Mary Lou Smith

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE 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. METHODS 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. RESULTS 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. RECOMMENDATIONS 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.

Recommendations for Incorporating Patient-Reported Outcomes Into Clinical Comparative Effectiveness Research in Adult Oncology

Examining the patients subjective experience in prospective clinical comparative effectiveness research (CER) of oncology treatments or process interventions is essential for informing decision making. Patient-reported outcome (PRO) measures are the standard tools for directly eliciting the patient experience. There are currently no widely accepted standards for developing or implementing PRO measures in CER. Recommendations for the design and implementation of PRO measures in CER were developed via a standardized process including multistakeholder interviews, a technical working group, and public comments. Key recommendations are to include assessment of patient-reported symptoms as well as health-related quality of life in all prospective clinical CER studies in adult oncology; to identify symptoms relevant to a particular study population and context based on literature review and/or qualitative and quantitative methods; to assure that PRO measures used are valid, reliable, and sensitive in a comparable population (measures particularly recommended include EORTC QLQ-C30, FACT, MDASI, PRO-CTCAE, and PROMIS); to collect PRO data electronically whenever possible; to employ methods that minimize missing patient reports and include a plan for analyzing and reporting missing PRO data; to report the proportion of responders and cumulative distribution of responses in addition to mean changes in scores; and to publish results of PRO analyses simultaneously with other clinical outcomes. Twelve core symptoms are recommended for consideration in studies in advanced or metastatic cancers. Adherence to methodologic standards for the selection, implementation, and analysis/reporting of PRO measures will lead to an understanding of the patient experience that informs better decisions by patients, providers, regulators, and payers.

Research Issues Affecting Preoperative Systemic Therapy for Operable Breast Cancer

Preoperative systemic therapy (PST) in operable breast cancer allows a small increase in breast conservation rates and has significant potential as a research platform. PST offers the ability to discern treatment effect in vivo, and may allow smaller trials targeting specific breast cancer subtypes and making more efficient use of resources. Early observations of a specific outcome of interest in individual patient subgroups may improve the design of larger definitive randomized adjuvant trials using survival as a main outcome. PST offers the potential for therapeutic adjustments midcourse, which assumes the existence of validated intermediate end points and effective alternative therapies. This article reviews critical research issues affecting the design of PST trials, including the appropriate selection of trial end points and markers for long-term outcome, baseline marker expression as a predictor of response, and statistical considerations using novel trial designs. Key issues regarding optimal tumor subtype selection for individual trials, novel approaches using nontherapeutic window trial designs, and ethical and advocacy considerations are also discussed. PST requires an experienced and cohesive multidisciplinary team for it to fulfill its potential in both research and clinical care.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: Little evidence of improvement over the past 30 years

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.

Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199

Purpose: Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design: We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results: When evaluating for grade 3–4 TIPN, 120 SNPs had a P value of <10−4 from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3–4 TIPN (P = 1.7 × 10−3; OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2–4 TIPN (HR, 2.1; P = 5.6 × 10−16) and grade 3–4 TIPN (HR, 2.6; P = 1.1 × 10−11) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2–4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10−7). Conclusions: rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN. Clin Cancer Res; 21(22); 5082–91. ©2015 AACR.

Methods for Developing Patient-Reported Outcome-Based Performance Measures (PRO-PMs)

OBJECTIVE To recommend methods for assessing quality of care via patient-reported outcome-based performance measures (PRO-PMs) of symptoms, functional status, and quality of life. METHODS A Technical Expert Panel was assembled by the American Medical Association-convened Physician Consortium for Performance Improvement. An environmental scan and structured literature review were conducted to identify quality programs that integrate PRO-PMs. Key methodological considerations in the design, implementation, and analysis of these PRO-PM data were systematically identified. Recommended methods for addressing each identified consideration were developed on the basis of published patient-reported outcome (PRO) standards and refined through public comment. Literature review focused on programs using PROs to assess performance and on PRO guidance documents. RESULTS Thirteen PRO programs and 10 guidance documents were identified. Nine best practices were developed, including the following: provide a rationale for measuring the outcome and for using a PRO-PM; describe the context of use; select a measure that is meaningful to patients with adequate psychometric properties; provide evidence of the measures sensitivity to differences in care; address missing data and risk adjustment; and provide a framework for implementation, interpretation, dissemination, and continuous refinement. CONCLUSION Methods for integrating PROs into performance measurement are available.

Measuring Quality of Life in Cancer Survivors

Over the past 15 years there has been a steady decline in cancer-related deaths in the United States. Although more than a million people are diagnosed with cancer annually, over half are estimated to live at least 5 years beyond their initial diagnosis.1 Roughly 3% of the U.S. population has survived cancer (about 10 million people), with nearly a million of these people living some 20 years after their diagnosis.2 Combined, these trends suggest that more people are living with or beyond cancer than ever before. Despite these promising developments, the quality of a cancer survivor’s life remains affected well past the completion of treatment. Health care professionals are continually challenged to better understand how cancer has impacted a person’s life and provide assistance in navigating the complex maze often inherent to survivorship.3−6,7−14 Due in part to improved therapeutic agents and supportive care regimens, attention to the enduring effects of cancer and its treatment has grown increasingly over the past two decades. Although empirical studies have documented the delayed negative impact of cancer and its treatment across physical and psychosocial domains, there are several limitations with this body of research. First, few studies have evaluated long-term survivorship (e.g., greater than 10 years). Related to this, little emphasis has been placed on lifespan development as it is affected by cancer. Further, the overall lack of emphasis on positive outcomes that encompass World Health Organization (WHO) criteria (e.g., physical, mental, and social well-being) additionally limits our ability to understand potential personal benefits that might accrue from successful cancer therapy, effectively promoting positive health among survivors. Finally, most previous research has overwhelmingly been retrospective and cross-sectional, without sufficient consideration of internal and external factors such

Generating and evaluating evidence of the clinical utility of molecular diagnostic tests in oncology

Purpose:Enthusiasm for molecular diagnostic (MDx) testing in oncology is constrained by the gaps in required evidence regarding its impact on patient outcomes (clinical utility (CU)). This effectiveness guidance document proposes recommendations for the design and evaluation of studies intended to reflect the evidence expectations of payers, while also reflecting information needs of patients and clinicians.Methods:Our process included literature reviews and key informant interviews followed by iterative virtual and in-person consultation with an expert technical working group and an advisory group comprising life-sciences industry experts, public and private payers, patients, clinicians, regulators, researchers, and other stakeholders.Results:Treatment decisions in oncology represent high-risk clinical decision making, and therefore the recommendations give preference to randomized controlled trials (RCTs) for demonstrating CU. The guidance also describes circumstances under which alternatives to RCTs could be considered, specifying conditions under which test developers could use prospective-retrospective studies with banked biospecimens, single-arm studies, prospective observational studies, or decision-analytic modeling techniques that make a reasonable case for CU.Conclusion:Using a process driven by multiple stakeholders, we developed a common framework for designing and evaluating studies of the clinical validity and CU of MDx tests, achieving a balance between internal validity of the studies and the relevance, feasibility, and timeliness of generating the desired evidence.Genet Med 18 8, 780–787.

Working after a metastatic cancer diagnosis: Factors affecting employment in the metastatic setting from ECOG-ACRIN's Symptom Outcomes and Practice Patterns study.

Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. A better understanding of how metastatic cancer affects employment is a necessary step toward the development of tools for assisting survivors in this important realm.