Fostamatinib or Thrombopoietic Receptor Agonists for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients: A Real-World Assessment of Safety, Effectiveness and Cost.

INTRODUCTION: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment is with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety, effectiveness and cost of care between fostamatinib vs. the TPOs was evaluated in a real-world setting. METHODS: A retrospective analysis from 17 community hematology practices across the United States was conducted to identify adult ITP patients who received one of the four agents. Data collection consisted of patient demographics, disease characteristics, as well as number and type of prior treatments. From the first day until the end of treatment, data were also collected on platelet (PLT) counts, adverse events, the use of rescue IVIG, platelet transfusions and corticosteroids. Multivariable logistic regression analysis was used to compare PLT related endpoints between agents. RESULTS: A sample of 179 ITP patients who had received at least one of the four agents was identified. This resulted in a final sample of 51, 87, 127 and 44 patients who received FOS, ELT, ROM or AVA respectively. At month six, there were no significant differences between FOS vs. the TPOs in terms of the proportion of patients with the PLT count being ≥ 30 x 103/µL, ≥ 50 x 103/µL as well as the proportion of patients whose PLTs levels doubled relative to baseline. The frequency of thromboembolic events (TEs) was 3.9% in FOS patients compared to 9.2%, 4.7% and 11.4% in the ELT, ROM and AVA groups. The mean cost per patient with FOS was $99,209 (95%CI: $59,595 to $115,074) compared to $92,341 (95:CI$68,331 to $115,519), $108,482 (95%CI: $84,782 to $132,182) and $131,050 (95%CI: $83,327 to $179,897) for ELT, ROM or AVA respectively. CONCLUSIONS: In this real-world analysis, FOS was comparable to the TPOs in maintaining PLTs at clinically beneficial levels. Given these findings, the choice of therapy should be based on overall patient safety, preexisting risk factors for TEs and cost effectiveness.

Diagnosis and management of systemic mastocytosis in a community hematology setting.

BACKGROUND: Systemic mastocytosis (SM) is a rare and potentially severe hematologic disorder characterized by the clonal proliferation of mast cells (MCs) into various organs. The clinical manifestations of advanced SM are caused by the uncontrolled release of cytokines and vasoactive amines from MC and disease-induced organ dysfunction. Patients with SM typically present with symptoms such as flushing, pruritus, diarrhea, and headaches, but outcomes following active treatment have not been well characterized. In this study, the clinical characteristics, treatment patterns, and natural history of an SM patient cohort diagnosed and treated within a community hematology network in the United States is described. METHODS: We identified 105 patients who were diagnosed and managed in one of 19 community hematology clinics up to an index date of 1 October 2022. Data collection included patient and disease characteristics, baseline biochemistry and hematology, SM diagnostic criteria being met, biomarkers tested, CD2 and/or CD25 expression in MCs as well as serum tryptase levels at presentation. Data abstraction also included supportive care drugs and anticancer therapy used, treatment response, reason for discontinuation, and overall survival by disease subtype. RESULTS: A total of 105 SM patients were identified who met the inclusion criteria. The specific SM subtypes were indolent (47.6%), aggressive (9.5%), SM with an associated hematological neoplasm (19.0%), MC leukemia (1.9%), and subtype not documented (21.9%). Regardless of subtype, approximately 62% of patients did not receive SM-directed active therapy. Only 26% of patients with indolent systemic mastocytosis (ISM) received treatment compared to 65.6% with advanced subtypes. Relative to ISM cohort, the relative risk of death in patients with the advanced SM subtypes was approximately 15 times greater (hazard ratio = 15.0; 95% confidence interval: 3.3 to 66.5). CONCLUSIONS: SM patients present with multiple underlying symptoms, within various disease subtypes that are difficult to diagnose in a timely manner. As a result, many patients do not receive active drug therapy for their disease. Therefore, greater disease awareness is required as well as new tools for earlier disease detection.

Dermatological Adverse Events in Prostate Cancer Patients Treated with the Androgen Receptor Inhibitor Apalutamide.

PURPOSE: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management. MATERIALS AND METHODS: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models. RESULTS: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002). CONCLUSIONS: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.

A real-world study to evaluate the safety and efficacy of three injectable neurokinin-1 receptor antagonist formulations for the prevention of chemotherapy-induced nausea and vomiting in cancer patients.

BACKGROUND: Three different injectable neurokinin-1 (NK-1) receptor antagonist formulations (CINVANTI® [C] vs. intravenous Emend® [E] vs. generic formulations of fosaprepitant [GFF]) were compared with respect to nausea and vomiting control, use of rescue therapy, and the development of infusion reactions over multiple cycles of chemotherapy. METHODS: A retrospective analysis from 17 community oncology practices across the USA was conducted on patients who received moderately or highly emetogenic chemotherapy. The co-primary endpoints were the control of chemotherapy-induced nausea and vomiting (CINV) from days 1 to 5 over all cycles and the frequency of infusion-related reactions. Propensity score weighted multivariable logistic regression analysis was used to compare complete CINV control, the use of rescue therapy, and the risk of infusion reactions between groups. RESULTS: The study enrolled 294 patients (C = 101, E = 101, GFF = 92) who received 1432 cycles of chemotherapy. Using CINVANTI® as the reference group, comparative effectiveness was suggested in CINV control over all chemotherapy cycles (odds ratio (OR): E vs. C = 1.00 [0.54 to 1.86] and GFF vs. C = 1.12 [0.54 to 2.32]). However, use of rescue therapy was significantly higher in the EMEND® group relative to CINVANTI® (OR = 2.69; 95%CI: 1.06 to 6.84). Infusion reactions were also numerically higher in the EMEND® group, but the difference did not reach statistical significance (OR = 4.35; 95%CI: 0.83 to 22.8). CONCLUSIONS: In this real-world analysis, patients receiving CINVANTI® had a reduced need for CINV rescue therapy and a numerically lower incidence of infusion reactions.

Development of a repeated-measures predictive model and clinical risk score for mortality in ventilated COVID-19 patients.

PURPOSE: The COVID-19 pandemic has caused intensive care units (ICUs) to reach capacities requiring triage. A tool to predict mortality risk in ventilated patients with COVID-19 could inform decision-making and resource allocation, and allow population-level comparisons across institutions. METHODS: This retrospective cohort study included all mechanically ventilated adults with COVID-19 admitted to three tertiary care ICUs in Toronto, Ontario, between 1 March 2020 and 15 December 2020. Generalized estimating equations were used to identify variables predictive of mortality. The primary outcome was the probability of death at three-day intervals from the time of ICU admission (day 0), with risk re-calculation every three days to day 15; the final risk calculation estimated the probability of death at day 15 and beyond. A numerical algorithm was developed from the final model coefficients. RESULTS: One hundred twenty-seven patients were eligible for inclusion. Median ICU length of stay was 26.9 (interquartile range, 15.4-52.0) days. Overall mortality was 42%. From day 0 to 15, the variables age, temperature, lactate level, ventilation tidal volume, and vasopressor use significantly predicted mortality. Our final clinical risk score had an area under the receiver-operating characteristics curve of 0.9 (95% confidence interval [CI], 0.8 to 0.9). For every ten-point increase in risk score, the relative increase in the odds of death was approximately 4, with an odds ratio of 4.1 (95% CI, 2.9 to 5.9). CONCLUSION: Our dynamic prediction tool for mortality in ventilated patients with COVID-19 has excellent diagnostic properties. Notwithstanding, external validation is required before widespread implementation.

RéSUMé: OBJECTIF: En raison de la pandémie de COVID-19, les unités de soins intensifs (USI) ont atteint des taux d'occupation nécessitant un triage. Un outil pour prédire le risque de mortalité chez les patients sous ventilation atteints de COVID-19 pourrait éclairer la prise de décision et l'attribution des ressources tout en permettant des comparaisons populationnelles entre les établissements. MéTHODE: Cette étude de cohorte rétrospective a inclus tous les adultes atteints de COVID-19 sous ventilation mécanique admis dans trois USI de centres de soins tertiaires à Toronto, en Ontario, entre le 1er mars 2020 et le 15 décembre 2020. Des équations d'estimation généralisées ont été utilisées pour identifier les variables prédictives de mortalité. Le critère d'évaluation principal était la probabilité de décès à des intervalles de trois jours à partir du moment de l'admission à l'USI (jour 0), avec un nouveau calcul du risque tous les trois jours jusqu'au jour 15; le calcul final du risque a estimé la probabilité de décès au jour 15 et au-delà. Un algorithme numérique a été mis au point à partir des coefficients du modèle final. RéSULTATS: Cent vingt-sept patients étaient éligibles à l'inclusion. La durée médiane de séjour à l'USI était de 26,9 jours (écart interquartile, 15,4 à 52,0). La mortalité globale était de 42 %. Du jour 0 au jour 15, les variables que sont l'âge, la température, les taux de lactate, le volume courant de ventilation et l'utilisation de vasopresseurs ont constitué des prédicteurs significatifs de mortalité. Notre score de risque clinique final avait une aire sous la courbe ROC de 0,9 (intervalle de confiance [IC] à 95 %, 0,8 à 0,9). Pour chaque augmentation de dix points du score de risque, l'augmentation relative des risques de décès était d'environ 4, avec un rapport de cotes de 4,1 (IC 95 %, 2,9 à 5,9). CONCLUSION: Notre outil de prédiction dynamique de la mortalité pour les patients ventilés atteints de COVID-19 possède d'excellentes propriétés diagnostiques. Néanmoins, une validation externe est nécessaire avant sa mise en œuvre généralisée.

Clinical utility of a prediction tool to differentiate between breast cancer patients at high or low risk of chemotherapy-induced nausea and vomiting.

BACKGROUND: A personalized risk model (PRM) that can categorize patients into high or low risk of ≥ grade 2 acute and/or delayed chemotherapy-induced nausea and vomiting (CINV) was previously developed. The current study assessed whether the PMR could accurately stratify patients' risk for other commonly used CINV endpoints. METHODS: Data was pooled from a previously reported trial evaluating CINV in patients with breast cancer (BC) receiving neo/adjuvant anthracycline-cyclophosphamide or carboplatin-based chemotherapy. The predictive ability of the PRM was compared to patient experience of any self-reported significant nausea, any vomiting, complete cycle response, and use of rescue medications, over all cycles of chemotherapy. RESULTS: Data was available from 242 patients over 819 chemotherapy cycles. Irrespective of the chosen antiemetics, significant nausea was common when evaluated across repeated cycles of treatment with an overall incidence of 24.2% in low-risk patients and 34.6% in high-risk patients. Patients identified as high risk of CINV using the PRM were 4.73 (p = 0.011) times more likely to develop significant nausea than those identified as low risk. The PRM did not show any significant statistical differences between both groups in overall vomiting, complete cycle response, or rescue medications use. CONCLUSION: The PRM was able to identify patients at greater risk of significant nausea but not the other CINV endpoints. As nausea remains a pertinent issue for patients with BC, the PRM could be used to identify these patients a priori for innovative treatment strategies.

Low-molecular-weight heparins for the prevention of recurrent venous thromboembolism in patients with cancer: A systematic literature review of efficacy and cost-effectiveness.

BACKGROUND: Patients with cancer have an elevated risk of venous thromboembolism. Importantly, patients with cancer, who have metastatic disease, renal insufficiency, or are receiving anticancer therapy, have an even higher risk of a recurrent event. Similarly, the risk of recurrent venous thromboembolism is higher than the risk of an initial event. To reduce the risk, extended duration of prophylaxis for up to six months with low-molecular-weight heparins such as dalteparin, enoxaparin, nadroparin, and tinzaparin is recommended by international guidelines. In this paper, the clinical and economic literature is reviewed to provide evidenced based recommendations based on clinical benefit and economic value. METHODS: A systematic review of major databases was conducted from January 1996 to October 2016 for randomized controlled trials evaluating the four distinct low-molecular-weight heparins against a vitamin K antagonists control group for the prevention of recurrent venous thromboembolism in patients with active cancer. This was then followed by the application of the National Institute of Health and Clinical Excellence guidance to assess the quality of all trials that met the inclusion criteria. Finally, the cost-effectiveness literature supporting the value proposition of each product was reviewed. RESULTS: Six randomized trials met the inclusion criteria. There were one, two, and three trials that compared dalteparin, tinzaparin, and enoxaparin to a vitamin K antagonists control group. However, there were no trials for nadroparin in the setting of secondary venous thromboembolism prevention. In addition, only the dalteparin and one of the tinzaparin trials were of high quality and adequately powered. Of the two studies, only the dalteparin trial reported a statistically significant benefit in terms of venous thromboembolism absolute risk reduction when compared to a vitamin K antagonists control group (HR = 0.48; p = 0.002). In addition, there was robust pharmacoeconomic data from Canada, the Netherlands, France, and Austria supporting the cost-effectiveness of dalteparin for this indication. There were no such studies for any of the other agents. CONCLUSIONS: The totality of high-quality clinical and cost-effectiveness data supports the use of dalteparin over other low-molecular-weight heparins for preventing recurrent venous thromboembolism in patients with cancer.

Patient monitoring programs in oncology pharmacy practice: A survey of oncology pharmacists in Atlantic Canada.

BACKGROUND: There has been a dramatic increase in new drug approvals in oncology, consisting of both small molecule inhibitors and monoclonal antibodies. However, Health Canada approval for many of the new agents was based on single randomized trials consisting of only a few hundred patients. As more patients get treated with these newer agents, there is the potential for new and discrete toxicities. Pharmacists are in an ideal position to identify, monitor, manage, and even preempt future events, given their close proximity to the patient. However, the extent of pharmacists' involvement in formal patient programs is unknown. To address this knowledge gap, a survey of oncology pharmacists practicing in Atlantic Canada was conducted. METHODS: A structured mailing strategy was adopted as recommended by Dillman (1978). Standardized data collection forms were electronically mailed to 60 oncology pharmacists. Survey items consisted of respondent demographic information, practice setting, the existence of a formal patient monitoring program managed, and if patients are contacted by telephone following the completion of their anticancer cycle. RESULTS: Overall, 31 completed surveys were received, for an overall response rate of 50%. Respondents had a median age of 42 and a median of 18 years' (range 1 to 25) professional experience as a pharmacist. Only 18 of the 31 (58%) respondents indicated that there was a formal monitoring and call back program managed by pharmacy available at their institution. For those without such programs, the main reasons were due to staffing issues and lack of adequately trained clinical personnel. Overall, 100% of respondents would favor the development of a formal monitoring program in hospitals with a high volume of anticancer drug prescribing. CONCLUSIONS: Even though the number of new anticancer drugs being introduced into clinical pharmacy practice is increasing, formal patient monitoring and patient call back programs are not universal in Atlantic Canada hospitals.

Dalteparin or vitamin K antagonists to prevent recurrent venous thromboembolism in cancer patients: a patient-level economic analysis for France and Austria.

BACKGROUND: International guidelines recommend extended duration secondary prophylaxis in cancer patients who develop primary venous thromboembolism (VTE). Agent selection is guided in part by one large randomized trial (i.e., CLOT; Lee et al., N Engl J Med 349:146-53, 2003) which demonstrated that dalteparin reduced the relative risk of recurrence by 52% compared with oral vitamin K antagonists (VKA; HR = 0.48, 95% CI, 0.30 to 0.77). In a subgroup analysis from that same trial, patients with renal impairment also derived benefit with dalteparin (VTE rates = 3% vs. 17%; p = 0.011). To measure the economic value of secondary VTE prophylaxis with dalteparin, a patient-level pharmacoeconomic analysis was conducted from the Austrian and French healthcare system perspectives. METHODS: Chapter 1 Healthcare resource use collected during the CLOT trial was extracted and converted into direct cost estimates. Incremental cost differences between the dalteparin and VKA groups were then combined with health state utilities to measure the cost per quality-adjusted life year (QALY) gained. RESULTS: The dalteparin group had significantly higher costs than the VKA group in both countries (Austria: dalteparin = €2687 vs. VKA = €2012; France: dalteparin = €2053 vs. VKA = €1352: p < 0.001). However, when the incremental costs were combined with the utility gain, dalteparin had a cost of €6600 and €4900 per QALY gained in Austria and France, respectively. The analyses in patients with renal impairment suggested an even better economic profile, with the cost per QALY gained being less than €4000 in both countries. CONCLUSIONS: Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

A cost-utility analysis of risk model-guided versus physician's choice antiemetic prophylaxis in patients receiving chemotherapy for early-stage breast cancer: a net benefit regression approach.

PURPOSE: We assessed the cost-effectiveness of a risk model-guided (RMG) antiemetic prophylaxis strategy compared with the physician's choice (PC) strategy in patients receiving chemotherapy for early-stage breast cancer. METHODS: We conducted a cost-utility analysis based on a published randomized controlled trial of 324 patients with early-stage breast cancer undergoing chemotherapy at two Canadian cancer centers. Patients were randomized to receive their antiemetic treatments according to either predefined risk scores or the treating physician's preference. Effectiveness was measured as quality-adjusted life years (QALYs) gained. Cost and utility data were obtained from the Canadian published literature. We used generalized estimating equations to estimate the incremental cost-effectiveness ratios (ICERs) and 95% confidence intervals (CIs) over a range of willingness-to-pay values. The lower and upper bounds of the 95% CIs were used to characterize the statistical uncertainty for the cost-effectiveness estimates and construct cost-effectiveness acceptability curves. RESULTS: From the health care system's perspective, the RMG strategy was associated with greater QALYs gained (0.0016, 95% CI 0.0009, 0.0022) and higher cost ($49.19, 95% CI $24.87, $73.08) than the PC strategy, resulting in an ICER of $30,864.28 (95% CI $14,718.98, $62,789.04). At the commonly used threshold of $50,000/QALY, the probability that RMG prophylaxis is cost-effective was >94%; this probability increased with greater willingness-to-pay values. CONCLUSION: The risk-guided antiemetic prophylaxis is an economically attractive option for patients receiving chemotherapy for early-stage breast cancer. This information supports the implementation of risk prediction models to guide chemotherapy-induced nausea and vomiting prophylaxis in clinical practices.

Choice of study endpoint significantly impacts the results of breast cancer trials evaluating chemotherapy-induced nausea and vomiting.

Multiple endpoints can be used to evaluate chemotherapy-induced nausea and vomiting (CINV). These endpoints reflect the various combinations of vomiting, nausea and rescue antiemetic use in the acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) periods after chemotherapy. As the choice of outcome measure could potentially change the interpretation of clinical trial results, we evaluated CINV rates using different endpoints on a single dataset from a prospective cohort. Data from 177 breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy was used to calculate CINV control rates using the 15 most commonly reported CINV endpoints. As nausea remains such a significant symptom, we explored the frequency at which pharmaceutical and non-pharmaceutical company-funded studies included measures of nausea in their primary study endpoint. CINV control rates ranged from 12.5 %, 95 % (CI 7.6-17.4 %) for total control (no vomiting, no nausea and no rescue medication) in the overall period to 77.4 %, 95 % (CI 71.2-83.6 %) for no vomiting in the overall period. Similar differences were found in the acute and delayed periods. Non-pharmaceutical company-funded trials were more likely to include a measure of nausea in the primary study outcome (9/18, 50 %) than pharmaceutical-funded trials (1/12, 8.3 %). The choice of trial endpoint has an important impact on reported CINV control rates and could significantly impact on interpretation of the results. Primary endpoints of studies, including those mandated by regulatory bodies, should account for nausea to reflect patient experience. Reporting of endpoints should be more comprehensive to allow for cross-trial comparisons.

FOLFOX chemotherapy can safely be given to neutropenic patients with early-stage colorectal cancer for higher dose intensity and fewer visits.

PURPOSE: How does giving adjuvant FOLFOX chemotherapy to patients with early-stage colorectal cancer (ESCRC) regardless of the day-before absolute neutrophil counts (ANC) effect chemotherapy-induced febrile neutropenia (CIFN) rates, received dose intensity (RDI), and chemotherapy cycle delay? Does an ANC level predict future neutropenia? METHODS: A retrospective chart review was conducted on all patients receiving adjuvant chemotherapy for ESCRC at a mid-sized community hospital in Toronto, Ontario, Canada between April 2005 and May 2014. All patients were under one medical oncologist. Day-before CBC data were collected along with other patient characteristics. CIFN was confirmed by hospital records. Inclusion criteria were met by 132 patients. Overall, 1074 cycles of chemotherapy were analyzed. RESULTS: Six episodes of CIFN were observed. There was a significant difference in the average day-before ANC between patients who developed CIFN (1.4 × 10(9)/L, 95 % CI 0.76-2.0 × 10(9)/L) and those who did not (2.9 × 10(9)/L, 95 % CI 2.8-3.0 × 10(9)/L, p = 0.03). The RDI for oxaliplatin was 0.95 and for 5-fluorouracil (5-FU) was 0.96. A total of 170 cycles were given at day-before ANC <1.5 × 10(9)/L (range 0.1 × 10(9)/L-1.4 × 10(9)/L), and 24 were delayed for 1 week for hematologic reasons. Cycles given with grade 2 neutropenia predicted higher grades of neutropenia with a sensitivity of 0.22 (95 % CI 0.12-0.38). CONCLUSIONS: Adjuvant FOLFOX chemotherapy may be given in the setting of low day-before ANC to patients with ESCRC. The benefits include higher RDI and a reduced number of clinic visits for the patient.

Measuring the impact of guideline-based antiemetic therapy on nausea and vomiting control in breast cancer patients with multiple risk factors.

PURPOSE: The objective of this exploratory analysis was to determine if individual patient risk factors could be used to optimize chemotherapy-induced nausea and vomiting (CINV). METHODS: Through validated risk prediction models which quantify patient risk factors, 152 patients with early-stage breast cancer scheduled to received adjuvant anthracycline-based chemotherapy were categorized as being at low (level 0) or high-risk (level 1) for CINV. Prior to the first cycle of chemotherapy, low-risk patients received ondansetron and dexamethasone, while high-risk level 1 patients also received aprepitant. For subsequent cycles, patients who experienced CINV had their antiemetics changed in a stepwise manner to level 2 (extended-duration dexamethasone) or level 3 (extended-duration dexamethasone and low-dose olanzapine). RESULTS: The study enrolled 152 patients who received 484 cycles of chemotherapy. Forty patient cycles were classified as low risk (level 0) compared to 201, 162 and 81 that were classified as high-risk levels 1, 2 and 3, respectively. Complete control of acute and delayed vomiting was comparable and was achieved in over 85 % of patients across all risk levels (p = 0.56 and p = 0.99). In contrast, complete control of acute and delayed nausea was reduced in risk levels 1 to 3 compared to level 0 (acute = 51.2, 58.0, 45.7 vs. 70.0 %; p = 0.013)-(delayed = 32.8, 45.7, 34.6 vs. 62.5 %; p < 0.001). CONCLUSIONS: Despite the addition of aprepitant, extended-duration dexamethasone and olanzapine, patients at high risk for CINV due to personal risk factors failed to achieve good nausea control.

Abraxane® versus Taxol® for patients with advanced breast cancer: A prospective time and motion analysis from a Chinese health care perspective.

BACKGROUND: Abraxane® and Taxol® are both effective drugs for the treatment of advanced stage breast cancer. However, each agent possesses unique drug delivery characteristics with the former not requiring premedication and having a considerably shorter recommended infusion time (i.e. 30 min vs. 2-4 h). To measure the overall efficiency and cost-saving potential associated with Abraxane® relative to Taxol®, a time and motion study was undertaken in breast cancer patients treated in China. METHODS: Baseline patient data collection included age, disease stage, number and sites of metastatic disease, and performance status. Time and resource use data were then collected from breast patients being treated with Abraxane® (n = 12) or Taxol® (n = 15) in one of three cancer clinics located in Jiangsu, Shanghai, and Beijing. Resource use and time impact on clinical staff were quantified using unit cost estimates. This included costs for drug preparation, administration, materials and supplies, premedication, patient chair time, labor costs, and all acute adverse drug reactions. Outcomes were presented as a mean total time and cost for delivering a dose of Abraxane® or Taxol® and were compared using parametric and non-parametric statistical tests where appropriate. All costs were reported in US dollars (US$1 = 6.1 RMB, as of January 2014). RESULTS: Patients were comparable with respect to mean age, number of metastatic sites, and performance status. Approximately 9 of 12 (75%) patients received Abraxane® as on a weekly schedule (vs. every 3 weeks) compared to 6 of 15 (40%) with Taxol®. There were 5 (33.3%) acute adverse drug reactions with Taxol®, 3 of which required a physician visit and the initiation of supportive interventions. In contrast, there was only one minor event with Abraxane® (8.3%), which was easily managed with a temporary stoppage of the infusion. From the time and motion study, the mean total time for Abraxane® and Taxol® delivery (preparation, administration, premedication, total chair time, and adverse effects management) was 84 and 282 min respectively (p < 0.001), with the associated costs being US$59 and US$254 respectively per dose (p < 0.001). CONCLUSION: To our knowledge, this is first such study in breast cancer patients to be undertaken in China. Abraxane® was associated with fewer acute adverse drug reactions and significant reductions in health care resources, physician/nurse time and overall drug delivery costs compared to Taxol®.

Clinico-morphological features of BRAF inhibition-induced proliferative skin lesions in cancer patients.

BACKGROUND: The use of BRAF inhibitors may lead to the development of cutaneous toxicities such as rashes, photosensitivity, alopecia, palmoplantar erythrodysesthesia, and proliferative skin lesions, including keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs). The latter are noteworthy for their potential to exhibit malignant features, and they may necessitate invasive treatment. Their prompt identification is of primary importance for directing supportive care efforts and maintaining dose intensity while minimizing the morbidity associated with supportive care interventions. Because such lesions are less familiar to oncologists, this study was designed to characterize their clinico-morphological features, which have not been hitherto described. METHODS: The clinical and dermoscopic characteristics and risk factors of new-onset proliferative skin lesions (benign verrucous lesions and KAs/cuSCCs) developing after the initiation of treatment with vemurafenib, dabrafenib, and XL281 were analyzed; the histopathological diagnoses were ascertained. RESULTS: The majority of the lesions were benign verrucous lesions (78%, n = 87), whereas KAs/cuSCCs represented 22% (n = 25). The median times to biopsy for the initial verrucous lesions and KAs/cuSCCs were 4.8 and 10.5 weeks, respectively. The clinico-morphological features significant for KAs/cuSCCs included a larger size (P < .001), a nodular appearance (P < .001), a central keratin plug (P < .001), a central ulceration or crust (P = .04), an adherent scale (P = .02), an erythematous halo (P = .03), and a scaly ring (collarette; P < .001) at the periphery. CONCLUSIONS: Our findings represent the first detailed description of the clinico-morphological characteristics that permit distinction between the benign and malignant skin lesions induced by BRAF inhibitors. They are valuable for the recognition of lesions that require intervention and/or a dermatology referral versus those that permit provisional monitoring.

Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis.

Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31% (i.e., model R (2)) of the variability between the PFS-OS association was accounted for. When trials were limited to ≥2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R (2) increased to 55%. However, the HRPFS-HROS association was no longer significant when only 1st-line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the ≥2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended.

Defining optimal control of chemotherapy-induced nausea and vomiting-based on patients' experience.

PURPOSE: A considerable challenge when comparing antiemetic trials for chemotherapy-induced nausea and vomiting (CINV) is the large number of outcome measures for nausea and vomiting. The objective of this study is to determine the optimal definition of CINV control from the patients' perspective. METHODS: Patients with early-stage breast cancer who had received anthracycline-cyclophosphamide-based chemotherapy were surveyed. They were asked about their experiences of CINV and perceptions of different CINV assessment tools. RESULTS: Of 201 patients approached, 168 (83 %) completed the survey. Patients consistently ranked nausea over vomiting as the "worst side effect from chemotherapy." Despite the use of multi-agent antiemetic regimens, 71 % of patients experienced nausea and 26 % vomiting. Only 57 % of patients with any nausea or vomiting took rescue medications and only then when the symptom was severe. Most (76 %) patients believed that the primary end point of antiemetic trials should include the absence of both nausea and vomiting. Patients felt that CINV should be evaluated for the overall period post chemotherapy (i.e., days 1-5) and not simply the acute (the first 24 h) or delayed (days 2-5) periods. CONCLUSIONS: Patients strongly favored a CINV end point that includes the absence of both nausea and vomiting. Patients' experience with CINV is underestimated when nausea is not included in composite end points. "Use of rescue medication," a commonly used surrogate for emesis control, is inappropriate as it underestimates nausea. A standardized primary end point that includes nausea is essential if CINV control is to be improved.

Development of prediction tools for diarrhea and rash in breast cancer patients receiving lapatinib in combination with capecitabine.

Lapatinib and capecitabine (L-CAP) is effective in HER-2 positive patients with metastatic breast cancer (MBC). However, moderate to severe diarrhea and rash (≥ grade 2) are problematic dose limiting toxicities. Since risk may vary over the course of therapy, we developed repeated measures models to predict the risk of ≥ grade 2 diarrhea and rash prior to each cycle of L-CAP. Data from 197 patients who received the L-CAP as part of a clinical trial were reviewed (Cameron, Breast Cancer Res Treat 112:533-543, 2008). Generalized estimating equations were used to develop the risk models using a backward elimination process. Risk scoring algorithms were then derived from the final model coefficients. Finally, a receiver operating characteristic curve (ROC) analysis was undertaken to measure the predictive accuracy of the scoring algorithms. Patient age, presence of skin metastases at baseline, treatment being initiated in the spring, earlier cycles, and grade I diarrhea in the prior cycle were identified as being significant predictors for ≥ grade 2 diarrhea. The ROC analysis indicated good predictive accuracy for the diarrhea algorithm with an area under the curve of 0.78 (95 %CI: 0.72-0.82). Prior to each cycle of therapy, patients with risk scores > 125 units would be considered at high risk for developing ≥ grade 2 diarrhea. A similar prediction index was also derived in the case of ≥ grade 2 rash. Our models provide patient-specific risk information that could be helpful in assessing the risks and benefits of L-CAP in the MBC patients.

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.

Are community pharmacists equipped to ensure the safe use of oral anticancer therapy in the community setting? Results of a cross-country survey of community pharmacists in Canada.

PURPOSE: Oral anticancer agents offer significant benefits over parenteral anticancer therapy in terms of patient convenience and reduced intrusiveness. Oral anticancer agents give many cancer patients freedom from numerous hospital visits, allowing them to obtain their medications from their local community pharmacy. However, a major concern with increased use of oral anticancer agents is shift of responsibility in ensuring the proper use of anticancer agents from the hospital/clinical oncology team to the patient/caregiver and other healthcare providers such as the community pharmacists who may not be appropriately trained for this. This study assessed the readiness of community pharmacists across Canada to play this increased role with respect to oral anticancer agents. METHODS: Using a structured electronic mailing strategy, a standardized survey was mailed to practicing pharmacists in five provinces where community pharmacists were dispensing the majority of oral anticancer agents. In addition to collecting basic demographic and their practice setting, the survey assessed the pharmacists' knowledge regarding cancer therapy and oral anticancer agents in particular, their education needs and access to resources on oral anticancer agents, the quality of prescriptions for oral anticancer agents received by them in terms of the required elements, their role in patient education, and steps to enhance patient and personal safety. RESULTS: There were 352 responses to the survey. Only 13.6% of respondents felt that they had received adequate oncology education at the undergraduate level and approximately 19% had attended a continuing education event related to oncology in the past 2 years. Only 24% of the pharmacists who responded were familiar with the common doses of oral anticancer agents and only 9% felt comfortable educating patients on these medications. CONCLUSIONS: A substantial portion of community pharmacists in Canada lack a solid understanding of oral anticancer agents and thus are poorly equipped to play a major role in ensuring their appropriate use. More education and training on oral anticancer agents are urgently required.