Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

PURPOSE: In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up. METHODS: In this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs). RESULTS: After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained. CONCLUSIONS: With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.

Perceptions of vascular access for intravenous systemic therapy and risk factors for lymphedema in early-stage breast cancer-a patient survey.

Background: The choice of vascular access for systemic therapy administration in breast cancer remains an area of clinical equipoise, and patient preference is not consistently acknowledged. Using a patient survey, we evaluated the patient experience with vascular access during treatment for early-stage breast cancer and explored perceived risk factors for lymphedema. Methods: Patients who had received systemic therapy for early-stage breast cancer were surveyed at 2 Canadian cancer centres. Results: Responses were received from 187 patients (94%). The route of vascular access was peripheral intravenous line (IV) in 24%, a peripherally inserted central catheter (picc) in 42%, and a surgically inserted central catheter (port) in 34%. Anthracycline-based regimens were associated with a greater use of central vascular access devices (cvads- that is, a picc or port; 86/97, 89%). Trastuzumab use was associated with greater use of ports (49/64, 77%). Although few patients (7%) reported being involved in the decisions about vascular access, most were satisfied or very satisfied (88%) with their access type. Patient preference centred mainly on avoiding delays in the initiation of chemotherapy. Self-reported rates of complications (183 evaluable responses) were infiltration with peripheral IVs (9/44, 20%), local skin infections with piccs (7/77, 9%), and thrombosis with ports (4/62, 6%). Perceived risk factors for lymphedema included use of the surgical arm for blood draws (117/156, 75%) and blood pressure measurement (115/156, 74%). Conclusions: Most patients reported being satisfied with the vascular access used for their treatment. Improved education and understanding about the evidence-based requirements for vascular access are needed. Perceived risk factors for lymphedema remain variable and are not evidence-based.

Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines.

Estrogen receptor modulators and estrogen deprivation have become standards of care for hormone receptor-positive metastatic breast cancer. However, after traditional first-line endocrine monotherapy treatment, the disease typically progresses despite the initial high rate of clinical benefit. Multiple studies have aimed at optimizing treatment strategies to improve upon clinical benefit beyond the traditional single-agent endocrine treatment. With the availability of new data and novel therapies, the clinical practice challenge becomes how best to define the optimal treatment sequence to maximize clinical benefit. In this review, we present treatment options clinically relevant to the management of hormone-positive, her2-negative metastatic breast cancer, and we propose a treatment algorithm based on the current literature.

Taxane acute pain syndrome (TAPS) in patients receiving chemotherapy for breast or prostate cancer: a prospective multi-center study.

BACKGROUND: Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 2-3 days after taxane-based chemotherapy and lasting up to 7 days. In the absence of validated tools, many studies use the presence of both the myalgia and arthralgia components of the Common Terminology Criteria for Adverse Events (CTCAE) to define TAPS. The present study prospectively evaluated the frequency, severity, and impact of TAPS in patients with breast or prostate cancer. PATIENTS AND METHODS: In this prospective, non-randomized study, patients with breast or prostate cancer commencing taxane-based chemotherapy completed the CTCAE (version 4.03), the Functional Assessment of Cancer Therapy-Taxane (FACT-T), and Brief Pain Inventory (BPI) questionnaires at baseline and once between days 5 and 7 of each chemotherapy cycle. RESULTS: From March 2015 to April 1, 2016, 75 patients (breast n = 66, prostate n = 9) were enrolled; 83% received docetaxel and 16% paclitaxel and 1% withdrew. After the first cycle of taxane, TAPS was reported by 25/69 (36.2%) patients; a further 8/69 (18.2%) reporting TAPS after a subsequent chemotherapy treatment. Overall incidence of TAPS was 33/75 (44%). While associated with detrimental scores on FACT-T and BPI as well as increased use of analgesics in 63% (21/33) of patients with TAPS, TAPS did not lead to alterations in chemotherapy dosing. CONCLUSIONS: TAPS is common after taxane-based chemotherapy, and its presence is associated with reduced quality of life and increased analgesic requirements. Prospective patient-reported outcome assessments are crucial to help individualize treatment strategies and improve management of TAPS.

Alberta CancerBridges development of a care plan evaluation measure.

BACKGROUND: No standardized measures specifically assess cancer survivors' and healthcare providers' experience of Survivor Care Plans (scps). We sought to develop two care plan evaluation (cpe) measures, one for survivors (cpe-s) and one for healthcare providers (cpe-p), examine initial psychometric qualities in Alberta, and assess generalizability in Manitoba, Canada. METHODS: We developed the initial measures using convenience samples of breast (n = 35) and head and neck (n = 18) survivors who received scps at the end of active cancer-centre treatment. After assessing Alberta's scp concordance with Institute of Medicine (iom) recommendations using a published coding scheme, we examined psychometric qualities for the cpe-s and cpe-p. We examined generalizability in Manitoba, Canada, with colorectal survivors discharged to primary care providers for follow-up (n = 75). RESULTS: We demonstrated acceptable internal consistency for the cpe-s and cpe-p subscales and total score after eliminating one item per subscale for cpe-s, two for cpe-p, resulting in revised scales with four 7-item and 6-item subscales, respectively. Subscale scores correlated highly indicating that for each measure the total score may be the most reliable and valid. We provide initial cpe-s discriminant, convergent, and predictive validity using the total score. Using the Manitoba sample, initial psychometrics similarly indicated good generalizability across differences in tumour groups, scp, and location. CONCLUSIONS: We recommend the revised cpe-s and cpe-p for further use and development. Studies documenting the creation and standardization of scp evaluations are few, and we recommend further development of patient experience measures to improve both clinical practice and the specificity of research questions.

Real-world adjuvant TAC or FEC-D for HER2-negative node-positive breast cancer in women less than 50 years of age.

PURPOSE: We compared the efficacy, toxicity, and use of granulocyte colony-stimulating factor (g-csf) with tac (docetaxel-doxorubicin-cyclophosphamide) and fec-d (5-fluorouracil-epirubicin-cyclophosphamide followed by docetaxel) in women less than 50 years of age. METHODS: The study included all women more than 18 years but less than 50 years of age with her2-negative, node-positive, stage ii or iii breast cancer diagnosed in Alberta between 2008 and 2012 who received tac (n = 198) or fec-d (n = 274). RESULTS: The patient groups were well-balanced, except that radiotherapy use was higher in the tac group (91.9% vs. 79.9%, p < 0.001). At a median follow-up of 49.6 months, disease-free survival was 91.4% for tac and 92.0% for fec-d (p = 0.76). Overall survival (os) was 96% with tac and 95.3% with fec-d (p = 0.86).The incidences of grades 3 and 4 toxicities were similar in the two groups (all p > 0.05). Overall, febrile neutropenia (fn) was reported in 11.6% of tac patients and 15.7% of fec-d patients (p = 0.26). However, use of g-csf was higher in the tac group than in the fec-d group (96.4% vs. 71.5%, p < 0.001). Hospitalization for fn was required in 10.5% of tac patients and 13.0% of fec-d patients (p = 0.41). In g-csf-supported and -unsupported patients receiving tac, fn occurred at rates of 11.1% and 33.3% respectively (p = 0.08); in patients receiving the fec portion of fec-d, those proportions were 2.9% and 8.1% respectively (p = 0.24); and in patients receiving docetaxel after fec, the proportions were 4.1% and 17.6% respectively (p < 0.001). CONCLUSIONS: In women less than 50 years of age receiving adjuvant tac or fec-d, we observed no differences in efficacy or other nonhematologic toxicities. Based on the timing and rates of fn, use of prophylactic g-csf should be routine for the docetaxel-containing portion of treatment; however, prophylactic g-csf could potentially be avoided during the fec portion of fec-d treatment.

Systemic treatment approaches in her2-negative advanced breast cancer-guidance on the guidelines.

Despite advancements in the treatment of early-stage breast cancer, many patients still develop disease recurrence; others present with de novo metastatic disease. For most patients with advanced breast cancer, the primary treatment intent is noncurative-that is, palliative-in nature. The goals of treatment should therefore focus on maximizing symptom control and extending survival. Treatments should be evaluated on an individualized basis in terms of evidence, but also with full respect for the wishes of the patient in terms of acceptable toxicity. Given the availability of extensive reviews on the roles of endocrine therapy and her2 (human epidermal growth factor receptor 2)-targeted therapies for advanced disease, we focus here mainly on treatment guidelines for the non-endocrine management of her2-negative advanced breast cancer in a Canadian health care context.

Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer.

UNLABELLED: The pi3k/Akt/mtor (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. METHODS: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of pi3k/Akt/mtor inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. RESULTS: Differing toxicities are associated with the various classes of pi3k/Akt/mtor pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. DISCUSSION: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future pi3k/Akt/mtor signalling pathway inhibitors.

Qualitative evaluation of care plans for Canadian breast and head-and-neck cancer survivors.

BACKGROUND: Survivorship care plans (scps) have been recommended as a way to ease the transition from active cancer treatment to follow-up care, to reduce uncertainty for survivors in the management of their ongoing health, and to improve continuity of care. The objective of the demonstration project reported here was to assess the value of scps for cancer survivors in western Canada. METHODS: The Alberta CancerBridges team developed, implemented, and evaluated scps for 36 breast and 21 head-and-neck cancer survivors. For the evaluation, we interviewed 12 of the survivors, 9 nurses who delivered the scps, and 3 family physicians who received the scps (n = 24 in total). We asked about satisfaction, usefulness, emotional impact, and communication value. We collected written feedback from the three groups about positive aspects of the scps and possible improvements (n = 85). We analyzed the combined data using qualitative thematic analysis. RESULTS: Survivors, nurses, and family physicians agreed that scps could ease the transition to survivorship partly by enhancing communication between survivors and care providers. Survivors appreciated the individualized attention and the comprehensiveness of the plans. They described positive emotional impacts, but wanted a way to ensure that their physicians received the scps. Nurses and physicians responded positively, but expressed concern about the time required to implement the plans. Suggestions for streamlining the process included providing survivors with scp templates in advance, auto-populating the templates for the nurses, and creating summary pages for physicians. CONCLUSIONS: The results suggest ways in which scps could help to improve the transition to cancer survivorship and provide starting points for larger feasibility studies.

Models of care for early-stage breast cancer in Canada.

There is growing evidence that follow-up for patients with early breast cancer (ebc) can be effectively carried out by the primary health care provider if a plan is in place. Here, we present data from a recent survey conducted in Ontario indicating that a shared-care model could work if communication between all health professionals involved in the care of ebc patients were to be improved. Patients and primary care providers benefit when the specialist provides written information about what their roles are and what to expect. Primary care providers need to have easy access to the specialist to discuss areas of concern. Patients also need to share responsibility for their care, ensuring that they attend follow-up visits on a regular basis and that they discuss areas of concern with their primary health care provider. A shared-care model has the potential to provide the best care for the least cost to the health system.

A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: This phase III randomized trial compared pemetrexed 500 mg/m(2) (P500) with pemetrexed 900 mg/m(2) (P900) to determine whether higher dosing benefits non-small-cell lung cancer (NSCLC) patients as second-line therapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week. RESULTS: Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837-1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817-1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories. CONCLUSIONS: P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

Cancer therapy disparity: unequal access to breast cancer therapeutics and drug funding in Canada.

Adjuvant therapy has made a significant contribution in reducing breast cancer-specific mortality. Standard chemotherapeutics and tamoxifen have been the mainstay treatment for years, but recent clinical evidence supports the use of novel small-molecule therapy and aromatase inhibitor therapy in selected settings, challenging not only the traditional paradigm of breast cancer treatment, but also provincial funding of oncologic care across Canada. The disparity in access to aromatase inhibitor therapy for postmenopausal women with early-stage hormone-sensitive breast cancer across Canada is highlighted as an example.

Adjuvant trastuzumab: progress, controversies, and the steps ahead.

The major breast cancer story of 2005 was trastuzumab, a monoclonal antibody directed against the Her-2 oncoprotein, and how it greatly improves outcomes for women with HER2-positive early-stage breast cancer. With early results showing that use of the drug can prevent roughly one half of relapses, adjuvant trastuzumab has been approved, funded, and accepted as the standard of care in many Canadian jurisdictions. In the present brief report, we summarize the four major adjuvant trials, outline some key controversies, and suggest steps to provide more-effective and better-tolerated adjuvant systemic therapy for the relevant patient subgroup.