The new CMSS code for interactions with companies managing relationships to minimize conflicts.

Conflicts of interest in medicine have received significant attention in recent years, through the public and professional media, federal and state governments, and through a 2009 report of the Institute of Medicine on Conflict of Interest in Medical Research, Education and Practice. The Council of Medical Specialty Societies (CMSS) Code for Interactions with Companies was adopted by the CMSS in April 2010. The Code guides specialty societies in the profession of medicine in ethical relationships between societies and the pharmaceutical and medical device industries. The Code serves to protect and promote the independence of specialty societies and their leaders in corporate sponsorships, licensing, advertising, society meetings, exhibits, educational programs, journals, clinical practice guidelines, and research.

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. METHODS: We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. FINDINGS: Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. INTERPRETATION: Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. FUNDING: National Cancer Institute (US National Institutes of Health).

Interventional Pharmacoeconomics.

The increasing cost of health care is a major challenge around the world, but particularly in the United States. One reason for increased costs is the rapidly rising cost of oncology drugs. Potential solutions to this problem involve broad changes to health policy. However, an alternative solution is the development of lower-cost off-label treatment regimens, based on pharmacologic rationale, with significant potential economic impact. The pharmacologic and clinical properties of many drugs allow for a variety of different strategies. We describe this approach of interventional pharmacoeconomics and provide multiple individual examples.

Interventional Pharmacoeconomics: A Novel Mechanism for Unlocking Value.

Cancer care's sustainability is challenged by drug expenditures. In the absence of systemic change, innovation is needed to curtail drug costs. Interventional pharmacoeconomics (IVPE) utilizes clinical research to identify safe, efficacious, cost-conscious dosing regimens to extract maximum value from expensive therapies. Strategies include de-escalation of dosage, treatment duration and administration frequency, and substitution with therapeutic alternatives. In this review, we discuss how IVPE strategies have been successfully used and could be implemented going forward.

Transforming the future of health together: The Learning Health Systems Consensus Action Plan.

The Learning Health Community is an emergent global multistakeholder grassroots incipient movement bonded together by a set of consensus Core Values Underlying a National-Scale Person-Centered Continuous Learning Health System developed at the 2012 Learning Health System (LHS) Summit. The Learning Health Community's Second LHS Summit was convened on December 8 to 9, 2016 building upon LHS efforts taking shape in order to achieve consensus on actions that, if taken, will advance LHSs and the LHS vision from what remain appealing concepts to a working reality for improving the health of individuals and populations globally. An iterative half-year collaborative revision process following the Second LHS Summit led to the development of the Learning Health Systems Consensus Action Plan.

The costs of conducting clinical research.

PURPOSE: Physicians frequently receive payment for enrolling subjects onto clinical trials. Some view these payments as conflicts of interest. Others contend that these payments are necessary reimbursements for conducting clinical research. We evaluated the clinical and nonclinical hours and costs associated with conducting a mock phase III clinical research trial. METHODS: We collected data from representatives of 21 clinical sites, on the numbers of hours associated with 13 activities necessary to the conduct of clinical research. The hours were based on enrolling 20 patients in a 12-month randomized placebo-controlled trial of a new chemotherapeutic agent. The outcome measures were disease progression and quality-of-life reports. These costs were evaluated for both government and pharmaceutical industry-sponsored trials. RESULTS: On average, 4,012 hours (range, 1,512 to 13,319 hours) were required for a government-sponsored trial, and 3,998 hours (range: 1735 to 15,699) were required for a pharmaceutical industry-sponsored trial involving 20 subjects with 17 office visits, or approximately 200 hours per subject. Thirty-two percent of the hours were devoted to nonclinical activities, such as institutional review board submission and completion of clinical reporting forms. On average, excluding overhead expenses, it cost slightly more than 6,094 dollars (range, 2,098 dollars to 19,285 dollars) per enrolled subject for an industry-sponsored trial, including 1,999 dollars devoted to nonclinical costs. CONCLUSION: Based on the results of our mock trial, the time required for nontreatment trial activities is considerable, and the associated costs are substantial.

Conservative surgery and radiotherapy for stage I/II breast cancer using lung density correction: 10-year and 15-year results.

PURPOSE: Radiotherapy (RT) planning for breast cancer using lung density correction improves dose homogeneity. Its use obviates the need for a medial wedge, thus reducing scatter to the opposite breast. Although lung density correction is used at many centers in planning for early-stage breast cancer, long-term results of local control and survival have not been reported. Since 1984, we have used lung density correction for dose calculations at the University of Michigan. We now present our 10-year and 15-year results. METHODS AND MATERIALS: The records of 867 patients with Stage I/II breast cancer treated with breast-conserving surgery and RT with or without systemic therapy were reviewed. Tangential fields delivering 45-50 Gy to the whole breast calculated using lung density correction were used. A boost was added in 96.8% of patients for a total median dose of 61.8 Gy. RESULTS: With a median follow-up of 6.6 years (range, 0.2-18.9 years), 5-, 10-, and 15-year actuarial rates of in-breast tumor recurrence as only first failure were 2.2%, 3.6%, and 5.4%, respectively. With surgical salvage, the 15-year cumulative rate of local control was 99.7%. Factors that significantly predicted for increased rate of local recurrence in multivariate analysis were age

Postmastectomy radiotherapy of the chest wall: dosimetric comparison of common techniques.

PURPOSE: To compare seven techniques for irradiation of the postmastectomy chest wall (CW) using normal tissue complication probability (NTCP) predictions for pneumonitis and ischemic heart disease and dose-volume histogram analyses for normal and target tissues. METHODS AND MATERIALS: Plan comparisons were performed for 20 left-sided postmastectomy CW RT cases using target volumes based on clinical delineation of standard field borders. Seven common treatment techniques were planned for each case, using a prescription of 50 Gy in 25 fractions to the CW and internal mammary node (IMN) targets. NTCP model metrics were used to quantify the risks of pneumonitis and ischemic heart disease, supplemented by dose-volume metrics to assess the target coverage to the CW and IMNs, as well as normal tissue dose (lung and heart). RESULTS: Overlap in the distributions of the CW mean dose for all plans was found, except cobalt, which was significantly less than the remaining techniques (global F test, F = 21.90, p <0.0001). Standard tangents produced a significantly lower IMN mean dose than all other methods, as expected (F = 59.55, p < 0.0001); the reverse hockey stick and cobalt techniques were lower than the other methods, which were statistically similar. Cobalt produced a significantly higher percentage of the heart that received >30 Gy (V30) than the other methods (F = 49.76, p <0.0001). Use of partially wide tangent fields (PWTFs) resulted in the smallest heart V30. Use of cobalt fields resulted in a significantly greater NTCP estimate for ischemic heart disease than all the remaining techniques (F = 70.39, p <0.0001). Standard tangents resulted in a percentage of the lung receiving >20 Gy (V20) significantly less than with PWTFs, 30/70 and 20/80 photon/electron mix, and reverse hockey stick techniques. NTCP estimates for pneumonitis revealed significantly better results with standard tangents (F = 6.57, p <0.0001). CONCLUSION: No one technique studied combines the best CW and IMN coverage with minimal lung and heart complication probabilities. The choice of technique should be based on clinical discretion and the technical expertise available to implement these complex plans. Of the seven techniques studied, this analysis supports PWTFs as the most appropriate balance of target coverage and normal tissue sparing when irradiating the CW and IMN.

Phase I study of involved-field radiotherapy preceding autologous stem cell transplantation for patients with high-risk lymphoma or Hodgkin's disease.

PURPOSE: This Phase I study was designed to evaluate the tolerability of involved-field radiotherapy (IFRT) to areas of persistent disease in patients with high-risk Hodgkin's disease and non-Hodgkin's lymphomas before autologous stem cell transplantation (ASCT). METHODS AND MATERIALS: Thirty-one patients with primary refractory or relapsed Hodgkin's disease (n = 13) and non-Hodgkin's lymphoma (n = 18) were treated with IFRT followed by high-dose chemotherapy and ASCT. All patients had bulky disease (> or =5 cm) and/or an inadequate response to salvage chemotherapy. The IFRT dose was escalated to a maximum of 36 Gy. Dose-limiting toxicity was defined as Grade 3-4 Bearman toxicity (life-threatening/fatal toxicity occurring within 28 days of ASCT). The chemotherapy regimen consisted of cyclophosphamide, etoposide, and carmustine. RESULTS: The delivered dose of IFRT was 20 Gy in 9 patients, 28-30 Gy in 20, and 32-36 Gy in 2 patients to mediastinal (n = 19) and nonmediastinal (n = 12) sites. The median interval between IFRT completion and ASCT was 19 days. One patient developed Bearman Grade 3 hepatic toxicity. No other Grade 3 or 4 Bearman toxicity was observed. An increased requirement for i.v. narcotics was observed in patients treated with mediastinal IFRT vs. nonmediastinal IFRT (p = 0.02). A trend toward increased mucositis severity was seen in patients previously treated with a larger number of chemotherapy agents (p = 0.09) and in those with a shorter interval between IFRT and ASCT (p = 0.12). Pulmonary toxicity was more common in patients treated with mediastinal IFRT than in those treated with nonmediastinal IFRT (21% vs. 0%, p = 0.13). The 2-year overall and progression-free survival rate was 70% and 49% for all patients, 84% and 50% for patients with Hodgkin's disease, and 59% and 47% for patients with non-Hodgkin's lymphoma, respectively. CONCLUSION: The maximal tolerated dose of IFRT was not reached when Grade 3-4 Bearman toxicity was dose limiting. Increased pulmonary toxicity and mucositis severity was seen after mediastinal IFRT compared with nonmediastinal IFRT. Because local control was excellent, higher doses of IFRT are not recommended. The absolute benefit of IFRT in this patient population needs investigation in future studies.