Jeffrey Peppercorn

American Society of Clinical Oncology Provisional Clinical Opinion: The Integration of Palliative Care Into Standard Oncology Care

PURPOSE An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCOs membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the integration of palliative care services into standard oncology practice at the time a person is diagnosed with metastatic or advanced cancer. CLINICAL CONTEXT Palliative care is frequently misconstrued as synonymous with end-of-life care. Palliative care is focused on the relief of suffering, in all of its dimensions, throughout the course of a patients illness. Although the use of hospice and other palliative care services at the end of life has increased, many patients are enrolled in hospice less than 3 weeks before their death, which limits the benefit they may gain from these services. By potentially improving quality of life (QOL), cost of care, and even survival in patients with metastatic cancer, palliative care has increasing relevance for the care of patients with cancer. Until recently, data from randomized controlled trials (RCTs) demonstrating the benefits of palliative care in patients with metastatic cancer who are also receiving standard oncology care have not been available. RECENT DATA Seven published RCTs form the basis of this PCO. PROVISIONAL CLINICAL OPINION Based on strong evidence from a phase III RCT, patients with metastatic non-small-cell lung cancer should be offered concurrent palliative care and standard oncologic care at initial diagnosis. While a survival benefit from early involvement of palliative care has not yet been demonstrated in other oncology settings, substantial evidence demonstrates that palliative care-when combined with standard cancer care or as the main focus of care-leads to better patient and caregiver outcomes. These include improvement in symptoms, QOL, and patient satisfaction, with reduced caregiver burden. Earlier involvement of palliative care also leads to more appropriate referral to and use of hospice, and reduced use of futile intensive care. While evidence clarifying optimal delivery of palliative care to improve patient outcomes is evolving, no trials to date have demonstrated harm to patients and caregivers, or excessive costs, from early involvement of palliative care. Therefore, it is the Panels expert consensus that combined standard oncology care and palliative care should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden. Strategies to optimize concurrent palliative care and standard oncology care, with evaluation of its impact on important patient and caregiver outcomes (eg, QOL, survival, health care services utilization, and costs) and on society, should be an area of intense research. NOTE ASCOs provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patients individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical trials and cannot be assumed to apply to the use of these interventions in the context of clinical practice. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCOs PCOs, or for any errors or omissions.

Web-Based Survey of Fertility Issues in Young Women With Breast Cancer

PURPOSE Young women with breast cancer often seek advice about whether treatment will affect their fertility. We sought to gain a better understanding of womens attitudes about fertility and how these concerns affect decision making. PATIENTS AND METHODS We developed a survey about fertility issues for young women with a history of early-stage breast cancer. The survey was e-mailed to all registered Young Survival Coalition survivor members (N = 1,702). E-mail reminders were used. RESULTS Six hundred fifty-seven eligible respondents completed the survey. Mean age at breast cancer diagnosis was 32.9 years; mean current age was 35.8 years. Ninety percent of women were white; 62% were married; 76% were college graduates. Stages at diagnosis were as follows: 0, 10%; I, 27%; II, 47%; III, 13%. Sixty-two percent of women were within 2 years of diagnosis. Fifty-seven percent recalled substantial concern at diagnosis about becoming infertile with treatment. In multivariate logistic regression, greater concern about infertility was associated with wish for children/more children (odds ratio [OR], 120; P < .0001), number of prior pregnancies (OR, 0.78; P = .01), and prior difficulty conceiving (OR, 1.86; P = .08). Twenty-nine percent of women reported that infertility concerns influenced treatment decisions. Seventy-two percent of women reported discussing fertility concerns with their doctors; 51% felt their concerns were addressed adequately. Women seemed to overestimate their risk of becoming postmenopausal with treatment. CONCLUSION Fertility after treatment is a major concern for young women with breast cancer. There is a need to communicate with and educate young patients regarding fertility issues at diagnosis and a need for future research directed at preserving fertility for young breast cancer survivors.

American Society of Clinical Oncology Statement: A Conceptual Framework to Assess the Value of Cancer Treatment Options

Health care costs in the United States present a major challenge to the national economic well being. The Centers for Medicare and Medicaid Services (CMS) has projected that US health care spending will reach

Clinical Trials and Medical Care: Defining the Therapeutic Misconception

4.3 trillion and account for 19.3% of the national gross domestic product by 2019.1 This growth in spending—both in absolute terms and as a proportion of our gross domestic product—has not been accompanied by commensurate improvements in health outcomes, despite expenditures far exceeding those of other countries.2–4 One of the fastest growing components of US health care costs is cancer care, the cost of which is now estimated to increase from

Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update

125 billion in 2010 to

Molecular Subtypes in Breast Cancer Evaluation and Management: Divide and Conquer

158 billion in 2020.1 Although cancer care represents a small fraction of overall health care costs, its contribution to health care cost escalation is increasing faster than those of most other areas because of several factors: the increasing prevalence of cancer due to the overall aging of the population and better control of some causes of competing mortality; the introduction of costly new drugs and techniques in radiation therapy and surgery; and the adoption of more expensive diagnostic tests. In some cases, the adoption of newer, more expensive diagnostic and therapeutic interventions may not be well supported by medical evidence, thereby raising costs without improving outcomes.5 Coupled with, or even driving, some of these rising costs are sometimes unrealistic patient and family expectations that lead clinicians to offer or recommend some of these services, despite the lack of supporting evidence of utility or benefit.6 Historically, most individuals in the United States were shielded from the acute economic impact of expensive care because they had health insurance. However, current trends suggest that patients will find themselves increasingly responsible for a greater proportion of the cost of their health care. Cost shifting or sharing can occur through the increased use of high-deductible policies and larger copayments. These increased costs are already commonplace and may not be affordable for many families. Indeed, health care expenditures are cited as a major cause of personal bankruptcy,7 and the term financial toxicity has entered the vernacular as a means of describing the financial distress that now often accompanies cancer treatment.8 Like other toxicities of cancer treatment, financial toxicity resulting from out-of-pocket treatment expenses can reduce quality of life and impede delivery of high-quality care.9,10 Patients experiencing high out-of-pocket costs have reported reducing their spending on food and clothing, reducing the frequency with which they take prescribed medications, avoiding recommended procedures, and skipping physician appointments to save money.10,11 These unintended consequences risk an increase in health disparities, which runs counter to some of the key goals of health care reform. In many communities, the high costs associated with cancer care have created a difficult situation for patients and the oncologists who care for them. Addressing this situation will require greater understanding of all the risks and benefits of various treatment options as well as the consequences of specific choices. In this regard, studies have shown that patients specifically want financial information about treatment alternatives along with information about medical effectiveness and treatment toxicity. However, they often do not receive it. Closing this knowledge gap will require educated providers who are able to sensitively initiate a dialogue about the cost of care with their patients when appropriate.12,13 Patients with cancer are often surprised by and unprepared for the high out-of-pocket costs of treatments. They also overestimate the benefits of treatments that sometimes extend life by only weeks or months or not at all. Oncologists are generally aware of this conundrum but uncertain about whether and how the cost of care should affect their recommendations.14 Although raising awareness of costs and providing tools to assess value may help to manage costs while maintaining high-quality care, some oncologists see this as being in conflict with their duty to individual patients.15 Recent American Society of Clinical Oncology Efforts Motivated by our responsibility to help oncologists deliver the highest-quality care to patients everywhere, the American Society of Clinical Oncology (ASCO) formed the Task Force on the Cost of Cancer Care in 2007. Its mission includes educating oncologists about the importance of discussing costs associated with recommended treatments, empowering patients to ask questions pertaining to the anticipated costs of their treatment options, identifying the drivers of the rising costs of cancer care, and ultimately developing policy positions that will help Americans move toward more equal access to the highest-quality care at the lowest cost.16 In 2012, through the work of the Task Force, ASCO responded to the Choosing Wisely Campaign of the American Board of Internal Medicine Foundation and identified specific instances of overuse in the delivery of cancer care. ASCO used a deliberative consensus process to identify five common clinical practices that are not supported by high-level evidence. A second list of five was developed using the same process and submitted to the Choosing Wisely Campaign in 2013. ASCO amplified the evidence basis for both top-five lists in two publications17,18 and is now developing measures to evaluate the use of these practices as part of its Quality Oncology Practice Initiative. These exercises have provided opportunities to develop a rigorous but flexible approach to assessing efficacy across diagnostic and treatment domains.

Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study

A key component of informed consent to participate in medical research includes understanding that research is not the same as treatment.

Updating the American Society of Clinical Oncology Value Framework: Revisions and Reflections in Response to Comments Received

Purpose To provide evidence-based recommendations to oncology clinicians, patients, family and friend caregivers, and palliative care specialists to update the 2012 American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) on the integration of palliative care into standard oncology care for all patients diagnosed with cancer. Methods ASCO convened an Expert Panel of members of the ASCO Ad Hoc Palliative Care Expert Panel to develop an update. The 2012 PCO was based on a review of a randomized controlled trial (RCT) by the National Cancer Institute Physicians Data Query and additional trials. The panel conducted an updated systematic review seeking randomized clinical trials, systematic reviews, and meta-analyses, as well as secondary analyses of RCTs in the 2012 PCO, published from March 2010 to January 2016. Results The guideline update reflects changes in evidence since the previous guideline. Nine RCTs, one quasiexperimental trial, and five secondary analyses from RCTs in the 2012 PCO on providing palliative care services to patients with cancer and/or their caregivers, including family caregivers, were found to inform the update. Recommendations Inpatients and outpatients with advanced cancer should receive dedicated palliative care services, early in the disease course, concurrent with active treatment. Referral of patients to interdisciplinary palliative care teams is optimal, and services may complement existing programs. Providers may refer family and friend caregivers of patients with early or advanced cancer to palliative care services.

Association between pharmaceutical involvement and outcomes in breast cancer clinical trials

In the 19th century, the Scottish surgeon, Dr. Thomas Beatson, recognized that some, but not all, cases of advanced breast cancer would regress in response to “hormonal therapy,” which he administered in 1896 through surgical removal of the ovaries (1). Though it was not recognized at the time, Dr. Beatson had produced the first evidence that, despite arising from the same anatomic area and having similar histological appearance, not all breast cancers were biologically the same. In the decades that followed, we have made many advances in breast cancer therapy but we have made inadequate progress in determining which patients are most likely to benefit from which therapies, and in identifying patients at highest risk for recurrence. Standard clinical prognostic features such as patient age, tumor size, nodal status, grade, and endocrine receptor or HER2 status provide valuable information about risk of relapse, however, these clinical risk estimates are crude. For example, using a conventional mathematical model using clinical features (2), a low-risk cancer (less than 1 cm, nodenegative, estrogen receptor-positive, and low grade occurring in a postmenopausal woman) will carry a 15% risk of recurrence, and a high-risk cancer (more than 5 cm, multimodepositive, estrogen receptor-negative, and high grade) will carry an 85% risk of recurrence. Thus, even in the most clinically compelling circumstances, conventional clinical prognosticators are inaccurate 15% of the time. As a result, many patients with early stage disease are treated with toxic therapies they may not need, and others are falsely reassured of a favorable prognosis based on clinical features that mask their true risk (3). Recent evidence suggests that we can do better. Gene expression profiling, which allows simultaneous assessment of the contribution of thousands of genes in a single tumor sample, reveals a biological diversity in breast cancer that mirrors the clinical diversity in outcomes. This technique reveals that regardless of clinical features, breast cancers are several different diseases on the molecular level (4). Differences in behavior and response that seem random on the basis of known prognostic factors can be predicted by gene expression profiles that reclassify breast tumors into distinct subtypes, which should be viewed as distinct entities and managed as such. Microarray analysis of gene expression thus represents a valuable tool for assessing potential biological differences between breast cancers that may otherwise seem similar, to identify additional molecular differences between tumors with different histological characteristics, to assess the potential biological basis for commonly observed differences in outcome, and to develop better predictive models for determination of prognosis and response to therapy based on tumor biology. This chapter explains how gene expression profiling has advanced our understanding of breast cancer biology, reviews the subtypes of breast cancer that have been identified through this new tool, and explores how these discoveries are helping us advance treatments for different classes of breast cancer. In addition, we identify some of the pitfalls of gene expression analysis and areas for future research in this field.

Patient-Oncologist Cost Communication, Financial Distress, and Medication Adherence

PURPOSE We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. PATIENTS AND METHODS One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. RESULTS As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower. CONCLUSION This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.