a 1-year period after the breast cancer diagnosis incidence 3.3%, 95% confidence interval (CI) 3.0–3.5%, at 1 year; higher rate in the first 60 days (0.6%/month). Comparatively, the incidence of new-onset AF in matched non-cancer controls was 1.8% (95% CI 1.6–2.0%). Apart from traditional demographic and cardiovascular risk factors, breast cancer stage was strongly associated with the development of AF American Joint Committee on Cancer (AJCC) Stage II/III/IV vs. I: adjusted hazard ratio (aHR) 1.51/2.63/4.21, respectively. New-onset AF after breast cancer diagnosis (aHR 3.00) is associated with increased 1-year cardiovascular mortality.
Conclusion
AF incidence is significantly higher in women after a breast cancer diagnosis. Higher breast cancer stages at diagnos are significantly associated with a higher risk of AF. New-onset AF in the new breast cancer diagnosis setting increases 1-year cardiovascular mortality but not breast cancer-related mortality.
Key Question
What are the incidence, prevalence, risk factors and mortality outcomes of atrial fibrillation (AF) in a multi-ethnic representative United States cohort of breast cancer patients?
Key Finding
Annual incidence for AF is 3.9% with highest rate in the first 60 days after cancer diagnosis. Cancer stage and grade are the strongest risk factors for AF. New onset AF after breast cancer increases all-cause and cardiovascular mortality.
Take Home Message
AF incidence is higher in breast cancer patients and is associated with later stage and grade at diagnosis of breast cancer. Involving cardio-oncology in those who develop AF after cancer diagnosis should be encouraged to improve their cardiovascular and overall prognosis.
Graphical Abstract
Structured Graphical Abstract
Cumulative incidence function plot for atrial fibrillation in breast cancer patients compared with matched non-cancer patients. The start of follow-up is at breast cancer diagnosis or pseudo-diagnosis date for the non-cancer cohort. Partial forest plot showing risk factor analysis of atrial fibrillation after breast cancer diagnosis. Partial forest plot showing fully adjusted model for all-cause, cardiovascular, and breast cancer-specific mortality in those after new-onset atrial fibrillation after breast cancer diagnosis as well as those with atrial fibrillation prior to breast cancer diagnosis. AF, atrial fibrillation; HR, hazard ratios; ref, reference; AJCC, American Joint Committee on Cancer.
Despite the importance of chemotherapy-associated adverse events in oncology practice and the broad range of interventions available to mitigate them, limited systematic efforts have been made to ...identify, critically appraise and summarize the totality of evidence on the effectiveness of these interventions. Herein, we review the most common long-term (continued beyond treatment) and late or delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments that pose major threats in terms of survival, quality of life and continuation of optimal therapy. These adverse effects often emerge during and continue beyond the course of therapy or arise among survivors in the months and years following treatment. For each of these adverse effects, we discuss and critically evaluate their underlying biological mechanisms, the most commonly used pharmacological and non-pharmacological treatment strategies, and evidence-based clinical practice guidelines for their appropriate management. Furthermore, we discuss risk factors and validated risk-assessment tools for identifying patients most likely to be harmed by chemotherapy and potentially benefit from effective interventions. Finally, we highlight promising emerging supportive-care opportunities for the ever-increasing number of cancer survivors at continuing risk of adverse treatment effects.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of several first-line chemotherapeutic agents, including platinum compounds, taxanes, vinca alkaloids, thalidomide, and ...bortezomib, which negatively affects the quality of life and clinical outcome. Given the dearth of effective established agents for preventing or treating CIPN, and the increasing number of cancer survivors, there is an urgent need for the identification and development of new, effective intervention strategies that can prevent or mitigate this debilitating side effect. Prior failures in the development of effective interventions have been due, at least in part, to a lack of mechanistic understanding of CIPN and problems in translating this mechanistic understanding into testable hypotheses in rationally-designed clinical trials. Recent progress has been made, however, in the pathogenesis of CIPN and has provided new targets and pathways for the development of emerging therapeutics that can be explored clinically to improve the management of this debilitating toxicity. This review focuses on the emerging therapeutics for the prevention and treatment of CIPN, including pharmacological and non-pharmacological strategies, and calls for fostering collaboration between basic and clinical researchers to improve the development of effective strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The causes of variation in toxicity to the same treatment regimen among seemingly similar patients remain largely unknown. There was tremendous optimism that the patient’s germline genome would be ...strongly predictive of treatment-related toxicity and could be used to personalize treatment and improve therapeutic outcomes. However, there has been limited success in discovering robust pharmacogenetic predictors of treatment-related toxicity and even less progress in translating the few validated predictors into clinical practice. It is apparent that identification of toxicity predictors that can be used to predict and prevent treatment-related toxicity will require thinking beyond germline genomics. To that end, we propose an integrated biomarker discovery approach that recognizes that a patient’s toxicity risk is determined by the cumulative effects of a broad range of “omic” and non-omic factors. This commentary describes the limited success in discovering and translating clinical and pharmacogenetic toxicity predictors into clinical practice. We illustrate the evolution of cancer toxicity biomarker discovery and translation through studies of taxane-induced peripheral neuropathy, which is one of the most common and debilitating side effects of cancer treatment. We then discuss the opportunities for discovering non-genomic (e.g., metabolomic, lipidomic, transcriptomic, proteomic, microbiomic, medical, behavioral, environmental) and integrated biomarkers that may be more strongly predictive of toxicity risk and the potential challenges with translating integrated biomarkers into clinical practice. This integrated biomarker discovery approach may circumvent some of the major limitations in toxicity biomarker science and move precision oncology treatment forward so that patients receive maximum treatment benefit with minimal toxicity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.
PubMed and ...the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations as needed.
The primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have similar efficacy and safety to reference products, although evidence in cancer remains limited.
ESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to < 10 g/dL. RBC transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.hematology.org/guidelines .
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