Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: An important goal of intermittent strategies of delivering systemic treatment as first-line treatment of metastatic colorectal cancer (mCRC) is to maintain efficacy while improving patients' quality of life (QoL). Given the varying impact on efficacy demonstrated in individual randomized, controlled trials (RCTs), a systematic review and meta-analysis of RCTs of these intermittent strategies was carried out. DESIGN: Relevant databases were systematically searched for the period 2000-2014. RCTs that compared a continuous versus intermittent strategy of delivering systemic treatment were identified by a systematic review. Overall survival (OS) hazard ratios (HRs) were extracted from the most recently reported trial results. The results of identified trials were clinically homogeneous so the data were pooled using Review Manager software (RevMan 5.1). RESULTS: Eleven RCTs were identified (n = 4 854). For the eight (n = 4508) trials with available HRs, the treatment patients received after induction was: none (five trials, n = 3036), fluoropyrimidine (one trial, n = 620), and biologic (two trials, n = 852). There were no statistically significant survival differences observed between the continuous and intermittent chemotherapy strategies. There was no statistically significant difference observed between continuous and intermittent strategies [HR = 1.03, 95% confidence interval (CI) 0.96-1.10, P = 0.38)]. Subgroup analyses demonstrated results were generally robust across induction and maintenance regimens. One subgroup analysis of the three trials (CAIRO3, OPTIMOX2, COIN, n = 2403) with combination treatment induction and no maintenance until progression revealed a statistically, but nonclinically significant benefit for continuous treatment (HR = 1.10, 95% CI 1.00-1.20, P = 0.049). QoL life was either the same in both arms in two trials (n = 912) or improved in the intermittent strategy arm in one trial (n = 1630). CONCLUSION: Intermittent strategies of delivering systemic treatment of mCRC do not result in a clinically significant reduction in OS compared with a continuous strategy of delivery, and should be part of an informed discussion of treatment options with patients with mCRC.

Cost-effectiveness analysis of selective first-line use of biologics for unresectable RAS wild-type left-sided metastatic colorectal cancer.

Background: Evidence from a retrospective analysis of multiple large phase iii trials suggested that primary tumour location (ptl) in RAS wild-type metastatic colorectal cancer (wtRAS mcrc) might have predictive value with respect to response to drug therapies. Recent studies also show a potential preferential benefit for epidermal growth factor inhibitors (egfris) for left-sided tumours. In the present study, we aimed to determine the incremental cost-effectiveness ratio (icer) for the first-line use of an egfri for patients with left-sided wtRAS mcrc. Methods: We developed a state-transition model to determine the cost effectiveness of alternative treatment strategies in patients with left-sided mcrc:■ Standard of care■ Use of an egfri in first-line therapyThe cohort for the study consisted of patients diagnosed with unresectable wtRAS mcrc with an indication for chemotherapy and previously documented ptl. Model parameters were obtained from the published literature and calibration. The perspective was that of a provincial ministry of health in Canada. We used a 5-year time horizon and an annual discount rate of 1.5%. Results: Selecting patients for first-line egfri treatment based on left-sided location of their colorectal primary tumour was more effective than the standard of care, resulting in an increase in quality-adjusted life-years (qalys) of 0.226 (or 0.644 life-years gained). However, the strategy was also more expensive, costing an average of $60,639 more per patient treated. The resulting icer was $268,094 per qaly. A 35% price reduction in the cost of egfri would be needed to make this strategy cost-effective at a willingness-to-pay threshold (wtp) of $100,000 per qaly. Conclusions: Selective use of an egfri based on ptl was more cost-effective than unselected use of those agents; however, based on traditional wtp thresholds, it was still not cost-effective. While awaiting the elucidation of more precise predictive biomarkers that might improve cost-effectiveness, the price of egfris could be reduced to meet the wtp threshold.

The cancer specific advance directive.

BACKGROUND: Advance directives are an important part of end of life care, but current advance directive documents do not address the specific issues facing cancer patients. The authors' purpose was: 1) to develop a cancer specific advance directive, 2) determine whether oncology outpatients find this directive more acceptable than a generic advance directive, and 3) describe oncology outpatient preferences for life-sustaining treatment. METHODS: A cancer specific advance directive ("The Cancer Living Will"; the full text of the updated version is available at the University of Toronto Joint Centre for Bioethics website [URL: www.utoronto.ca/jcb]) was developed in four steps: 1) literature search, 2) key informant interviews, 3) focus groups, and 4) evaluation of face and content validity. Subsequently, 91 volunteer oncology patients were given copies of the cancer specific advance directive and the generic advance directive ("The University of Toronto Centre for Bioethics Living Will") from which it was adapted. Acceptability of the advance directive was measured by determining the participants' preferred directive. Participants recorded their treatment preferences in both the cancer specific and generic advance directives. RESULTS: Of 60 patients who returned their questionnaires, 50 expressed a preference for the advance directive. Thirty-two patients (64%; 95% confidence interval (CI), 49-77%) preferred the disease specific Cancer Living Will and 18 patients (36%; 95% CI, 23-51%) preferred the generic Centre for Bioethics Living Will. Most participants who preferred the Cancer Living Will did so because it was more specific and relevant to their situation. CONCLUSIONS: The authors have developed and evaluated a cancer specific advance directive that they believe can be recommended for clinical use with cancer patients.

Compositional and structural control in bone regenerative coatings.

The development of a low-temperature method of producing bioactive coatings for medical implants has been shown to bypass the problems associated with high temperature processing routes, in particular the appearance of amorphous phases and non-stoichiometric hydroxyapatite (HA), and delamination of the coating from the substrate. An electric field/aqueous solution technique for producing adherent, crack-free calcium phosphate coatings on titanium and stainless steel substrates is described. The characteristics of the coating are a function of electrode spacing, supersaturation, temperature and current and voltage conditions. Scanning electron microscopy (SEM) characterized the surface morphology of the coatings, which were shown to be HA. The possibility of producing a coating of carbonate-substituted HA having the same chemical composition as bone apatite, and forming at physiological temperatures, has also been demonstrated. The size of the microstructure decreased and the morphology changed as the carbonate ion concentration in the calcium and phosphate ion solution increased.