INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors.

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.

The COVID-19 pandemic and its effects on follow-up of patients with early breast cancer: A patient survey.

PURPOSE: Despite limited evidence supporting its effectiveness, most guidelines recommend long-term, routinely scheduled in-person surveillance of patients with early breast cancer (EBC). The COVID-19 pandemic led to increased use of virtual care. This survey evaluated patient perspectives on follow-up care. METHODS: Patients with EBC undergoing surveillance were surveyed about follow-up protocols, perceptions, and interest in clinical trials assessing different follow-up strategies. RESULTS: Of 402 approached patients 270 completed the survey (response rate 67%). Median age 62.5 years (range 25-86) and median time since breast cancer diagnosis was 3.8 years (range < 1-33 years). Most (n = 148/244, 60%) were followed by more than one provider. Routine follow-ups with breast examination were mostly conducted by medical/radiation oncologists every 6 months (n = 110/236, 46%) or annually (n = 106/236, 44%). Participants felt routine follow-up was useful to monitor for recurrence, manage side effects of cancer treatment and to provide support/reassurance. Most participants felt regular follow-up care would detect recurrent cancer earlier (n = 214/255, 96%) and increase survival (n = 218/249, 88%). The COVID-19 pandemic reduced the number of in-person visits for 54% of patients (n = 63/117). Patients were concerned this reduction of in-person visits would lead to later detection of both local (n = 29/63, 46%) and distant recurrences (n = 25/63, 40%). While many felt their medical and radiation oncologists were the most suited to provide follow-up care, 55% felt comfortable having their primary care provider (PCP) conduct surveillance. When presented with a scenario where follow-up has no effect on earlier detection or survival, 70% of patients still wanted routine in-person follow-up for reassurance (63%) with the goal of earlier recurrence detection (56%). CONCLUSIONS: Despite limited evidence of effectiveness of routine in-person assessment, patients continue to place importance on regularly scheduled in-person follow-up.

A randomized clinical trial comparing physician-directed or fixed-dose steroid replacement strategies for incomplete dexamethasone dosing prior to docetaxel chemotherapy.

PURPOSE: Prior to docetaxel chemotherapy, incomplete dosing of steroid premedication is common. The lack of standardized steroid replacement strategies can lead to variability in care and delays in starting docetaxel. METHODS: This randomized trial compared physician-directed with fixed-dose dexamethasone. Patients who had missed at least one dose of steroid premedication were randomized to physician-directed replacement (any choice of steroid, dose or route) or to dexamethasone 8 mg oral before starting docetaxel. The primary outcome was time from randomization to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin toxicity. RESULTS: Of 60 eligible patients, 30 (50%) and 30 (50%) were randomized to physician-directed and fixed-dose arms, respectively. Overall tumour types: breast (42 [70%]), gastrointestinal (7 [12%]), prostate (7 [12%]) and lung (3 [7%]). Dexamethasone was most commonly incompletely taken with cycles 1 (28 [48%]) and 2 (13 [22%]) of docetaxel. Seven different replacement strategies were used in the physician-choice arm. Patients in the fixed-dose arm received docetaxel a mean of 21.2 (95% CI for the difference is 2.1 to 44.6) minutes earlier than the physician-choice arm (p = 0.033 Wilcoxon rank sum test or p = 0.073 two-sample t test). Median time to docetaxel was 47.5 vs 61 min (mean 62.2 vs 83.4 min) by arm, respectively. No significant difference in toxicity rates was observed. CONCLUSION: While not meeting our predefined criteria of improving the time from randomization to starting docetaxel by 30 min, the fixed-dose replacement strategy reduced both the time to starting docetaxel and treatment variability. Fixed dosing with oral dexamethasone 8 mg should be the preferred standard of care. REGISTRATION: www.clinicaltrials.gov NCT02815319 REGISTRATION DATE: June 28, 2016.

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.

BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.

Why "Reply All" Can Push All the Wrong Buttons.

Technology has changed the way medicine is practiced. This commentary considers the effect of digital communications and offers advice on e­mail etiquette.

A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229).

BACKGROUND: Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints. PATIENTS AND METHODS: Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D. RESULTS: Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ≥3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD-L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration. CONCLUSION: The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC. IMPLICATIONS FOR PRACTICE: This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the "cold" tumors to be able to combine current immune-oncology agents.

Randomized window of opportunity trial evaluating high-dose vitamin D in breast cancer patients.

PURPOSE: Epidemiologic and preclinical data suggest a potential role for vitamin D in breast cancer treatment and prevention. However, results of prospective randomized trials are inconsistent. The objective of this study was to assess the effects of high-dose cholecalciferol (vitamin D3) on breast tumour proliferation and apoptosis. METHODS: We conducted a prospective, randomized, phase 2, double-blinded pre-surgical window of opportunity trial. Newly diagnosed breast cancer patients were randomized to receive 40,000 IU of vitamin D3 per day or placebo for 2 to 6 weeks prior to breast surgery. The primary outcome was the relative change in proliferation (Ki67) and apoptosis (cleaved caspase 3 apoptotic assay [CC3]) in primary breast cancer cells pre and post treatment. RESULTS: Of 83 patients randomized, 80 completed the study (43 (53.8%) vitamin D and 37 (46.3%) placebo). Mean duration of drug intake was 19 days (range 9-28 days). There were no significant differences between the control arm and the vitamin D arm in percent changes of either Ki67 index (1.6% vs. 16.7%, p = 0.25) or CC3 (- 55.9% vs. - 45.9%, p = 0.28). Serum 25-hydroxyvitamin D (25-OHD) levels were 3 times higher in the vitamin D arm (62 nmol/L vs. 246 nmol/L, p < 0.001). Adverse effects were minimal and all classified as grade 1. CONCLUSIONS: Despite significantly higher levels of serum 25-OHD in the vitamin D-treated group, this was not associated with any significant effects on tumour proliferation or apoptosis. These findings are consistent with the lack of benefit observed in prospective prevention trials. TRIAL REGISTRY: Trial registration clinicaltrials.gov NCT01948128.

A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients.

PURPOSE: Chloroquine has demonstrated anti-tumor activities through autophagy inhibition and cell cycle disruption. This study aimed to assess the effect of single-agent chloroquine on breast tumor cellular proliferation in a randomized, phase II, double-blind, placebo-controlled, pre-surgical window of opportunity trial. METHODS: Patients with newly diagnosed breast cancer were randomized 2:1 to chloroquine 500 mg daily or placebo for 2- to 6-weeks prior to their breast surgery. The primary outcome was the relative change in measures of proliferation (Ki67) in primary breast cancer cells pre- and post-treatment. Adverse events and toxicity profiles were also evaluated. RESULTS: From September 2015 to December 2016, 70 patients were randomized [46 (66%) chloroquine and 24 (34%) placebo]. Ten patients who were randomized to chloroquine withdrew from study due to adverse events. Mean duration of drug intake was 15 days (range 14-29 days). There were no significant differences between the chloroquine or placebo arms with respect to either the percentage change (- 0.4 vs. - 1.2, p = 0.088) or absolute change (- 2.0% vs. - 5.2%, p = 0.066) in Ki67 index pre- and post-drug treatment. Although adverse effects were minimal and all classified as grade 1, the effects were significant enough to cause nearly 15% of patients to discontinue therapy. CONCLUSIONS: Treatment with single-agent chloroquine 500 mg daily in the preoperative setting was not associated with any significant effects on breast cancer cellular proliferation. It was, however, associated with toxicity that may affect its broader use in oncology.

De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis.

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.

Creating a pragmatic trials program for breast cancer patients: Rethinking Clinical Trials (REaCT).

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.

A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors.

Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.

Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC).

PURPOSE: Optimal primary febrile neutropenia (FN) prophylaxis (i.e. ciprofloxacin or granulocyte-colony stimulating factors [G-CSF]) for patients receiving docetaxel-cyclophosphamide (TC) chemotherapy is unknown. We assessed the feasibility of using a novel pragmatic comparative effectiveness trial to compare these standard-of-care options. METHODS: Early-stage breast cancer patients receiving TC chemotherapy were randomised to either ciprofloxacin or G-CSF. Trial methodology consists of broad eligibility criteria, simply-defined endpoints, integrated consent model incorporating oral consent, and web-based randomisation in the clinic. Primary feasibility endpoints included patient and physician engagement (if > 50% of patients approached agree to participate and if > 50% of physicians approached patients for the study). Secondary clinical endpoints included the following: first occurrence rates of FN, treatment-related hospitalisation, or chemotherapy dose reduction/delay/discontinuation, as well as patient satisfaction with the oral consent process. RESULTS: Of 204 patients approached, 91.2% (186/204) agreed to randomisation. Sixteen of twenty (80%) participating medical oncologists randomised patients. Median patient age was 57.7 (range 31.8-84.1). The 186 patients received 557 cycles of chemotherapy. Overall incidences of first events by patient (n = 186) were as follows: FN (18/186, 21.43%), treatment-related hospitalisation (11/186, 13.10%), chemotherapy reduction (19/186, 22.62%), chemotherapy discontinuation (16/186, 19.05%), and chemotherapy delays (5/186, 5.95%). A total of 37.77% (69/186) of patients and 12.39% (69/557) of chemotherapy cycles had at least one of these first events. Patients were highly satisfied with the oral consent process. CONCLUSION: This study met its feasibility endpoints. This model offers a means of comparing standard-of-care treatments in a practical and cost-efficient manner. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov : NCT02173262.

A prospective intervention to improve happiness and reduce burnout in oncologists.

BACKGROUND: There is a paucity of data about effective interventions to improve happiness and reduce burnout in oncologists. Benjamin Franklin developed a 13-week program of "necessary activities" or "virtues" (temperance, silence, order, resolution, frugality, industry, sincerity, justice, moderation, cleanliness, tranquility, chastity, and humility) to follow, in his attempt at self-improvement. In this pilot study, we explored whether using a modified version of this was associated with any discernable impact on physician happiness, burnout, or compliance with each of the virtues. METHODS: Self-reported happiness (Oxford happiness scores) and burnout (Abbreviated Maslach Burnout Inventory) were completed at baseline (pre-study), week 13, and 1 month after completion of the program. Each day during the 13-week program, oncologists were emailed a list of virtues to focus on and scored how they felt they were complying with them. The oncologist's spouses also assessed how they felt the oncologist was complying with the virtues. RESULTS: Thirteen physicians completed the baseline scores, 11 completed Maslach/Oxford scores at the end of the study, and 8 the 1-month post-study assessment. No significant improvements in happiness and burnout (emotional exhaustion, depersonalization, personal accomplishment) scores were observed. Statistically significant changes in self-rated virtue scores were observed for temperance (p = 0.046), order (p = 0.049), and resolution (p = 0.014). Additionally, although not reaching statistical significance, 11 of 13 virtues (excepting sincerity and chastity) assessed by spouses indicated a positive change over time. CONCLUSION: In this hypothesis generating study, daily reflection on personal virtues was not associated with any statistically significant change in happiness or burnout scores. Alternative strategies should be considered.

Optimal vascular access strategies for patients receiving chemotherapy for early-stage breast cancer: a systematic review.

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.

A multi-center pragmatic, randomized, feasibility trial comparing standard of care schedules of filgrastim administration for primary febrile neutropenia prophylaxis in early-stage breast cancer.

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.

Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.

PURPOSE: Despite its widespread use as primary febrile neutropenia (FN) prophylaxis during chemotherapy for early-stage breast cancer, the optimal duration of daily filgrastim is unknown. Using the minimum effective duration may improve patient comfort and acceptability while reducing costs. Yet, suboptimal dosing may also negatively impact patient care. A survey was performed to obtain information regarding current practices for granulocyte colony-stimulating factor (G-CSF) use. METHODS: Canadian oncologists involved in the treatment of breast cancer patients, as well as patients who had received neo/adjuvant chemotherapy for breast cancer, were surveyed. Standardized surveys were designed to collect information on perceived reasons for G-CSF use and current practices. RESULTS: The surveys were completed by 38/50 (76%) physicians and 95/97 (98%) patients. For physicians, there was variability in the choice of chemotherapy regimens that required G-CSF support, the dose of filgrastim prescribed and the number of days prescribed. The majority of physicians reported using 5 (31.6%), 7 (47.4%), or 10 (13.2%) days of therapy. Nearly half of the patients (46.3%) recalled having experienced at least one of the chemotherapy-related complications including chemotherapy delays, dose reductions, and FN. While on filgrastim, 66.3% of patients reported myalgia and bone pain. Both physicians and patients expressed interest in participating in clinical trials designed to optimize the duration of filgrastim administration. CONCLUSIONS: Significant variability in practice exists with respect to filgrastim administration. Definitive studies are therefore required to standardize and improve care, as this has the potential to impact treatment outcomes, patient quality of life, and cost savings.

Enhancing accrual to chemotherapy trials for patients with early stage triple-negative breast cancer: a survey of physicians and patients.

PURPOSE: The optimal chemotherapy regimen for patients with early stage triple-negative breast cancer (TNBC) remains unknown. The purpose of the study is to survey physicians and breast cancer patients about preferred chemotherapy regimens for early stage TNBC and clinical trial strategies. METHODS: A standardised online questionnaire was developed and circulated to medical oncologists known to treat breast cancer. A separate questionnaire was given to patients who had received chemotherapy for breast cancer. RESULTS: The questionnaire was completed by 41/84 medical oncologists (48.8% response rate) and 74 patients. The most commonly used neoadjuvant and adjuvant chemotherapy regimens for TNBC were dose-dense doxorubicin and cyclophosphamide (AC)-paclitaxel (P), dose-dense AC followed by weekly P and fluorouracil, epirubicin, cyclophosphamide-docetaxel (FEC-D). The majority of medical oncologists (80%) would be willing to enrol patients in trials evaluating the most effective chemotherapy regimen for TNBC. Oncologists favoured a three arm trial design comparing currently available standard of care treatments (36%) and trials of novel or non-standard of care agents 22% (9/41). Sixty percent (41/74) of patients indicated that they would be willing to be enrolled in trials evaluating various adjuvant regimens for TNBC. Both oncologists and patients were interested in novel consent approaches such as using the integrated consent model. CONCLUSION: Optimisation of chemotherapy for TNBC is an important and unmet clinical need. It is apparent that various chemotherapy regimens are used for patients with early stage TNBC. The majority of medical oncologists and patients are interested in entering trials to optimise chemotherapy choices.

Mammographic microcalcifications and breast cancer tumorigenesis: a radiologic-pathologic analysis.

BACKGROUND: Microcalcifications (MCs) are tiny deposits of calcium in breast soft tissue. Approximately 30% of early invasive breast cancers have fine, granular MCs detectable on mammography; however, their significance in breast tumorigenesis is controversial. This study had two objectives: (1) to find associations between mammographic MCs and tumor pathology, and (2) to compare the diagnostic value of mammograms and breast biopsies in identifying malignant MCs. METHODS: A retrospective chart review was performed for 937 women treated for breast cancer during 2000-2012 at St. Michael's Hospital. Demographic information (age and menopausal status), tumor pathology (size, histology, grade, nodal status and lymphovascular invasion), hormonal status (ER and PR), HER-2 over-expression and presence of MCs were collected. Chi-square tests were performed for categorical variables and t-tests were performed for continuous variables. All p-values less than 0.05 were considered statistically significant. RESULTS: A total of 937 patient charts were included. About 38.3% of the patients presented with mammographic MCs on routine mammographic screening. Patients were more likely to have MCs if they were HER-2 positive (52.9%; p < 0.001). There was a significant association between MCs and peri-menopausal status with a mean age of 50 (64%; p = 0.012). Patients with invasive ductal carcinomas (40.9%; p = 0.001) were more likely to present with MCs than were patients with other tumor histologies. Patients with a heterogeneous breast density (p = 0.031) and multifocal breast disease (p = 0.044) were more likely to have MCs on mammograms. There was a positive correlation between MCs and tumor grade (p = 0.057), with grade III tumors presenting with the most MCs (41.3%). A total of 52.2% of MCs were missed on mammograms which were visible on pathology (p < 0.001). CONCLUSION: This is the largest study suggesting the appearance of MCs on mammograms is strongly associated with HER-2 over-expression, invasive ductal carcinomas, peri-menopausal status, heterogeneous breast density and multifocal disease.

A phase II, multicentre trial evaluating the efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal-related events.

The optimal frequency of intravenous (IV) bisphosphonate administration is unclear. We thus performed a study evaluating the effects of switching from 3-4 to 12 weekly therapy in patients with biochemically defined low-risk bone metastases. Patients with serum C-telopeptide (CTx) levels ≤600 ng/L after ≥3 months of 3-4 weekly IV pamidronate were switched to 12 weekly therapy for 48 weeks. Primary endpoint was the proportion of patients maintaining CTx levels in the lower-risk range. All endpoints (serum CTx and bone-specific alkaline phosphatase (BSAP), skeletal-related events (SREs) and self-reported pain) were measured at baseline, 6, 12, 24, 36 and 48 weeks. Treatment failure was defined as biochemical failure (CTx > 600 ng/L) or a SRE. Exploratory biomarkers including; serum TGF-ß, activin-A, bone sialoprotein (BSP), procollagen type 1 N-terminal propeptide and urinary N-telopeptide (NTx) were assessed at baseline as predictors for failure to complete treatment. Seventy-one patients accrued and 43 (61 %) completed 48 weeks of de-escalated therapy. Reasons for failure to complete treatment included; biochemical failure (CTx > 600 ng/L) (n = 10, 14.1 %), on-study SRE (n = 9, 12.7 %), disease progression (n = 7, 9.9 % including death from disease [n = 1, 1.4 %]) or patient choice (n = 2, 2.8 %). Elevated baseline levels of CTx, BSAP, NTx and BSP were associated with treatment failure. The majority of patients in this biochemically defined low-risk population could switch from 3-4 weekly to 12 weekly bisphosphonate therapy with no effect on CTx levels or SREs during the 48 week study. Larger trials are required to assess the roles of biomarkers as predictors of adequacy of de-escalated therapy.