Ethical Issues and Recommendations in Grateful Patient Fundraising and Philanthropy.

Grateful patients provide substantial philanthropic funding for health care institutions, resulting in important societal benefits. Although grateful patient fundraising (GPFR) is widespread, it raises an array of ethical issues for patients, physicians, development professionals, and institutions. These issues have not been described comprehensively, and there is insufficient guidance to inform the ethical practice of GPFR. Consequently, the authors convened a "Summit on the Ethics of Grateful Patient Fundraising," with the goal of identifying primary ethical issues in GPFR and offering recommendations regarding how to manage them. Participants were 29 experts from across the United States who represented the perspectives of bioethics, clinical practice, development, law, patients, philanthropy, psychology, and regulatory compliance. Intensive discussions resulted in articulating ethical issues for physicians and other clinicians (discussions with patients about philanthropy; physician-initiated discussions; clinically vulnerable patients; conflicts of obligation and equity regarding physician's time, attention, and responsiveness and the provision of special services; and transparency and respecting donor intent) as well as for development officers and institutions (transparency in the development professional-donor relationship; impact on clinical care; confidentiality and privacy; conflicts of interest; institution-patient/donor relationship; concierge services for grateful patients; scientific merit and research integrity; transparency in use of philanthropic gifts; and institutional policies and training in responsible GPFR). While these recommendations promise to mitigate some of the ethical issues associated with GPFR, important next steps include conducting research on the ethical issues in GPFR, disseminating these recommendations, developing standardized training for clinicians regarding them, and revising them as warranted.

Recommendations to Sustain the Academic Mission Ecosystem at U.S. Medical Schools.

Academic medical center (AMC) faculty, administrators, and leaders have the critical tasks of teaching and training the next generation of health care providers and biomedical researchers, as well as generating new knowledge that improves the health of all. In the United States, medical schools and their affiliated hospitals train remarkably high-quality physicians and scientists, and the research conducted at these institutions results in advances in health. To that end, AMCs have become essential engines for driving better health in the United States and the rest of the world; they also have become essential engines driving the economies of their respective communities and regions. The education and research missions, however, require subsidization because tuition and extramural grant funding do not cover the costs of these endeavors. This subsidization largely has come from revenues generated by AMCs' clinical endeavors. The viability of this cross-subsidization, however, is increasingly threatened in the current clinical environment. The authors of this Perspective discuss these issues in depth and provide some concrete recommendations to address these challenges. They hope to stimulate discussion and, ultimately, ensure the financial viability of U.S. AMCs-a national resource of utmost importance. Recommendations to sustain research include creating strategic biomedical research plans, developing a defined and sustained model to support National Institutes of Health funding that keeps pace with inflation, and evolving funding mechanisms. Recommendations to sustain medical education include limiting student debt, creating more cost-effective curricula, and ensuring that clinical training opportunities that meet national standards are available to students.

Developing Core Competencies for the Prevention and Management of Prescription Drug Misuse: A Medical Education Collaboration in Massachusetts.

Drug overdose has become the leading cause of injury death in the United States. More than half of those deaths involve prescription drugs, specifically opioids. A key component of addressing this national epidemic is improving prescriber practices.A review of the curricula at the four medical schools in Massachusetts revealed that, although they taught components of addiction medicine, no uniform standard existed to ensure that all students were taught prevention and management strategies for prescription drug misuse. To fill this gap, the governor and the secretary of health and human services invited the deans of the state's four medical schools to convene to develop a common educational strategy for teaching safe and effective opioid-prescribing practices. With leadership from the Department of Public Health and Massachusetts Medical Society, the deans formed the Medical Education Working Group in 2015. This group reviewed the relevant literature and current standards for treating substance use disorders and defined 10 core competencies for the prevention and management of prescription drug misuse.The medical schools have incorporated these competencies into their curricula and have committed to assessing students' competence in these areas. The members of the Medical Education Working Group have agreed to continue to work together on key next steps, including connecting these competencies to those for residents, equipping interprofessional teams to address prescription drug misuse, and developing materials in pain management and opioid misuse for practicing physicians. This first-in-the-nation partnership has yielded cross-institutional competencies that aim to address a public health emergency in real time.

Research in academic medical centers: two threats to sustainable support.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

High-dose chemotherapy with blood or bone marrow transplants for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, is cured with conventional therapy in 70%. However, the 5-year survival for those who relapse is about 30%, and drops to about 15% for those with unfavorable histologies (alveolar/undifferentiated subtypes). We describe outcomes of 62 subjects receiving autologous blood/bone marrow (BM) transplants for RMS between 1989 and 2003, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). Histologic subtype was confirmed by reviewing pathology reports. Treatment-related mortality (TRM), progression-free survival (PFS), and overall survival (OS) were evaluated. Overall, 73% of subjects were <20 years; 39% had cancer bulk >5 cm, 63% had metastasis at diagnosis, 55% had unfavorable histologies, 92% had cancer responsive to chemotherapy pretransplant, and 67% were in first remission. The 1-year TRM was 5% (95% confidence interval [CI], 1%-12%) and the 5-year PFS and OS were 29% (95% CI, 18%-41%) and 32% (95% CI, 21%-44%), respectively. There was only a 4% relapse rate after the first year. There were no differences in 5-year PFS or survival based on histological subtype, transplant in first remission versus relapse (36% versus 29%; P = .5), or transplantation for poor-risk histologies in first remission versus relapse (34% versus 33%; P = .9). Our data indicate that autotransplants for RMS disease are typically done in patients with disease responsive to chemotherapy pretransplant, with approximately one-third long-term survivors. Despite high-risk factors, we also found a low TRM, perhaps reflecting the migration from marrow to blood stem cells as the graft source. Even when performed after relapse for alveolar/undifferentiated histologies, long-term survivals were seen seemingly better than results with conventional therapies.

Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer.

PURPOSE Conventional medicine has had little to offer patients with inoperable pancreatic adenocarcinoma; thus, many patients seek alternative treatments. The National Cancer Institute, in 1998, sponsored a randomized, phase III, controlled trial of proteolytic enzyme therapy versus chemotherapy. Because most eligible patients refused random assignment, the trial was changed in 2001 to a controlled, observational study. METHODS All patients were seen by one of the investigators at Columbia University, and patients who received enzyme therapy were seen by the participating alternative practitioner. Of 55 patients who had inoperable pancreatic cancer, 23 elected gemcitabine-based chemotherapy, and 32 elected enzyme treatment, which included pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. Primary and secondary outcomes were overall survival and quality of life, respectively. Results At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. Kaplan-Meier analysis found a 9.7-month difference in median survival between the chemotherapy group (median survival, 14 months) and enzyme treatment groups (median survival, 4.3 months) and found an adjusted-mortality hazard ratio of the enzyme group compared with the chemotherapy group of 6.96 (P < .001). At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P < .01). CONCLUSION Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment.

Specific barriers to the conduct of randomized trials.

Large randomized trials are required to provide reliable evidence of the typically moderate benefit of most interventions. To be affordable, such trials need to be simple; to be widely applicable, they need to be close to normal clinical practice. However, current regulations and guidelines have hugely increased trial complexity, effectively becoming barriers to their design and conduct. Key barriers include inadequate funding, overly complex regulations producing needlessly complex trial procedures, excessive monitoring, over restrictive interpretation of privacy laws without evidence of subject benefit, and inadequate understanding of methodology. Complex regulations result in multiple ethics approvals for a multi-center study, unnecessary complexity in the study protocol, delays in securing regulatory approval, and cumbersome regulatory procedures, even for drugs widely used in clinical practice. The type of detailed safety monitoring currently needed in trials of new drugs is being applied indiscriminately to all studies including a simpler and basic level of monitoring that constitutes good practice in most trials could be agreed on, with that level being exceeded only in specific instances. More evidence about the pros and cons of alternative approaches to data quality monitoring would help inform this process. Complex procedures in the form of multiple-page consent forms, overzealous monitoring of side effects and adverse events, source data verification, and over-restrictive approaches to protocol amendments, can impede, rather than facilitate, trial objectives. Finally, further education on the nuances and functions of randomisation would facilitate trial conduct, and reduce the need for burdensome complexity. A radical re-evaluation of existing trial guidelines is needed, based on a clear understanding of the important principles of randomized trials, with the objective of eliminating unnecessary documentation and reporting without sacrificing validity or safety. Researchers should encourage public debate about how best to strike the balance between regulation and cost.

A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study.

BACKGROUND: Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified. METHODS: We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits--prostate cancer and breast cancer--in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multivariable-adjusted residuals, computed using Cox proportional hazards models, were tested for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate > or =80%, minor allele frequency > or =10%, Hardy-Weinberg test p > or = 0.001) using generalized estimating equations (GEE) models and family based association tests (FBAT). RESULTS: There were 58 women with breast cancer and 59 men with prostate cancer. No SNP associations attained genome-wide significance. The top SNP associations in GEE models for each trait were as follows: breast cancer, rs2075555, p = 8.0 x 10(-8) in COL1A1; and prostate cancer, rs9311171, p = 1.75 x 10(-6) in CTDSPL. In analysis of selected candidate cancer susceptibility genes, two MSR1 SNPs (rs9325782, GEE p = 0.008 and rs2410373, FBAT p = 0.021) were associated with prostate cancer and three ERBB4 SNPs (rs905883 GEE p = 0.0002, rs7564590 GEE p = 0.003, rs7558615 GEE p = 0.0078) were associated with breast cancer. The previously reported risk SNP for prostate cancer, rs1447295, was not included on the 100K chip. Results of cancer phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. CONCLUSION: Although no association attained genome-wide significance, several interesting associations emerged for breast and prostate cancer. These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility.

Update on malignant mesothelioma.

Mesotheliomas are uncommon in the United States, with an incidence of about 3,000 new cases per year (or a risk of about 11 per million Americans per year). Incidence and mortality, however, are probably underestimated. Most are associated with asbestos, although some have arisen in ports of prior radiation, and a reported association with simian virus (SV)40 remains controversial. About 85% of mesotheliomas arise in the pleura, about 91% in the peritoneum, and a small percentage in the pericardium or tunica vaginalis testis. The histology of about half of mesotheliomas is epithelial (tubular papillary), with the remainder sarcomatous or mixed. Multicystic mesotheliomas and well-differentiated papillary mesotheliomas are associated with long survival in the absence of treatment and should be excluded from clinical trials intended for the usual rapidly lethal histologic variants of the disease. The median survival is under a year, although longer median survivals for selected patients, particularly those with epithelial histology, have been reported in some combined-modality studies. Recent randomized trials have shown significant improvement in time to progression and survival for the addition of new antifolates to platinum-based chemotherapy.

Adjuvant therapy of osteosarcoma--A Phase II trial: Southwest Oncology Group study 9139.

BACKGROUND: The objective of this study was to estimate the time to treatment failure and survival rate of the three-drug combination of doxorubicin, cisplatin, and ifosfamide as primary and postoperative, adjunctive treatment for teenagers and adults with osteosarcoma (OS). METHODS: Sixty-three eligible patients with nonmetastatic OS of the extremities were registered from 24 institutions from February, 1992 through December, 1996. Chemotherapy was comprised of doxorubicin at a dose of 75 mg/m2 and cisplatin at a dose of 120 mg/m2, alternating with doxorubicin at a dose of 50 mg/m2 and ifosfamide at a dose of 8 g/m2. Four cycles were given prior to surgical resection, and four cycles were given after surgery. Outcome measures included the time to treatment failure, overall survival, toxicity, and centralized assessment of tumor necrosis. RESULTS: Thirty-one of 63 eligible patients died, for a 5-year overall survival rate of 58% (95% confidence interval [95% CI], 46-71%). The median time to treatment failure was 19 months (95% CI, 12-41 months). A good pathologic response (> or = 90% necrosis) to neoadjuvant chemotherapy was observed in 48% of patients who underwent surgery. There was no correlation noted between response to neoadjuvant chemotherapy and patient outcome. Grade 4 hematologic toxicities were frequent (89%), although serious nonhematologic toxicities other than nausea and emesis were uncommon. CONCLUSIONS: The regimen and schedule used in the current study did not improve outcomes compared with prior trials of doxorubicin and cisplatin alone. New, more effective drugs are needed for the treatment of patients with OS. The identification and utilization of molecular markers to predict outcome and response to therapy would facilitate clinical management, limiting exposure to toxic therapies for patients with favorable molecular profiles and identifying those patients who may fail with current approaches as candidates for clinical trials.

High-dose ifosfamide with mesna and granulocyte-colony-stimulating factor (recombinant human G-CSF) in patients with unresectable malignant mesothelioma.

BACKGROUND: The current study was conducted to assess the activity and toxicity of high-dose ifosfamide and mesna with recombinant human granulocyte-colony-stimulating factor (rhG-CSF), given in an outpatient setting, in the treatment of patients with unresectable malignant mesothelioma. METHODS: Between September 1994 and September 1996, 41 patients with histologically verified, unresectable malignant mesothelioma were registered, 38 of whom were analyzable (2 were ineligible and 1 was nonanalyzable). Patients received intravenous ifosfamide at a dose of 2.8 g/m2 over 3 hours (total dose of 14 g/m2), plus mesna at a dose of 0.56 g/m2 prior to and at 4 hours and 8 hours after ifosfamide infusion daily for 5 days every 21 days. rhG-CSF at a dose of 5 microg/kg/day was administered subcutaneously on days 6-15. RESULTS: Response assessment could be determined adequately in 21 patients. Two patients obtained responses; 1 was a confirmed partial response (3%; 95% confidence interval [95% CI], 0-14%) and 1 was an unconfirmed response (3%; 95% CI, 5-14%). Eleven patients had stable disease (29%), 7 patients developed disease progression (18%), 1 patient had an early death (3%), and 17 patients had inadequate assessment (45%). At the time of last follow-up, 36 of the 38 eligible patients had developed disease progression, with a median progression-free survival of 5 months (95% CI, 3-7 months) and 34 patients had died with a median survival of 7 months (95% CI, 6-9 months). Twenty-four patients (63%) and 7 patients (18%), respectively, had Grade (according to Southwestern Oncology Group Toxicity Criteria) 4 hematologic toxicities and Grade 4 nonhematological toxicities. There was one treatment-related death, the result of infection, pulmonary edema, and renal failure. CONCLUSIONS: This regimen demonstrated a low overall objective response rate with substantial toxicity, and in the opinion of the authors does not warrant further investigation in the treatment of patients with unresectable malignant mesothelioma.

A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma.

BACKGROUND: The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC). METHODS: Thirty-six patients with MBC were treated with estramustine 900 mg/m(2) per day divided into 3 doses given on Days 1-3 and docetaxel 70 mg/m(2) given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC. RESULTS: Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14-48%). The median progression free survival was 4 months (range, 1-41 months), and the median overall survival was 17 months (range, 2-45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life. CONCLUSIONS: The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life.

Reducing disparities in breast cancer survival: a Columbia University and Avon Breast Cancer Research and Care Network Symposium.

On November 8th, 2001, faculty from Universities, government and non-profit community organizations met to determine how, separately and together, they could address disparities in survival of women with breast cancer in the diverse patient populations served by their institutions. Studies and initiatives directed at increasing access had to date met modest success. The day was divided into three sections, defining the issues, model programs, government initiatives and finally potential collaborations. By publishing these proceedings, interested readers will be aware of the ongoing programs and studies and can contact the investigators for more information. The Avon Foundation funded this symposium to bring together interested investigators to share programmatic experiences, data and innovative approaches to the problem.

Randomized trials of high-dose chemotherapy in breast cancer: fraud, the press and the data (or lessons learned in medical policy governing clinical research).

High dose therapy for breast cancer remains controversial. Of the 15 randomized trials of high dose therapy in breast cancer reported to date, two South African studies have been discredited leaving 13 remaining studies. Mortality was consistently low, in the 0 to 2.5% range, except for the BCNU containing American Intergroup study, which had a 7.4% toxic mortality rate. Seven of the remaining 13 studies randomized fewer than 200 patients. Three of these small studies have significant differences in disease free survival, and a fourth study has a trend in favor of high dose therapy. The other three small studies cannot exclude a survival difference of 20%. Of the 6 remaining moderately large trials of 219 to 885 randomized patients, 5 are adjuvant studies and one included patients with metastatic disease. Of the five adjuvant trials, four have significant differences in relapse rate favoring the high dose arm, and the remaining study has a trend (with a high dose sequential single agent design rather than combination therapy as in the other studies). A planned subset analysis of the first 284 patients in the largest study funded by the Dutch insurance industry showed a significant advantage for high dose therapy. Given the 2-year median time to relapse and an addition 2-year median to death after relapse, the follow up for survival of 3-5 years on these studies is still short. In the only moderately sized metastatic trial from the National Cancer Institute of Canada with a very short median follow-up of 19 months, a significant difference in disease free survival has emerged, with no difference in survival.

Phase II trial of topotecan by continuous infusion in patients with advanced soft tissue sarcomas, a SWOG study. Southwest Oncology Group.

PURPOSE: Based upon the hypothesis that prolonged exposure to the S-Phase specific agent topotecan would be more efficacious in the treatment of soft tissue sarcomas than a conventional 5-day schedule of the drug, the Southwest Oncology Group performed a Phase II trial of topotecan administered as a continuous infusion in adult patients with advanced soft tissue sarcomas. METHODS: Patients who had received no prior chemotherapy for advanced disease were treated with topotecan at a dose of 0.50 mg/m2/day on days 1-21 of repeated 28 day cycles. RESULTS: Twenty-two patients were enrolled on the study, of whom 21 were eligible. No objective responses were observed (95% confidence interval of 0-16%). The median survival was 12 months (95% confidence interval of 5-16 months). CONCLUSIONS: We conclude that topotecan, given either according to a 5-day or a 21-day schedule, has minimal activity in the treatment of adult soft tissue sarcomas.

High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: To assess survival of patients with metastatic breast cancer treated with high-dose chemotherapy (HDC) versus standard-dose chemotherapy (SDC). PATIENTS AND METHODS: SDC in four Cancer and Leukemia Group B (CALGB) trials was compared with hematopoietic stem-cell support in patients from the Autologous Blood and Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. A total of 1,509 women were enrolled onto CALGB trials, and 1,188 women received HDC. No significant survival differences existed by CALGB trial or HDC regimen. Consideration was restricted to candidates for both SDC and HDC. The resulting sample included 635 SDC and 441 HDC patients. The outcome of interest was overall survival. RESULTS: The HDC group displayed better performance status. The SDC group had slightly better survival in first year after treatment. The HDC group had lower hazard of death from years 1 to 4 and had somewhat higher probability of 5-year survival (adjusted probabilities [95% confidence intervals], 23% [17% to 29%] v 15% [11% to 19%], P =.03). CONCLUSION: After controlling for known prognostic factors in this nonrandomized analysis of two large independent data sets, women receiving HDC versus SDC for metastatic breast cancer have a similar short-term probability of survival, and might have a modestly higher long-term probability of survival.