Utilization and toxicity patterns of 2-weekly (Q2W) versus 4-weekly (Q4W) nivolumab for treatment of adjuvant and metastatic melanoma at BC cancer.

BACKGROUND: Nivolumab, an immune checkpoint inhibitor used to treat several malignancies, is associated with immune-related adverse events (IrAEs). Original dosing for melanoma was 3 mg/kg (maximum 240 mg) every 2 weeks (Q2W). Based on simulation studies depicting similar efficacy and toxicity to original dosing, extended interval dosing of 6 mg/kg (maximum 480 mg) every 4 weeks (Q4W) was introduced. OBJECTIVE: This study will compare safety between Q2W and Q4W dosing at BC Cancer in melanoma patients. METHODS: Retrospective chart review for reported incidence, onset, and severity of IrAEs in melanoma patients treated with nivolumab Q2W and Q4W dosing was completed. Fisher's test was conducted for first incidence IrAEs using Microsoft Excel. RESULTS: Seventy-one patients were identified (Q2W n = 35, Q4W n = 36). Baseline characteristics were similar in both groups. No statistically significant difference was found in incidence of IrAEs between Q2W and Q4W dosing (Q2W 40% vs Q4W 50%, p = 0.477). Rash was most common (Q2W 79% vs Q4W 50%) followed by hypothyroidism (Q2W 33% vs Q4W 20%). Median onset of IrAEs seemed later with Q4W dosing (Q2W cycle 1 vs Q4W cycle 4). Regardless of dosing, most IrAEs were grade 1-2 in severity (Q2W 100% vs Q4W 89%). CONCLUSION: Q4W dosing is associated with comparable incidence and potentially later onset of IrAEs compared to Q2W dosing. Most IrAEs in both dosing groups were similar and mild. Therefore, Q4W dosing offers a safe alternative to Q2W dosing while providing benefits including decreased workload for staff, decreased clinic visits, and viral exposure by patients.

International society of oncology pharmacy practitioners (ISOPP) position statement: The role of oncology pharmacy practitioners in immunotherapy treatment with immune checkpoint inhibitors for malignant conditions.

Oncology pharmacists, pharmacy technicians and assistants are key members of the multidisciplinary health care team (MHT) caring for patients receiving immunotherapy with immune checkpoint inhibitors. The International Society of Oncology Pharmacy Practitioners (ISOPP) developed this position statement to provide guidance on the role of oncology pharmacy practitioners in caring for patients receiving immune checkpoint inhibitors.Four key recommendations were identified: 1) participation as an integrated, collaborative member of the MHT;2) provision of education and training for patients, students, residents, fellows and other members of the MHT;3) involvement in clinical governance to optimise the use of immune checkpoint inhibitors and4) involvement in research and development in the field of immunotherapy.In summary, oncology pharmacy practitioners play essential roles within the MHT in caring for patients receiving immune checkpoint inhibitors.

Real-world incidence of venetoclax toxicities in British Columbia.

INTRODUCTION: Venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (r/r CLL). Tumour lysis syndrome (TLS) is a serious toxicity associated with venetoclax, and real-world studies suggest that the incidence may be higher than in clinical trials. The purpose of this study is to describe the incidence of venetoclax toxicities in British Columbia (BC). METHODS: Retrospective review of electronic medical charts for patient characteristics and clinical outcomes of patients treated with venetoclax for r/r CLL in BC. Patients were classified according to their risk for developing TLS. The incidence of TLS was categorized based on laboratory metrics or clinical diagnosis. Other non-TLS toxicities were also collected. RESULTS: Of 33 patients identified, 40%, 33%, and 27% were at low, intermediate, and high risk for TLS, respectively. Laboratory TLS occurred in 1/33 patients (3%), and no clinical TLS was reported. Grade 3 or 4 toxicities occurred in 19/33 patients (58%). Of these, neutropenia was the most common, occurring in 16 patients (84%) followed by thrombocytopenia, which occurred in 8 patients (42%). CONCLUSIONS: The incidence of TLS in patients treated with venetoclax for r/r CLL in BC was lower than in other real-world studies. Findings may warrant further investigation to determine if the higher incidence of TLS in real-world reports may be mitigated through modifying TLS risk categorization and associated prophylactic measures. Neutropenia was the most common grade 3 or 4 venetoclax toxicity reported, and the incidence in BC is comparable to other centres.

Defining cytotoxic drugs - you know it when you see it?

Safe handling precautions are an important measure used to prevent occupational exposure to hazardous antineoplastic drugs. Historically, the terms 'antineoplastic', 'chemotherapy' and 'cytotoxic' are frequently conflated. However, many current antineoplastic drugs do not have cytotoxic mechanisms of actions, leading to confusion when developing safe handling policies. Based on the mechanistic criteria outlined in this review, we have compiled a list of the most commonly used antineoplastic drugs with their cytotoxic or non-cytotoxic designations. We propose that this list can be used when discussing drug-specific safe handling precaution measures.

International Society of Oncology Pharmacy Practitioners global position on the use of biosimilars in cancer treatment and supportive care.

With the development of innovative cancer treatments over recent decades, the cost of cancer care has risen exponentially, limiting patient access to patented originator biotherapeutics in many countries. The introduction of biosimilars to the market has created new opportunities as well the need for changes in practice within healthcare institutions. A 'biosimilar' is a biotherapeutic product which is highly similar in terms of quality, safety and efficacy to an already licensed originator product. Although biosimilars lack clinically meaningful differences in therapeutic activity as compared to the originator product, these complex biological molecules are not considered identical chemical copies, unlike generics, and minor differences in molecular structure and inactive compounds may exist. A thorough understanding of these differences and their clinical implications is necessary for optimising medicines-use practices involving biosimilars. This position statement, developed by the International Society of Oncology Pharmacy Practitioners Biosimilars Taskforce, aims to provide the global oncology pharmacy community with guidance to support decisions around biosimilar use. The 11 statements cover the regulation and evaluation of biosimilars, practical issues around local implementation, the education of healthcare staff and patients, and the requirement for ongoing pharmacovigilance and outcome monitoring.

Survival outcomes associated with different sunitinib dosing regimens in metastatic renal cell carcinoma.

BACKGROUND: Standard dosing regimen of sunitinib for metastatic renal cell carcinoma consists of four weeks treatment followed by two weeks rest (intermittent dosing). Alternative regimens have been suggested, including continuous daily dosing (continuous dosing) and non-conventional dosing (non-conventional dosing: e.g. two weeks on/one week off, non-conventional dosing), to provide more individualized therapy with less toxicities. It is unclear whether non-standard sunitinib dosing affects survival outcomes. PATIENTS: Metastatic renal cell carcinoma patients treated with sunitinib between 1 July 2007 and 1 July 2011 at our institution. METHODS: Medical records and dispensing data were reviewed retrospectively to categorize sunitinib dosing as intermittent dosing, continuous dosing, or non-conventional dosing. Primary outcome was to compare overall survival associated with varying regimens, with secondary outcomes of progression-free survival and incidence of treatment discontinuation due to adverse effects. RESULTS: A total of 180 patients were identified. Most patients received intermittent dosing (n = 120, 67%), followed by continuous dosing (n = 32, 18%) and non-conventional dosing (n = 28, 16%). Compared to intermittent dosing, continuous dosing was associated with similar overall survival (median 9 vs. 13 months, HR 0.67, 95% CI: 0.43-1.06, p = 0.088) while non-conventional dosing was associated with significantly longer overall survival (median 9 vs. 23 months, HR 0.55, 95% CI: 0.34-0.90, p = 0.016). Progression-free survival was significantly better for continuous dosing (median 4 vs. 9 months, HR 0.61, 95% CI: 0.40-0.94, p = 0.025) and non-conventional dosing (median 4 vs. 10 months, HR 0.61, 95% CI: 0.39-0.95, p = 0.03) when compared to intermittent dosing. Similar to prior sunitinib trials, a significant proportion of patients (20%) discontinued sunitinib therapy due to adverse effects. CONCLUSIONS: Based on retrospective, real-world data, alternative sunitinib dosing regimens appear to be viable options for patients with metastatic renal cell carcinoma.

Clinical considerations of hyaluronidase as an adjunct to subcutaneous rituximab injection.

Subcutaneous rituximab injectables are formulated with recombinant human hyaluronidase as an adjunct to facilitate the absorption of the large volume of rituximab. We review the clinical considerations regarding the potential for systemic hyaluronidase toxicity and increased systemic absorption of subcutaneous or topical drugs administered subsequent to rituximab.

Efficacy of nivolumab four-weekly dosing schedule based on body weight.

Nivolumab has received regulatory approval to be given by weight-based or flat dosing every two weeks or by flat dosing every four weeks. However, flat dosing would lead to unnecessarily high doses for patients with lower body weight, increasing the drug usage and probability of toxicity. We review the rationale of using a four-weekly hybrid dosing strategy using weight-based and flat-dosing regimens adopted by some jurisdictions.

Approach to initiating QT-prolonging oncology drugs in the ambulatory setting.

Since the introduction of regulatory drug approval guidance on the evaluation of QT interval prolongation, an increasing number of drug monographs has included cautions on the risk of QT prolongation. For example, QT prolongation is mentioned in the Canadian product monographs of 29 drugs commonly seen in oncology practice. This presents two major challenges. First, most guidelines and risk predictive tools for QT prolongation have been developed for hospitalized patients in acute care settings. In contrast, most QT-prolonging oncology drugs are used in medically stable patients in the ambulatory setting. Second, many oncology drugs are unique for their indications and non-QT prolonging alternative agents are often not available. In this review, we will outline an empiric initial approach to ambulatory cancer patients who are treated with oncology drugs which may prolong QT interval. This includes the predictive value of QT prolongation on torsades de pointes, the risk factors of the patients and the drugs, and the limitations of existing guidance in this area.

Challenges of dispensing costly tablets with short shelf-life.

Afatinib, trametinib and regorafenib are three costly oral oncology drugs with a short shelf-life after the original container has been opened. Their short shelf-lives are due to degradation on exposure to moisture. Therefore, manufacturers recommend them to be dispensed in the original packaging with the desiccant. However, the prescribed quantities do not always match the quantities in the original packaging, usually because of dose modifications for toxicities. This leads to potentially significant drug wastage and financial losses. We describe some potential approaches to this issue.

Efficacy of bevacizumab and temozolomide therapy in locally advanced, recurrent, and metastatic malignant solitary fibrous tumour: A population-based analysis.

BACKGROUND: Patients with locally advanced, recurrent or metastatic solitary fibrous tumour are often treated with bevacizumab and temozolomide based on the clinical efficacy reported in a case series of 14 patients. Given the rarity of solitary fibrous tumour, large trials are not feasible. We report the efficacy of this regimen based on a population-based analysis. METHODS: This was a population-based retrospective, multi-centre analysis using patient data from a provincial cancer registry and treatment database. Cases from June 2006 through October 2016 were identified for patients receiving bevacizumab and temozolomide for locally advanced, recurrent or metastatic solitary fibrous tumour or hemangiopericytoma, which is sometimes used to describe tumours arising from the meninges. The primary outcome was overall response rate. Secondary outcomes included time to response, progression free survival and overall survival estimated using the Kaplan-Meier method. RESULTS: Fourteen patients were identified: median age 59 (range 44-70), male 78.6%. Diagnoses were solitary fibrous tumour in 10 (71.4%) and hemangiopericytoma in four (28.6%), with metastatic disease in 10 (72.7%) patients. The most common primary sites were meninges in four (28.6%) and pelvis in three (21.4%) patients. The median follow-up was 15.5 months, with median treatment of four months. Overall response rate was 21.4% (no complete response, 3 partial response), with median time to response of four months. Median progression free survival, six-month progression free survival and overall survival were 17 months, 65.0%, and 45 months, respectively. CONCLUSIONS: Efficacy of bevacizumab and temozolomide in solitary fibrous tumour appeared to be similar to that previously reported. Our findings confirmed that bevacizumab and temozolomide is an effective and tolerated treatment for this patient population.

Evaluation of the role of pharmacy technicians in reviewing the eligibility for Oncotype DX genomic test and the impact of the test on treatment plans in breast cancer patients.

PURPOSE/OBJECTIVES: The Oncotype DX genomic test is a treatment decision-making tool. Test results are presented as recurrence scores which are used to help decide between adjuvant hormonal therapy (low recurrence score) or chemotherapy (high recurrence score). Since 2014, the Oncotype DX test has been funded at the cancer treatment centres in our province for patients with early breast cancer. Eligibility criteria for funding include patient and tumour characteristics. Pharmacy technicians were assigned to review and approve requests based on the eligibility criteria and with access to consultation to an oncology pharmacist and a medical oncologist. We assessed the clinical role of pharmacy technicians in this review process and the impact of recurrence score on treatment decisions. METHODS: This was a retrospective, multi-centre study to evaluate the Oncotype DX test eligibility review process from June 2014 to May 2015. The main objectives were to assess (1) the discrepancy rate of approval by the pharmacy technicians in this review process and (2) the concordance rate between the recurrence score from the Oncotype DX test and the adjuvant treatment given. RESULTS: Four hundred and forty requests for Oncotype DX test were received during the study period. A total of 90.8% of requests were approved and 9.2% were denied. The discrepancy rate of approval by pharmacy technicians was 1.1%. The average review time was 13.8 min, with the reviewing pharmacist and oncologist consulted in 5.5 and 15.2% of the requests, respectively. The concordance rate between the recurrence score and given treatment was 96%. DISCUSSION: The discrepancy rate of our pharmacy technicians appears to be similar to that reported with other expanded technician roles in literature, suggesting that the current task and other similar clinical tasks can be reliably delegated to technicians. The concordance rate of the recurrence score and given treatment in our study was higher than what has been reported in literature, suggesting that most of our patients were treated in accordance to recurrence score-based recommendations. CONCLUSION: Pharmacy technicians were able to expand their clinical role by accurately reviewing the Oncotype DX test requests with a low discrepancy rate. The Oncotype DX test results appeared to successfully guide the adjuvant treatment given to patients in accordance to recurrence score-based recommendations.

Clinical effectiveness of bevacizumab in patients with recurrent brain tumours: A population-based evaluation.

Background Bevacizumab is an antiangiogenic agent active in patients with recurrent malignant gliomas. However, evidence for its clinical efficacy is relatively limited so that bevacizumab is approved for this indication in Canada and the United States, but not in the European Union. We reviewed the effectiveness of bevacizumab in patients with recurrent brain tumour using a large population database. Methods This was a retrospective, multicentre, study conducted at the BC Cancer Agency, a public cancer care organisation for the residents of the Canadian province of British Columbia. Cases were identified from the provincial registry and drug database. Patients were eligible if they were treated with bevacizumab with or without lomustine or etoposide for recurrent brain tumour between April 2011 and March 2014. The primary end points were progression-free survival. Secondary endpoints were overall survival and objective response rate. Results A total of 160 patients were included, with a median age of 55 years. The most common diagnosis was glioblastoma multiforme (70.6%), followed by oligodendroglioma (10.6%). Half of the patients had prior metronomic dosing of temozolomide. The median duration of therapy was 3 months. The median progression-free survival was 4.0 months and the 6-month progression-free survival was 29.4%. The median overall survival was 7 months and the 9-month and 12-month overall survival was 28.1% and 20.6%, respectively. The objective response rate was 23.1%. The most common documented reason for bevacizumab discontinuation was disease progression (66.9%), followed by toxicity (6.9%). Conclusions Bevacizumab therapy seems to be effective in delaying disease progression in patients with recurrent brain tumour, but with limited benefits on the overall survival, when used outside the clinical trial setting.

Development of a systematic approach to pharmaceutical industry's patient assistance programs on accessing unfunded cancer drugs.

Background New oncology drugs usually become commercially available several months before the funding decisions are made by provincial public payers. Increasingly, patient assistance programs are being set up by pharmaceutical companies in order to facilitate access of their new cancer drugs before public funding decisions are finalized. We discovered that there is a need to keep this information up to date and available in a central repository, thus we have created a centralized patient assistance chart for use by all who require information on accessing unfunded drugs in our province. Methodology The project was carried out at a publicly funded provincial cancer care organization that oversees parenteral and oral chemotherapy treatments across our province. The drug information pharmacist at this organization developed a method of scoping information on upcoming therapies by reviewing a series of recommendations made by various organizations that review oncology treatments. A standard process was developed for including information on the patient assistance chart that is available on the organizations website. Results As of May 2016, the repository contains information on 47 patient assistance programs involving 24 unfunded antineoplastic drugs for various indications. This compared to (7) when it was maintained by a single centre in 2004 and 10 when the process was first centralized in 2009. Conclusion The benefit of patient assistance program availability allows patients to access medications when provincial funding is not available. A standardized approach and methodology to evaluating information was established by our drug information pharmacist; thus allowing for a consistent approach to dissemination of information on assessing unfunded cancer drugs in our province.

Safe handling of monoclonal antibodies: Too large to be hazardous?

It has been argued that the larger molecular weight of hazardous monoclonal antibodies may prevent their dermal absorption via occupational exposure. However, this assertion does not seem to be supported by direct evidence. Although the larger molecular weight may render monoclonal antibodies less probable to achieve therapeutic systemic level through dermal absorption, the concern in occupational health is whether these drugs can possibly attain a detectable level through repeated dermal exposure. Currently, there is no direct evidence to support a particular molecular weight above which a drug cannot achieve a detectable level following repeated occupational exposure. Therefore, the precautionary principle would dictate that repeated exposure of healthcare workers to hazardous monoclonal antibodies should be kept to a minimum.

Loperamide and cardiac events: Is high-dose use still safe for chemotherapy-induced diarrhea?

High-dose loperamide is often used for the acute management of chemotherapy-induced diarrhea, with a maximum daily dosing of up to 24 mg. Recently, the US Food and Drug Administration has issued a warning that loperamide can cause rare serious cardiac events, including QT prolongation, torsades de pointes, cardiac arrest and death. Most events were reported in patients taking very high doses for an extended period of time. Daily intake ranged from 64 mg to 1600 mg, often continuously for weeks or months. In addition, the reported serum levels of loperamide ranged from 22 ng/mL to 210 ng/mL, which is likely significantly higher than that expected from patients taking the recommended doses for chemotherapy-induced diarrhea. Overall, the incidence of serious cardiac events associated with loperamide remains low. In balance, the risk of uncontrolled complications from chemotherapy-induced diarrhea is likely greater than the rare cardiac risk associated with the chronic misuse of much higher doses of loperamide.

A deliberative framework to identify the need for real-life evidence building of new cancer drugs after interim funding decision.

BACKGROUND: With the rising cost of new oncology treatments, it is no longer sustainable to base initial drug funding decisions primarily on prospective clinical trials as their performance in real-life populations are often difficult to determine. In British Columbia, an approach in evidence building is to retrospectively analyse patient outcomes using observational research on an ad hoc basis. METHODS: The deliberative framework was constructed in three stages: framework design, framework validation and treatment programme characterization, and key informant interview. Framework design was informed through a literature review and analyses of provincial and national decision-making processes. Treatment programmes funded between 2010 and 2013 were used for framework validation. A selection concordance rate of 80% amongst three reviewers was considered to be a validation of the framework. Key informant interviews were conducted to determine the utility of this deliberative framework. RESULTS: A multi-domain deliberative framework with 15 assessment parameters was developed. A selection concordance rate of 84.2% was achieved for content validation of the framework. Nine treatment programmes from five different tumour groups were selected for retrospective outcomes analysis. Five contributory factors to funding uncertainties were identified. Key informants agreed that the framework is a comprehensive tool that targets the key areas involved in the funding decision-making process. CONCLUSIONS: The oncology-based deliberative framework can be routinely used to assess treatment programmes from the major tumour sites for retrospective outcomes analysis. Key informants indicate this is a value-added tool and will provide insight to the current prospective funding model.

Adherence with capecitabine: A population-based analysis based on prescription refill data.

Background Patient adherence is important with the increasing use of oral anticancer drugs. Recent studies reported different capecitabine adherence rates based on self-reporting and microelectronic monitoring of the medication bottle. Patient's awareness of being monitored may confound these results. Prescription records provide a larger and more objective dataset for adherence investigation. We report the use of computer algorithm and manual review of prescription and medical documentation to determine the rate of capecitabine adherence. Methods Two years of capecitabine prescription records from five ambulatory cancer centres were reviewed. Prescription data were extracted using a custom Java-based software tool to compare the predicted vs. actual dispensing date. The difference between the dates was the primary adherence measure (altered treatment date incident) and estimated using a computer algorithm and by manual review of medical charts. Results Of 4412 refill prescriptions, 45.2% was associated with an altered treatment date incident based on the initial computer algorithm. This was reduced to 29.5% after adjusting for clinic scheduling processes and 10.2% after manual chart review to adjust for valid reasons for delay. The reasons for altered treatment date incident were not identified in 52.2% of prescriptions. Conclusions Adherence rate of capecitabine based on refill data seem to be high and consistent with other findings based on patient self-report. Population analysis of prescription data with custom computer algorithm may identify trends in capecitabine adherence with some efficiency. Manual review would likely be required to verify these results. The accuracy of using altered prescription refill dates as an adherence measure requires further studies.

Rationalizing the use of auxiliary label for oral oncology drugs.

Objective The objective of this study is to develop a systematic approach to standardize the use of auxiliary labels for oral oncology drugs. Design The project was multi-phased: environmental scan of auxiliary labels used at six BC Cancer Agency centre pharmacies, develop guidelines to support auxiliary labels standardization, develop inclusion criteria for common warnings and standardize warnings based on guiding principles and evidence (Canadian Compendium of Pharmaceutical Specialties, BC Cancer Agency Cancer Drug Manual, British National Formulary, literature). Results Consistent auxiliary labels use was rare (7% of drugs). No explicit methodology for determining previous auxiliary labels use was identified. Guiding principles developed include auxiliary labels supplement counselling and drug-specific patient handouts; a maximum of four auxiliary labels (limited container size and alert fatigue); identify hazardous drugs with auxiliary labels; auxiliary labels not intended for universal warnings (e.g., keep out of reach of children); warnings prioritized by impact on storage, efficacy (e.g., administration instructions), toxicity (including interactions) and other clinical issues. Inclusion criteria were developed for warnings on pregnancy, crushing/chewing, taking with plenty of water, drowsiness/dizziness, alcohol, grapefruit juice, hazardous and sunlight exposure. First list of standardized auxiliary labels was completed in June 2014. Conclusion A systematic approach was developed to determine and prioritize auxiliary labels for oral oncology drugs. This has led to a standardized and more accurate labelling throughout the six BC Cancer Agency centres' pharmacies.

Evidence-based practice in times of drug shortage.

Shortage of oncology drugs is a particularly complicated issue because there are usually limited therapeutic options. Moreover, oncology practice may employ medications for supportive indications which differ from their main usage. This means shortage of oncology drugs is not usually addressed by the major drug shortage guidelines. We have previously shown that, during a shortage crisis, it is possible to make a recommendation on the use of an expired drug supply based on a reasonable estimate of its safety and efficacy. Here, we would like to share further examples on how to deduce potential therapeutic alternatives based on pharmacokinetic and pharmacodynamic principles in the absence of direct clinical evidence in the literature.