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Purpose: While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial. Methods: Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS). Results: 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS. Conclusion: A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing. [ABSTRACT FROM AUTHOR]

Purpose: All vascular access strategies foradministering chemotherapy in early stage breast cancer (EBC) are associated with risks and benefits. As the most effective type of access is unknown a feasibility trial, prior to conducting a large pragmatic trial, was undertaken. Methods: The trial methodology utilized broad eligibility criteria and the integrated consent model incorporating oral consent. EBC patients receiving non-trastuzumab-containing chemotherapy were randomized to peripheral access or central line insertion. The a priori definition of feasibility was: > 25% of patients approached agreed to randomisation and > 25% of physicians approached patients. Secondary outcomes included rates of line-associated complications. Results: Of 159 patients approached, 150 (94.3%) agreed to randomisation, 77 (51.3%) were randomized to peripheral and 73 (48.7%) to central access. 6/26 (23.1%) of medical oncologists approached patients. Rates of complications per chemotherapy cycles in the peripheral vs central access groups with risk difference (RD) (95% CI) were: thrombotic events requiring anticoagulation [1 (0.3%) vs. 3 (1.0%), RD − 0.7(− 1.9,0.5)], line infections [0 (0%) vs. 1 (0.3%), RD − 0.3(− 0.9,0.3)], phlebitis [2 (0.6%) vs. 0 (0%), RD 0.3(− 0.3,0.8)], and tissue infiltrations [4 (1.1%) vs. 1 (0.3%), RD 0.8(− 0.4,2.1)]. Overall, 8.0% (6/75) and 7.7% (5/65) of patients had at least one of these complications in the peripheral and central access arms respectively [RD − 0.9(− 9.4,7.6)]. The study was terminated early due to slow accrual. Conclusion: While meeting its a priori feasibility criteria for patient engagement, the slow accrual means that conducting a large pragmatic trial would require overcoming the barriers to physician recruitment. TRIAL REGISTRATION: NCT02688998 [ABSTRACT FROM AUTHOR]

Background: The proportion of breast cancer patients enrolled in clinical trials is falling. The Rethinking Clinical Trials (REaCT) program was developed to challenge some of the contemporary barriers responsible for this fall in accrual. In this article, we review the successes and challenges our program has faced. Methods: The REaCT program was created to improve care and outcomes for cancer patients through surveys of patients and healthcare providers, systematic reviews, economic evaluations, and the performance of pragmatic randomized trials with patient-centered outcomes. Likely, the greatest difference to conventional trial methodologies has been our widespread use of the integrated consent model (ICM) incorporating oral consent. Results: Between 2014 and 2018, the program has recruited over 2000 patients to 15 randomized studies at 11 Canadian cancer centers. The REaCT program has completed and published five patient surveys, six healthcare provider surveys, ten systematic reviews, performed four economic evaluations, opened 15 clinical trials comparing standard of care interventions (two surgical, two adjuvant chemotherapy, five adjuvant supportive care, one radiology, two vascular devices, two palliative supportive care, and one molecular diagnostics). Patient surveys have shown high levels of satisfaction with the ICM. Conclusion: The REaCT program was developed to tackle important practice questions that will better guide optimal practice and to increase the availability of pragmatic clinical trials. While many challenges remain, future strategies will involve including more study sites and efforts to integrate novel information technology strategies. [ABSTRACT FROM AUTHOR]

Purpose: Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA's in patients with bone metastases from breast cancer. Methods: We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014–March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI). Results: From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88–1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15–1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation. Conclusions: These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer. [ABSTRACT FROM AUTHOR]

Importance: Systemic chemotherapy can be administered either through a peripheral vein (IV), or centrally through peripherally inserted central catheter (PICC), totally implanted vascular access devices (PORTs) or tunnelled cuffed catheters. Despite the widespread use of systemic chemotherapy in patients with breast cancer, the optimal choice of vascular access is unknown.Objective: This systematic review evaluated complication rates and patient satisfaction with different access strategies for administering neo/adjuvant chemotherapy for breast cancer.Evidence reviewed: Ovid Medline, EMBASE and the Cochrane Central Register of Controlled Trials were searched from 1946 to September 2017. Two reviewers independently assessed each citation. The Newcastle-Ottawa scale was used to assess the quality of cohort and case-control studies.Findings: Of 1584 citations identified, 15 unique studies met the pre-specified eligibility criteria. There were no randomised studies comparing types of vascular access. Reports included six single-institution retrospective cohort studies, one retrospective multi-institution cohort, one retrospective cohort database study, five prospective single-institution studies, one prospective multi-institution study and one nested case-control study. Median complication rates were infection: 6.0% PICC (2 studies) versus 2.1% PORT (8 studies); thrombosis: 8.9% PICC (2 studies) versus 2.6% PORT (9 studies); extravasation: 0 PICC (1 study) versus 0.4% PORT (4 studies) and mechanical issues: PICC 3.8% (1 study) versus 1.8% PORT (9 studies). Satisfaction/quality of life appeared high with each device.Conclusion: In the absence of high-quality data comparing vascular access strategies, randomised, adequately powered, prospective studies would be required to help inform clinical practice and reduce variation. [ABSTRACT FROM AUTHOR]

Introduction: The most effective duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer (EBC) patients is unknown. Despite significant differences in cost and toxicity, no prospective trial has been performed to optimize practice. We assessed the feasibility of using a novel pragmatic trial model to compare the most commonly used schedules of filgrastim.Methods: Early breast cancer patients receiving chemotherapy were randomized to 5, 7, or 10 days of filgrastim as primary FN prophylaxis. The trial methodology integrated broad eligibility criteria, simply defined endpoints, an integrated consent model incorporating oral consent, and web-based randomization in the clinic. Feasibility was reflected through a combination of primary endpoints including patient and physician engagement (if > 50% of appropriate patients approached agree to participate, and if > 50% of physicians approached patients for the study). Secondary endpoints included the first occurrence rates of FN, treatment-related hospital admission, or chemotherapy dose reductions/delays/discontinuation.Results: From May 2015 to August 2016, 142/149 (95.3%) patients approached agreed to participate and were randomized. Seventeen of 24 (70.8%) medical oncologists approached and randomized patients. The 142 patients received a total of 495 cycles of chemotherapy. Aggregate incidences of a first event by patient were FN (8/142, 5.6%), treatment-related hospitalization (6/142, 4.2%), chemotherapy discontinuation (7/142, 4.9%), chemotherapy delays (5/142, 3.5%), and chemotherapy dose reduction (18/142, 12.7%). Overall, 31.7% (45/142) of patients and 9.0% (45/495) of chemotherapy cycles were associated with one of these first events.Conclusion: This study met its feasibility endpoints. This novel pragmatic trial approach offers a means of comparing standard of care treatments in a practical and cost-effective manner. The trial will now be expanded to compare rates of FN between the three filgrastim schedules.Trial registration: ClinicalTrials.gov: NCT02428114. [ABSTRACT FROM AUTHOR]

Background: Due to the high rate of febrile neutropenia (FN) with docetaxel-cyclophosphamide (DC) chemotherapy, primary FN prophylaxis is recommended. However, the optimal choice of prophylaxis [i.e., granulocyte-colony stimulating factors (G-CSF) or antibiotics] is unknown. A systematic review was performed to address this knowledge gap. Methods: Embase, Ovid Medline, Pubmed, the Cochrane database of systematic reviews, and Cochrane register of controlled trials were searched from 1946 to April 2016 for studies evaluating primary prophylactic FN treatments in breast cancer patients receiving DC chemotherapy. Outcome measures evaluated included: incidence of FN and treatment-related hospitalizations, chemotherapy dose reduction/delays/discontinuations, and adverse events. Screening and data collection were performed by two independent reviewers. Results: Of 2105 identified records, 7 studies ( n = 2535) met the pre-specified eligibility criteria. Seven additional studies ( n = 621) were identified from prior systematic reviews. There were 3 randomized controlled trials (RCTs) ( n = 2256) and 11 retrospective studies ( n = 900). Study sample sizes ranged from 30 to 982 patients (median 99.5), evaluating pegfilgrastim ( n = 1274), filgrastim ( n = 1758), and oral ciprofloxacin ( n = 108). Given the heterogeneity of patients and study design, a narrative synthesis of results was performed. Median FN rates with and without primary prophylaxis were 6.6 % (IQR 3.9-10.6 %) and 31.3 % (IQR 25-33 %), respectively. No FN-related deaths were reported. No RCT directly compared G-CSF with antibiotic interventions. Conclusions: Primary FN prophylaxis reduces the incidence of FN. Despite considerable cost and toxicity differences between G-CSF and antibiotics, there is insufficient data to make a recommendation of one strategy over another. [ABSTRACT FROM AUTHOR]