Cost-effectiveness of febrile neutropenia prevention with primary versus secondary G-CSF prophylaxis for adjuvant chemotherapy in breast cancer: a systematic review.

The adoption of primary (PP) versus secondary prophylaxis (SP) of febrile neutropenia (FN), with granulocyte colony-stimulating factors (G-CSF), for adjuvant chemotherapy (AC) regimens in breast cancer (BC) could be affected by its "value for money". This systematic review examined (i) cost-effectiveness of PP versus SP, (ii) FN threshold at which PP is cost-effective including the guidelines 20 % threshold and (iii) potential impact of G-CSF efficacy assumptions on outcomes. The systematic review identified all cost-effectiveness/cost-utility analyses (CEA/CUA) involving PP versus SP G-CSF for AC in BC that met predefined inclusion/exclusion criteria. Five relevant CEA/CUA were identified. These CEA/CUA examined different AC regimens (TAC = 2; FEC-D = 1; TC = 2) and G-CSF formulations (filgrastim "F" = 4; pegfilgrastim "P" = 4) with varying baseline FN-risk (range 22-32 %), mortality (range 1.4-6.0 %) and utility (range 0.33-0.47). The potential G-CSF benefit, including FN risk reduction with P versus F, varied among models. Overall, relative to SP, PP was not associated with good value for money, as per commonly utilized CE thresholds, at the baseline FN rates examined, including the consensus 20 % FN threshold, in most of these studies. The value for money associated with PP versus SP was primarily dependent on G-CSF benefit assumptions including reduced FN mortality and improved BC survival. PP G-CSF for FN prevention in BC patients undergoing AC may not be a cost-effective strategy at the guidelines 20 % FN threshold.

Cost-utility of adjuvant zoledronic acid in patients with breast cancer and low estrogen levels.

BACKGROUND: Adjuvant zoledronic acid (za) appears to improve disease-free survival (dfs) in women with early-stage breast cancer and low levels of estrogen (lle) because of induced or natural menopause. Characterizing the cost-utility (cu) of this therapy could help to determine its role in clinical practice. METHODS: Using the perspective of the Canadian health care system, we examined the cu of adjuvant endocrine therapy with or without za in women with early-stage endocrine-sensitive breast cancer and lle. A Markov model was used to compute the cumulative costs in Canadian dollars and the quality-adjusted life-years (qalys) gained from each adjuvant strategy, discounted at a rate of 5% annually. The model incorporated the dfs and fracture benefits of adjuvant za. Probabilistic and one-way sensitivity analyses were conducted to examine key model parameters. RESULTS: Compared with a no-za strategy, adjuvant za in the induced and natural menopause groups was associated with, respectively, $7,825 and $7,789 in incremental costs and 0.46 and 0.34 in qaly gains for cu ratios of $17,007 and $23,093 per qaly gained. In one-way sensitivity analyses, the results were most sensitive to changes in the za dfs benefit. Probabilistic sensitivity analysis suggested a 100% probability of adjuvant za being a cost-effective strategy at a threshold of $100,000 per qaly gained. CONCLUSIONS: Based on available data, adjuvant za appears to be a cost-effective strategy in women with endocrine-sensitive breast cancer and lle, having cu ratios well below accepted thresholds.

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.

Is adjuvant trastuzumab a cost-effective therapy for HER-2/neu-positive T1bN0 breast cancer?

BACKGROUND: In light of clinical uncertainty and the high acquisition costs of trastuzumab, we examined the value for money associated with concurrent or sequential trastuzumab in women with HER-2/neu-positive breast cancer with small node-negative tumours (T1bN0). MATERIALS AND METHODS: A probabilistic economic model was developed to estimate the likelihood of adjuvant trastuzumab meeting a $100 000 per quality-adjusted life year gained threshold over a range of 10-year recurrence risks by age. The primary analysis took an incremental approach, comparing trastuzumab plus chemotherapy with chemotherapy alone. A secondary analysis took an 'all-or-nothing' approach, comparing trastuzumab plus chemotherapy with neither treatment. RESULTS: The primary analysis suggested that concurrent trastuzumab plus adjuvant chemotherapy was likely to meet the $100 000 threshold at recurrence risks of 29-35%. Sequential trastuzumab was less likely to meet such a threshold. The secondary analysis was more favourable for both trastuzumab strategies, but of limited relevance as clinical benefits were predominantly driven by chemotherapy without trastuzumab. CONCLUSIONS: Concurrent trastuzumab plus adjuvant chemotherapy appears to offer favourable value for money at the upper ranges of baseline recurrence risks reported to date, although more precise estimates of underlying risk are required to confirm the cost-effectiveness of adjuvant trastuzumab in T1bN0 breast cancer.

Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial.

BACKGROUND: The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. PATIENTS AND METHODS: Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. RESULTS: Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C→T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H→T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). CONCLUSION: PLD+C+H→T+H is feasible and results in lower early cardiotoxicity rates compared with A+C→T+H.

Identifying mental health services in clinical genetic settings.

The purpose of this study was to examine the mental health needs of individuals at risk for adult onset hereditary disorder (AOHD) from the perspective of their genetic service providers, as it is unknown to what extent psychosocial services are required and being met. A mail-out survey was sent to 281 providers on the membership lists of the Canadian Association of Genetic Counsellors and the Canadian College of Medical Geneticists. The survey assessed psychosocial issues that were most commonly observed by geneticists, genetic counsellors (GCs), and nurses as well as availability and types of psychosocial services offered. Of the 129 respondents, half of genetic service providers reported observing signs of depression and anxiety, while 44% noted patients' concerns regarding relationships with family and friends. In terms of providing counselling to patients, as the level of psychological risk increased, confidence in dealing with these issues decreased. In addition, significantly more GCs reported that further training in psychosocial issues would be most beneficial to them if resources were available. As a feature of patient care, it is recommended that gene-based predictive testing include an integrative model of psychosocial services as well as training for genetic service providers in specific areas of AOHD mental health.

Management of skin rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: Canadian recommendations.

The epidermal growth factor receptor (EGFR) is often overexpressed or dysregulated in a variety of solid tumours, including gastrointestinal (GI) malignancies. Agents targeting the EGFR-mediated signalling pathway are increasingly part of the therapeutic armamentarium for the treatment of advanced lung, head-and-neck, and colorectal carcinoma. The EGFR inhibitors (EGFRIS) approved in Canada include the tyrosine kinase inhibitors erlotinib and gefitinib (in selected cases), and the monoclonal antibodies (mAbs) panitumumab and cetuximab. Although EGFRIS have been proven effective in the treatment of a variety of malignancies, the entire class of agents is associated with a high prevalence of dermatologic side effects, most commonly skin rash. This reversible condition requires intervention in approximately one third of patients. A proactive, multidisciplinary approach to management can help to improve skin rash and optimize clinical outcomes by preventing EGFRI dose reduction or discontinuation. In addition, effective management and patient education may help to alleviate the significant social and emotional anxiety related to this manageable side effect, thus resulting in improved quality of life. The present article focuses on EGFR-targeted mAbs for the treatment of gi malignancy, addressing the pathophysiology, clinical presentation, and incidence of skin rash caused by this class of agents. Recommendations aimed at establishing a framework for consistent, proactive management of skin rash in the Canadian setting are presented.

The role of HER2-targeted therapies in women with HER2-overexpressing metastatic breast cancer.

The role of targeted therapies in the treatment of women with breast cancer has been rapidly evolving. Trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), was the first HER2-targeted therapy that clearly demonstrated a significant clinical benefit for women with HER2-overexpressing metastatic breast cancer (mbc). However, in recent years it has become increasingly apparent that, when trastuzumab is used in the first-line setting in combination with chemotherapy, most women eventually develop progressive disease. Determining the treatment options available to women who have progressed while on trastuzumab therapy has been hampered by a paucity of high-quality published data. In addition, with the standard use of trastuzumab in the adjuvant setting (for eligible HER2-positive patients), the role of anti-HER2 agents for patients who experience a breast cancer relapse has become a clinically relevant question. This manuscript reviews current available data and outlines suggestions from a panel of Canadian oncologists about the use of trastuzumab and other HER2-targeted agents in two key mbc indications:Treatment for women with HER2-positive mbc progressing on trastuzumab (that is, treatment beyond progression)Treatment for women with HER2-positive mbc recurring following adjuvant trastuzumab (that is, re-treatment)The suggestions set out here will continue to evolve as data and future trials with trastuzumab and other HER2-targeted agents emerge.

The role of scientific evidence in decisions to adopt complex innovations in cancer care settings: a multiple case study in Nova Scotia, Canada.

BACKGROUND: Health care delivery and outcomes can be improved by using innovations (i.e., new ideas, technologies, and practices) supported by scientific evidence. However, scientific evidence may not be the foremost factor in adoption decisions and is rarely sufficient. The objective of this study was to examine the role of scientific evidence in decisions to adopt complex innovations in cancer care. METHODS: Using an explanatory, multiple case study design, we examined the adoption of complex innovations in five purposively sampled cases in Nova Scotia, Canada. Data were collected via documents and key informant interviews. Data analysis involved an in-depth analysis of each case, followed by a cross-case analysis to develop theoretically informed, generalizable knowledge on the role of scientific evidence in innovation adoption that may be applied to similar settings and contexts. RESULTS: The analyses identified key concepts alongside important caveats and considerations. Key concepts were (1) scientific evidence underpinned the adoption process, (2) evidence from multiple sources informed decision-making, (3) decision-makers considered three key issues when making decisions, and (4) champions were essential to eventual adoption. Caveats and considerations related to the presence of urgent problems and short-term financial pressures and minimizing risk. CONCLUSIONS: The findings revealed the different types of issues decision-makers consider while making these decisions and why different sources of evidence are needed in these processes. Future research should examine how different types of evidence are legitimized and why some types are prioritized over others.

Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies.

Anthracycline-trastuzumab-containing regimens demonstrate significant clinical activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, the utility of this strategy is limited by unacceptably high rates of significant cardiotoxicity, particularly with concurrent administration. Anthracycline-induced cardiotoxicity is thought to be mediated primarily through increased myocardial oxidative stress, modified partly by the activity of neuregulins. Trastuzumab-induced cardiotoxicity is thought to be mediated by the ErbB/neuregulin system, with exposure to trastuzumab partly blocking the protective effect of neuregulins on the myocardium. As a result, trastuzumab increases the risk of anthracycline-induced cardiotoxicity. Several strategies have been adopted in attempts to minimize cardiotoxicity, including patient selection on the basis of preexisting cardiac risk, monitoring of cardiac function during treatment, and early management of cardiac dysfunction. The use of less cardiotoxic anthracyclines may be one strategy to lessen the risk of cardiotoxicity. Liposomal doxorubicin products offer similar efficacy compared with conventional doxorubicin, with significantly less cardiotoxicity, and have been successfully used in combination with trastuzumab in the metastatic and neo-adjuvant setting. Clinical trials are currently underway to assess the safety of pegylated liposomal doxorubicin during concurrent administration with trastuzumab compared with standard sequential treatment using conventional doxorubicin in the adjuvant setting.

The cost burden of trastuzumab and bevacizumab therapy for solid tumours in Canada.

OBJECTIVE: Monoclonal antibodies (MAbs) such as trastuzumab and bevacizumab have become important yet expensive components of systemic cancer therapy across a variety of disease sites. We assessed the potential cost implications of adopting trastuzumab and bevacizumab therapy in the context of their potential utilization in breast, lung, and colorectal cancers. DESIGN: We first estimated MAb costs per patient and treatment indication and then included the MAb acquisition cost and the costs of medical resource utilizations required for therapy delivery. Drug costs were based on 2005 average Canadian wholesale prices, assuming full drug delivery and uncomplicated cycles. A direct-payer perspective was undertaken, and results are reported in Canadian dollars. Potential lifetime costs were then derived according to constructed schema, which account for absolute numbers of target patients and systemic therapy utilization. We subsequently estimated costs of MAb therapy relative to total costs of conventional management without MAb therapy. RESULTS: Trastuzumab costs $49,915 and $28,350 per patient treated in the adjuvant and metastatic breast cancer settings, respectively; bevacizumab costs $48,490 and $39,614 per patient treated in the metastatic lung and colorectal cancer settings, respectively. Potential lifetime absolute costs to Canada's health care system were approximately $127 million and $299 million for trastuzumab and bevacizumab respectively, corresponding to an average increase in health care expenditure of approximately 19% for breast cancer and 21% for lung and colorectal cancer over conventional management without MAbs. CONCLUSIONS: Novel Mab-based therapies such as trastuzumab and bevacizumab will likely add a significant cost burden to Canada's publicly funded health care system.

Cost-utility of adjuvant hormone therapies with aromatase inhibitors in post-menopausal women with breast cancer: upfront anastrozole, sequential tamoxifen-exemestane and extended tamoxifen-letrozole.

This evaluation adapts a previous Canadian analysis of upfront and sequential adjuvant AI strategies in postmenopausal women with breast cancer to a Belgian perspective and includes an extended aromatase inhibitor (AI) strategy. A Markov model calculated monthly costs and outcomes in a hypothetical cohort of postmenopausal women with early-stage breast cancer. Baseline event rates and hazard ratios were derived from the Arimidex, Tamoxifen Alone or in Combination trial, International Exemestane Study and MA.17 trials. The analysis took a Belgian healthcare payer perspective with a 20-year time horizon. Costs and outcomes were discounted by 3%. Costs are in 2005 Euros. The cost-utility of all three strategies was favourable (<30,000 euros per QALY gained). Based on indirect comparisons using tamoxifen (TAM) alone as a common comparator, sequential TAM-AI was less costly and more effective than upfront or extended strategies. All three AI strategies were cost-effective alternatives to TAM alone, but sequential TAM-AI appears to be the economically preferred strategy.

Canadian supportive care recommendations for the management of anemia in patients with cancer.

Anemia is a common finding in cancer patients, most often as a result of chemotherapy. Management of anemia requires a comprehensive approach of appropriate diagnosis, exclusion of reversible causes, use of erythropoiesis-stimulating agents (ESAS), and iron supplementation. Recently, consensus guidelines on the management of chemotherapy-induced anemia were published in Europe and the United States. The present review is intended to be a practical guide for Canadian physicians, based on published guidelines, but specifically tailored to the Canadian environment. Recommendations for the use of ESAS are presented, including initiation, target hemoglobin, dosing and adjustments, monitoring, and re-initiation. Issues of safety are also addressed, including thromboembolic risk, impact on survival, and tumour progression. The importance of iron metabolism and the use of iron supplementation (both oral and parenteral) is discussed.

Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group.

Carcinoid tumours are relatively rare and, in general, slow growing. They can be "non-functioning" tumours, presenting as a tumour mass, or "functioning" tumours secondary to the production of several biopeptides leading to the carcinoid syndrome. Though these tumours represent 0.25% of an oncology practice, a proper understanding of the clinical course of the disease and of the importance of appropriate diagnostic and therapeutic measures is very important. Proper patient management can lead to cure, particularly if the tumour can be fully resected, or to long-term palliation with medical treatment or cytoreductive surgery, or both, with significant prolongation of survival. A good understanding of the use of somatostatin analogues to achieve effective symptomatic control and of the importance of adequate follow-up and cardiac monitoring to prevent or effectively treat cardiac complications can contribute significantly to optimal control of this complex disease, ultimately improving the quality of life of affected patients. This article, developed by a group of Canadian experts, provides a framework that will assist clinicians in taking an optimal approach to managing their patients with carcinoid tumour.

Scleromyxedema: a complete response to prednisone.

Scleromyxedema is a disorder characterized by a typical rash due to the accumulation of mucin in the dermis. It is always associated with a monoclonal protein in the serum and can have a wide variety of systemic manifestations. We describe a 40-year-old woman who had scleromyxedema associated with a monoclonal G lambda protein. Severe systemic symptoms included fatigue, esophageal dysmotility, and myopathy. Symptoms resolved completely with oral prednisone therapy, and she remained in clinical remission 24 months after use of prednisone was discontinued. Scleromyxedema is commonly treated with alkylating agents, which have been associated with pronounced morbidity and mortality. We suggest that oral corticosteroid therapy may be a reasonable initial choice for treating this disease and that alkylating agents be reserved for corticosteroid-refractory disease.

Chemotherapy uptake and wait times in early-stage non-small-cell lung cancer.

BACKGROUND: Treatment uptake and elapsed times along the care path have emerged as potential quality indicators for cancer care delivery. This retrospective study examined changes in adjuvant chemotherapy uptake and elapsed times along the care path for patients in 2005 and in 2007 who had early-stage non-small-cell lung cancer (nsclc) and who underwent curative-intent surgery in Nova Scotia, Canada. METHODS: All patients who underwent curative-intent surgery for stages i-iii nsclc in the two years of interest were included. Logistic regression and general linear models were used to examine factors associated with chemotherapy uptake patterns and, at various resolutions (low, intermediate, high), elapsed times between all care events in the care path. RESULTS: In the 223 patients who underwent curative-intent surgery (108 in 2005, 115 in 2007), several factors were associated with uptake patterns and elapsed times. Cohort year (2007 vs. 2005) was not associated with referral to medical oncology [odds ratio (or): 1.05; 95% confidence interval (ci): 0.51 to 2.15; p = 0.905], but it was associated with less treatment after referral (or: 0.34; 95% ci: 0.11 to 1.00; p = 0.057) and less overall uptake (or: 0.35; 95% ci: 0.13 to 0.95; p = 0.040). Patients were referred sooner to medical oncology in 2007 than in 2005 (21 days vs. 35 days, p = 0.008), but experienced longer waits between consultation and chemotherapy delivery (18 days vs. 7 days, p = 0.001). CONCLUSIONS: Significant differences were observed in care patterns over time. Frequent monitoring of care patterns at high resolution may optimize insights into emerging trends within cancer care systems.

The cost-utility of adjuvant chemotherapy using docetaxel and cyclophosphamide compared with doxorubicin and cyclophosphamide in breast cancer.

PURPOSE: The adoption of a chemotherapeutic regimen in oncologic practice is a function of both its clinical and its economic impacts on cancer management. For breast cancer, U.S. Oncology trial 9735 reported significant improvements in disease-free and overall survival favoring adjuvant tc (docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks for 4 cycles) compared with ac (doxorubicin 60 mg/ m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks for 4 cycles). We carried out an economic evaluation to examine the cost-utility of adjuvant tc relative to ac, in terms of cost per quality-adjusted life year (qaly) gained, given the improved breast cancer outcomes and higher costs associated with the tc regimen. METHODS: A Markov model was developed to calculate the cumulative costs and qalys gained over a 10-year horizon for hypothetical cohorts of women with breast cancer treated with ac or with tc. Event rates, costs, and utilities were derived from the literature and local resources. Efficacy and adverse events were based on results reported from U.S. Oncology trial 9735. The model takes a third-party direct payer perspective and reports its results in 2008 Canadian dollars. Costs and benefits were both discounted at 3%. RESULTS: At a 10-year horizon, tc was associated with $3,960 incremental costs and a 0.24 qaly gain compared with ac, for a favorable cost-utility of $16,753 per qaly gained. Results were robust to model assumptions and input parameters. CONCLUSIONS: Relative to ac, tc is a cost-effective adjuvant chemotherapy regimen, with a cost-effectiveness ratio well below commonly applied thresholds.