Chemotherapy and Supportive Care Agents as Essential Medicines for Children With Cancer.

In resource-rich countries, 5-year survival rates for children with cancer approach 85%. This impressive statistic is largely the result of integrating research with clinical care. At the core of this endeavor are multiagent combination chemotherapy and supportive care agents (CASCA). Most CASCAs belong to the class of sterile injectable drugs, which make up the backbone of many proven and life-saving pediatric oncology regimens. There are few if any alternative agents available to treat most life-threatening childhood cancers. In the United States, shortages of CASCAs are now commonplace. The consequences of drug shortages are far reaching. Beyond the economic costs, these shortages directly affect patients' lives, and this is especially true for children with cancer. Drug shortages in general and shortages of CASCAs specifically result in increased medication errors, delayed administration of life-saving therapy, inferior outcomes, and patient deaths. One way to mitigate drug shortages is to adopt an essential medicines list and ensure that these medications remain in adequate supply at all times. We argue for creation of a CASCA-specific essential medicines list for childhood cancer and provide ethical and policy-based reasoning for this approach. We recognize that such a call has implications beyond pediatric cancer, in that children with other serious disease should have an equal claim to access to guaranteed evidence-based medicines. We provide these arguments as an example of what should be claimed for medical indications that are deemed essential to preserve life and function.

An Ethical Framework for Allocating Scarce Life-Saving Chemotherapy and Supportive Care Drugs for Childhood Cancer.

Shortages of life-saving chemotherapy and supportive care agents for children with cancer are frequent. These shortages directly affect patients' lives, compromise both standard of care therapies and clinical research, and create substantial ethical challenges. Efforts to prevent drug shortages have yet to gain traction, and existing prioritization frameworks lack concrete guidance clinicians need when faced with difficult prioritization decisions among equally deserving children with cancer. The ethical framework proposed in this Commentary is based upon multidisciplinary expert opinion, further strengthened by an independent panel of peer consultants. The two-step allocation process includes strategies to mitigate existing shortages by minimizing waste and addresses actual prioritization across and within diseases according to a modified utilitarian model that maximizes total benefit while respecting limited constraints on differential treatment of individuals. The framework provides reasoning for explicit decision-making in the face of an actual drug shortage. Moreover, it minimizes bias that might occur when individual clinicians or institutions are forced to make bedside rationing and prioritization decisions and addresses the challenge that individual clinicians face when confronted with bedside decisions regarding allocation. Whenever possible, allocation decisions should be supported by evidence-based recommendations. "Curability," prognosis, and the incremental importance of a particular drug to a given patient's outcome are the critical factors to consider when deciding how to allocate scarce life-saving cancer drugs.

Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data.

BACKGROUND: Alzheimer's disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha-tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N-methyl-D-aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD. METHODS: The Veterans Affairs Cooperative Studies Program initiated a multicenter, randomized, double-blind, placebo-controlled trial in August 2007, with enrollment through March 2012 and follow-up continuing through September 2012. Participants with mild-to-moderate AD who were taking an acetylcholinesterase inhibitor were assigned randomly to 2000 IU/day of alpha-tocopherol, 20 mg/day memantine, 2000 IU/day alpha-tocopherol plus 20 mg/day memantine, or placebo. The primary outcome for the study is the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory. Secondary outcome measures include the Mini-Mental State Examination; the Alzheimer's Disease Assessment Scale, cognitive portion; the Dependence Scale; the Neuropsychiatric Inventory; and the Caregiver Activity Survey. Patient follow-up ranged from 6 months to 4 years. RESULTS: A total of 613 participants were randomized. The majority of the patients were male (97%) and white (86%), with a mean age of 79 years. The mean Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory score at entry was 57 and the mean Mini-Mental State Examination score at entry was 21. CONCLUSION: This large multicenter trial will address the unanswered question of the long-term safety and effectiveness of alpha-tocopherol, memantine, and their combination in patients with mild-to-moderate AD taking an acetylcholinesterase inhibitor. The results are expected in early 2013.

Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review.

Childhood cancer survivors are at risk for development of subsequent neoplasms of the CNS. Better understanding of the rates, risk factors, and outcomes of subsequent neoplasms of the CNS among survivors of childhood cancer could lead to more informed screening guidelines. Two investigators independently did a systematic search of Medline and Embase (from January, 1966, through March, 2012) for studies examining subsequent neoplasms of the CNS among survivors of childhood cancer. Articles were selected to answer three questions: what is the risk of CNS tumours after radiation to the cranium for a paediatric cancer, compared with the risk in the general population; what are the outcomes in children with subsequent neoplasms of the CNS who received CNS-directed radiation for a paediatric cancer; and, are outcomes of subsequent neoplasms different from primary neoplasms of the same histology? Our search identified 72 reports, of which 18 were included in this Review. These studies reported that childhood cancer survivors have an 8·1-52·3-times higher incidence of subsequent CNS neoplasms compared with the general population. Nearly all cancer survivors who developed a CNS neoplasm had been exposed to cranial radiation, and some studies showed a correlation between radiation dose and risk of subsequent CNS tumours. 5-year survival ranged from 0-19·5% for subsequent high-grade gliomas and 57·3-100% for meningiomas, which are similar rates to those observed in patients with primary gliomas or meningiomas. The quality of evidence was limited by variation in study design, heterogeneity of details regarding treatment and outcomes, limited follow-up, and small sample sizes. We conclude that survivors of childhood cancer who received cranial radiation therapy have an increased risk for subsequent CNS neoplasms. The current literature is insufficient to comment about the potential harms and benefits of routine screening for subsequent CNS neoplasms.

Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group.

With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.

Effect of difficulty affording health care on health status after coronary revascularization.

BACKGROUND: An objective of the United States' Healthy People 2010 Initiative is to eliminate disparities based on socioeconomic status. We assessed the effect of difficulty affording health care on the health status (symptoms, function, and quality of life) of patients treated with percutaneous coronary intervention or CABG. METHODS AND RESULTS: A consecutive, single-center cohort of 480 patients undergoing coronary revascularization received the Seattle Angina Questionnaire at the time of their procedure and at subsequent monthly intervals for 6 months. At baseline, patients who reported somewhat of a burden to a severe burden in affording health care had significantly lower scores on the Seattle Angina Questionnaire (mean+/-SD) with respect to angina (55+/-29 versus 68+/-25, P<0.0001), physical limitation (55+/-26 versus 72+/-24, P<0.0001), and quality of life (46+/-22 versus 56+/-22, P<0.0001) than those who did not perceive healthcare costs to be burdensome. Although both groups of patients improved after revascularization, poorer health status persisted among those with difficulty affording health care after percutaneous coronary intervention (6-month mean+/-SE: angina 79+/-2.5 versus 88+/-1.9, P=0.002; physical function 61+/-2.7 versus 80+/-2.0, P<0.0001; quality of life 67+/-2.4 versus 82+/-1.8, P<0.0001) but not after CABG (angina 91+/-2.5 versus 93+/-1.6, P=0.47; physical function 75+/-3.4 versus 81+/-2.2, P=0.13; quality of life 84+/-3.1 versus 84+/-2.0, P=0.81). Similar differences remained after adjustment for demographic and clinical characteristics. CONCLUSIONS: Patients reporting difficulty affording health care have worse health status at the time of coronary revascularization. A persistent disparity exists after percutaneous but not surgical revascularization. Additional inquiry into the mechanism of this disparity is needed so that the goals of equitable health care, irrespective of treatment strategy, can be achieved.

Hypochondriacal concerns in panic disorder and major depressive disorder: a comparison.

OBJECTIVE: To gain perspective on the relationship between hypochondriasis and panic disorder, we compared the occurrence of hypochondriasis in patients with panic disorder (N= 59) and major depressive disorder (N= 27). METHODS: Patients who participated in separate drug treatment trials were assessed at baseline and eight weeks using the Whiteley Index of Hypochondriasis. RESULTS: At baseline, the Whiteley Index score was greater for patients with panic disorder than for those with major depressive disorder. At eight weeks, a statistically significant reduction in the mean hypochondriasis score was observed in panic patients who had improved but not in major depressive patients who had improved. Modest correlations were observed between hypochondriasis and symptoms of panic and major depressive disorder, but in depressed patients, hypochondriasis was positively correlated with anxiety symptoms as well. CONCLUSION: A unique relationship appears to exist between hypochondriasis and panic disorder. The nature of this relationship and its implications for classification are discussed.