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Phase I trials often represent the first occasion where new cancer strategies are tested in patients. Various developments in cancer biology, methodology, regulation, and medical ethics have altered the ethical landscape of such trials. We provide a narrative review of contemporary ethical challenges in design, conduct, and reporting of phase I cancer trials and outline recommendations for addressing each. We organized our review around four topics, supplementing the first three with scoping reviews: (1) benefit/risk, (2) research biopsies, (3) therapeutic misconception and misestimation, and (4) reporting. The main ethical challenges of conducting phase I trials stem from three issues. First, phase I trials often involve higher research burden and scientific uncertainty compared with other cancer trials. Second, many patients arrive at phase I trials at a transitional point in their illness trajectory where they have exhausted standard survival-extending options. Third, phase I trial results play a major role in informing downstream drug development and regulatory decisions. Together, these issues create distinct pressures for study design, ethical review, informed consent, and reporting. Developments in methodology, regulation, cancer biology, and ethical awareness have helped mitigate some of these challenges, while introducing others. We conclude our review with a series of recommendations regarding trial design, ethical review, consent, and reporting. We also outline several unresolved questions that, if addressed, would strengthen the ethical foundation of phase I cancer trials.

PURPOSE The 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor–positive (ER+) and human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles. METHODS The Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2− breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node–negative (N0) and limited node–positive (N1) breast cancer. RESULTS Among eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively. CONCLUSION The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.

PURPOSE: We sought to generate informed and considered opinions regarding acceptable secondary uses of deidentified health information and consent models for oncology learning health care systems. METHODS: Day-long democratic deliberation sessions included 217 patients with cancer at four geographically and sociodemographically diverse sites. Patients completed three surveys (at baseline, immediately after deliberation, and 1-month follow-up). RESULTS: Participants were 67.3% female, 21.7% black, and 6.0% Hispanic. The most notable changes in perceptions after deliberation related to use of deidentified medical-record data by insurance companies. After discussion, 72.3% of participants felt comfortable if the purpose was to make sure patients receive recommended care (v 79.5% at baseline; P = .03); 24.9% felt comfortable if the purpose was to determine eligibility for coverage or reimbursement (v 50.9% at baseline; P < .001). The most notable change about secondary research use related to believing it was important that doctors ask patients at least once whether researchers can use deidentified medical-records data for future research. The proportion endorsing high importance decreased from baseline (82.2%) to 68.7% immediately after discussion (P < .001), and remained decreased at 73.1% (P = .01) at follow-up. At follow-up, non-Hispanic whites were more likely to consider it highly important to be able to conduct medical research with deidentified electronic health records (96.8% v 87.7%; P = .01) and less likely to consider it highly important for doctors to get a patient’s permission each time deidentified medical record information is used for research (23.2% v 51.6%; P < .001). CONCLUSION: This research confirms that most patients wish to be asked before deidentified medical records are used for research. Policies designed to realize the potential benefits of learning health care systems can, and should be, grounded in informed and considered public opinion.

In contrast to clinical biopsies, where tissue is collected to inform patient care, research biopsies are performed for scientific purposes to potentially enhance understanding of the biologic bases of cancer and drug action, thereby improving diagnosis and treatment, but they may offer no direct benefit to participants and have known risks. The widespread use of research biopsies that do not have the potential to directly benefit participants has come under scrutiny, with critics raising ethical concerns related to the adequacy of participant protections, informed consent, and participant understanding of the risks and benefits, as well as the scientific impact of research biopsies on drug development and treatment. This manuscript presents the American Society of Clinical Oncology’s (ASCO’s) ethical framework for incorporation of research biopsies in trials. The framework provides guidance on the circumstances to include optional and mandatory biopsies, as well as provides recommendations to stakeholders on necessary steps for improving the conduct of research biopsies overall.

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.

Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's 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 patient's 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 Panel's 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. ASCO's 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 patient's 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 ASCO's PCOs, or for any errors or omissions.

Purpose Young women with breast cancer often seek advice about whether treatment will affect their fertility. We sought to gain a better understanding of women’s 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.