Christopher K. Daugherty

Perceptions of cancer patients and their physicians involved in phase I trials.

PURPOSE In an attempt to understand some of the complex issues related to the participation of cancer patients in phase I trials, and the perceptions of patients toward these trials, we conducted a pilot survey study of 30 cancer patients who had given informed consent to participate in a phase I trial at our institution. Concurrently, the oncologists identified by the surveyed patients as responsible for their care were surveyed as well. PATIENTS AND METHODS Twenty-seven of 30 consecutive patients agreed to and completed the survey. Patients were surveyed before they received any investigational agents. Eighteen oncologists participated in this survey study. RESULTS Eighty-five percent of patients decided to participate in a phase I trial for reasons of possible therapeutic benefit, 11% because of advice/trust of physicians, and 4% because of family pressures. Ninety-three percent said that they understood all (33%) or most (60%) of the information provided about the trials in which they had decided to participate. Only 33% were able to state the purpose of the trial in which they were participating, with patients able to state the purpose of phase I trials being more educated (P = .01). Surveyed oncologists had wide-ranging beliefs regarding expectations of possible benefits and toxicities for their patients participating in phase I trials. CONCLUSION Cancer patients who participate in phase I trials are strongly motivated by the hope of therapeutic benefit. Altruistic feelings appear to have a limited and inconsequential role in motivating patients to participate in these trials. Cancer patients who participate in phase I trials appear to have an adequate self-perceived knowledge of the risks of investigational agents. However, only a minority of patients appear to have an adequate understanding of the purpose of phase I trials as dose-escalation/dose-determination studies.

Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

PURPOSE This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

Quantitative analysis of ethical issues in phase I trials: a survey interview of 144 advanced cancer patients.

ington, D.C.: Government Printing Office, 1977. DHEW Publication No. (OS) 77-0004. 12. Ellis GB. Federal policy for protection of human subjects. In: Report on the Public Forum on Informed Consent in Clinical Research Conducted in Emergency Circumstances. Washington, D.C.: U.S. Food and Drug Administration /National Institutes of Health, 1995. 13. National Institutes of Health. NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, March 1998 (http://www.nih.gov/ grants/guide/notice-files/not98024.html) 14. Food and Drug Administration Rules and Regulations 21 CFR 201, 312, 314, 601 (Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients; Final Rule). Federal Register 1998;63(231):66632. 15. Shirkey HC. Therapeutic orphans. Journal of Pediatrics 1968;72:119120. 16. American Academy of Pediatrics. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 1977; 60:91-101.

Use of the Internet to Obtain Cancer Information Among Cancer Patients at an Urban County Hospital

PURPOSE To evaluate rates, predictors, and barriers to use of the Internet to obtain cancer information among a cohort of cancer patients at an urban county hospital. PATIENTS AND METHODS Of 208 cancer patients approached, 200 patients completed a structured interview study examining Internet use, perceptions of the accuracy of Internet information, and barriers to use. RESULTS Only 10% of participants reported using the Internet themselves to obtain cancer information. Another 21% reported exposure to Internet information through proxies. The most common barrier to Internet use cited was lack of Internet access, with 44% reporting that they would use the Internet to obtain cancer information if they had Internet access. Younger age and more years of formal education were significantly associated with Internet use, although race and income were not. Less education, African American race, and female sex were associated with lower estimates of the accuracy of Internet information. Fewer years of formal education was associated with increased likelihood of reporting confusion after reading Internet information. CONCLUSION Very few cancer patients in this study of a cohort of generally disadvantaged individuals used the Internet themselves to obtain cancer information, although many more desired to do so. Significant opportunities for Web-based interventions aimed at improving cancer care outcomes in this population of cancer patients exist. However, further study will be needed to determine how to make such intervention accessible, trustworthy, and understandable to the disadvantaged.

General internists' preferences and knowledge about the care of adult survivors of childhood cancer: a cross-sectional survey.

Context Most adult childhood cancer survivors (CCSs) receive health care from primary care physicians. Contribution This survey of general internists found that about half provided care for adult CCSs but most had never received a treatment summary from a referring cancer center. Internists were somewhat uncomfortable caring for survivors of Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma. In a vignette case, most general internists did not recommend appropriate surveillance for a Hodgkin lymphoma survivor. Implication Although general internists see adult CCSs, many are unfamiliar with recommended surveillance practices and lack coordinated communication processes with oncologists and cancer centers. The Editors More than 350 000 childhood cancer survivors (CCSs) live in the United States, and this population continues to expand (1, 2). In 2002, the Institute of Medicine recognized the substantial health risks facing CCSs, including end-organ dysfunction, second malignant neoplasms, and cognitive impairment (39). The Institute of Medicine recommended lifelong, risk-based health care to mitigate these late effects. Such care includes a systematic plan for periodic surveillance and prevention that is adapted to the specific risks from the individual patients previous cancer, therapy, genetic predisposition, health behaviors, and comorbid conditions (3, 10). In response, various international groups created and disseminated guidelines for the risk-based care of CCSs (1115). In 2003, the North American Childrens Oncology Group (COG) published the Long-Term Follow-Up (LTFU) Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer, which provide surveillance guidelines based on survivors exposure to cancer therapies (11, 15). Yet, more than a decade after the Institute of Medicine report, most CCSs are not engaged in appropriate risk-based health care (1620). Several factors contribute to this lack of engagement. Survivors treated at a young age often have limited knowledge of the therapies they had and their consequences (21). Many adult CCSs have difficulty obtaining adequate health insurance (2126). Finally, transitions from pediatric to adult-care providers and from tertiary care cancer centers to community clinicians contribute to suboptimal care (27, 28). Previous studies of pediatric oncologists suggest that insufficient understanding of late effects and publically available surveillance guidelines contribute to ineffectual transitions (23, 2931). More than 80% of adult CCSs receive health care from a primary care physician (PCP) in their community, yet our understanding of the care delivered by PCPs to this growing and clinically challenging population is limited (16). As more than half of the adult-focused PCPs in the United States are general internists (32), we conducted a nationally representative survey of practicing general internists to assess their attitudes and knowledge about the care of CCSs. Methods Study Population Using methods from previous studies (33, 34), we selected a national probability sample of practicing physicians who listed general internal medicine as their primary specialty from the American Medical Association Physician Masterfile, a database intended to include all physicians in the United States. We selected 2000 physicians from approximately 148 000, giving a sampling percentage of 1.35% (or 1 physician sampled of every 74 physicians in the population). We obtained approval from the University of Chicagos institutional review board before study initiation. Survey Mailings Surveys were mailed to physicians between September 2011 and August 2012, with a prenotification letter and postcard reminder. Up to 4 mailings were sent to increase response rates. A

How Often Do BRCA Mutation Carriers Tell Their Young Children of the Family's Risk for Cancer? A Study of Parental Disclosure of BRCA Mutations to Minors and Young Adults

10 incentive was included in the first mailing. The third mailing included a

Outcomes of patients with AML and MDS who relapse or progress after reduced intensity allogeneic hematopoietic cell transplantation.

5 incentive, and the fourth and final mailing included

Psychosocial adjustment of patients and caregivers prior to allogeneic bone marrow transplantation.

20 on receipt of a completed survey. During the fourth mailing, physicians were called if a phone number was available. We used the Google search engine (Google, Mountainview, California) to identify discrepant addresses from data provided by the American Medical Association Physician Masterfile for nonrespondents. If an alternate address was identified, subsequent mailings were sent to the new address. Internists were excluded from the analytic sample if surveys were returned 2 or more times with incorrect addresses or if participants were identified as deceased, retired, or no longer practicing internal medicine. Survey Instrument The survey was derived from previous surveys about physician attitudes and knowledge about cancer care (29, 35, 36). A CCS was defined as a patient diagnosed with cancer at or before age 21 years, at least 5 years from cancer therapy completion, and who was cancer free. This definition was chosen to capture physician experiences with patients who had survived the period in which relapse is the predominant health threat and is consistent with terminology used by several groups that research the long-term effects of pediatric cancer (for example, the North American Childhood Cancer Survivor Study and the British Childhood Cancer Survivor Study) (8, 37). The 18-item survey assessed respondents demographics, medical education, and practice structure. We asked internists about the number of CCSs they had cared for in the past 5 years and how frequently they had received a cancer treatment summary (documenting the survivors diagnosis, cancer therapy, and follow-up plan) from a referring cancer center. We assessed comfort level with caring for survivors of acute lymphoblastic leukemia, Hodgkin lymphoma, and osteosarcoma with a 7-point Likert scale, with scores ranging from 1 (very uncomfortable) to 7 (very comfortable). A similar Likert scale assessed familiarity with the available monitoring guidelines for childhood, adolescent, and young adult cancer survivors (scores ranging from 1 [very unfamiliar] to 7 [very familiar]). We asked internists whether they prefer to care for survivors independently, in consultation with a cancer centerbased physician or LTFU clinic, or by referral to a cancer centerbased physician or another PCP. The survey included a hypothetical vignette describing a 29-year-old female survivor of Hodgkin lymphoma whose therapy included mantle radiation and anthracycline chemotherapy (cumulative dose, 150 mg/m2) at age 16 years. Using a set of preselected responses, we asked internists about their approach to breast cancer and cardiac and thyroid surveillance for this patient. We compared responses with the COG LTFU guidelines (15). Finally, we asked internists to rate the usefulness of 11 tools that might assist them in independently caring for such a survivor using a scale ranging from 1 (not at all useful) to 4 (very useful). Statistical Analysis Descriptive statistics included frequency counts and percentages, means with SDs, and medians with ranges. Chi-square tests or 2-sample t tests were conducted for comparisons between groups. We calculated Spearman rank correlation coefficients when determining associations between 2 continuous or ordinal variables. We fit multivariate linear and logistic regression models to examine internists comfort with caring for CCSs and knowledge of surveillance guidelines, respectively. Covariates, chosen a priori, were sex, years of practice, number of patients seen per week, having seen at least 1 CCS in the past 5 years, and practice environment. Age was highly correlated with years of practice (r = 0.92) and was not included in the multivariate models. All analyses were conducted by using Stata software, version 12 (StataCorp, College Station, Texas). Role of the Funding Source The National Cancer Institute provided financial support for this work through a grant to Dr. Henderson. The funding source played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Results We received 1110 completed questionnaires out of 1801 potential respondents (response rate, 61.6%) (Appendix Figure). Characteristics of the participating internists are detailed in Table 1. We found no statistically significant differences in sex, age, or geographic location of practice between respondents and nonrespondents. Appendix Figure. Study flow diagram. AMA = American Medical Association. Table 1. Demographic and Practice Characteristics of Respondents and Nonrespondents Fifty-one percent of respondents reported having cared for at least 1 adult CCS in the 5 years preceding the survey (Table 1). Among this subset, 72.0% reported never having received a treatment summary. Only 61 internists (5.5%) preferred to care for CCSs independently. Most (84.0%) preferred to work in collaboration with a cancer centerbased physician or LTFU clinic, and 10.5% indicated that they would refer CCSs to a cancer centerbased physician, LTFU program, or another PCP. On average, internists reported being somewhat uncomfortable caring for CCSs. Only 36.9%, 27.0%, and 25.0% of respondents indicated that they were somewhat comfortable or comfortable (Likert score 5) caring for Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma survivors, respectively. In multivariate analyses, comfort levels were higher among internists with a larger patient volume, those who had seen at least 1 CCS in the preceding 5 years, and men (Appendix Table 1). Appendix Table 1. Multivariate Linear Regression on Comfort Levels* With CCSs General Internists Familiarity and Knowledge of Published LTFU Guidelines Internists reported being generally unfamiliar with available surveillance guidelines for CCSs. Only 12.0% stated that they felt at least somewhat familiar with available guidelines (Likert score 5). Knowledge of available surveillance guidelines for breast cancer and cardiac and thyroid function was assessed by using the

Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin’s disease and non-Hodgkin’s lymphoma

PURPOSE Predictive genetic testing for adult-onset diseases is generally discouraged until the age at which interventions are believed to be helpful. Yet, many BRCA mutation carriers discuss their results with their children. This study describes the prevalence and experiences of parental communication of BRCA results to children under the age of 25 years old. PATIENTS AND METHODS Forty-two BRCA mutation carriers completed semistructured telephone interviews assessing self-reported disclosure to offspring and parent experiences with disclosure. Qualitative responses were coded for themes. chi(2) tests and logistic regression analyses with robust variance estimates were used to evaluate parent and child characteristics associated with disclosure. RESULTS Fifty-five percent of parents reported discussing hereditary risk of cancer with at least one child. By parent report, 49% of the 86 offspring learned of their parents genetic test results or the hereditary cancer risk. Offspring age was strongly associated with disclosure (P = .001), and the majority of adolescent and adult children learned of the familial mutation or the hereditary risk of cancer. Parents reported that some offspring did not appear to understand the significance of the information shared, and that some offspring had initial negative reactions to disclosure. Physician (14%) and genetic counselor (21%) involvement in parent decisions to disclose were low. CONCLUSION Children of BRCA mutation carriers learn of their parents genetic test results many years before preventive interventions are indicated. Further research is needed to examine how young individuals understand this information and its psychosocial impact and influence on subsequent lifestyle and health behaviors.

Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials

We describe treatment, outcomes and prognostic factors for patients who relapse following transplantation with a reduced intensity conditioning regimen. Seventy consecutive patients with high-risk myeloid malignancies underwent transplant and 25 (36%) relapsed, a median of 120 days later. The median percentage of bone marrow blasts at relapse was 24, the median donor chimerism was 73% and new karyotypic abnormalities occurred in 8 out of 20 (40%) evaluable patients. Twenty-one patients (84%) received aggressive treatment for relapse, including chemotherapy (60%), second hematopoietic cell transplantation (HCT; 52%) and/or donor lymphocyte infusion (DLI; 12%). Thirteen achieved a complete response (CR) and four remain in CR. Median overall survival (OS) after relapse was 6 months (95% confidence interval=2.7–9.9 months), and actuarial 1 year OS was 24%. Most deaths were due to disease progression (17/20, 85%). We did not observe an advantage for cellular therapy (DLI or second transplant) compared to chemotherapy. Salvage therapy for relapse after reduced intensity HCT is feasible, associated with low treatment-related mortality, and may result in prolonged survival in select patients. Studies exploring the optimal treatment for relapse following reduced intensity HCT are warranted.