Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma.

OBJECTIVES: To evaluate the efficacy and tolerability of ipilimumab in an Australian clinical setting, and to assess the association of response with melanoma subtype, BRAF mutation status, absolute lymphocyte count and incidence of serious immune-related adverse events (AEs). DESIGN, SETTING AND PARTICIPANTS: Retrospective review of patients with unresectable or metastatic melanoma treated with ipilimumab at an Australian oncology centre between July 2010 and April 2012. MAIN OUTCOME MEASURES: Overall survival (OS), progression-free survival (PFS), incidence and severity of AEs. RESULTS: 104 patients were retrospectively followed for a median of 7 months (range 0-30 months). Median OS was 9.6 months (95% CI, 6.6-12.4), and median PFS was 3.0 months (95% CI, 2.7-3.4). The 1- and 2-year survival rates were 42% (95% CI, 32%-52%) and 18% (95% CI, 9%-30%), respectively. Median OS for patients with non-cutaneous (mucosal and uveal) melanomas was almost half that of patients with cutaneous melanoma: 5.8 months (95% CI, 2.8-12.4) v 11.7 months (95% CI, 7.1-13.8); P = 0.11. Raised absolute lymphocyte count was associated with increased PFS (P ≤ 0.005 at all measured time points) but not with OS (P > 0.15). Sex, age, brain metastases, BRAF mutation status, incidence of severe immune-related AEs and baseline lactate dehydrogenase levels did not affect OS or PFS (P > 0.05). Eighteen of 104 patients experienced serious AEs (≥ grade 3), including two treatment-related deaths. CONCLUSION: In an Australian clinical practice setting, ipilimumab achieved efficacy and tolerability measures similar to those reported in clinical trials. The frequency and severity of ipilimumab-related AEs (including death) are notable, and treatment should occur under the supervision of an experienced clinical team.

A case of delayed methotrexate clearance following administration of a complementary medication containing chlorophyll.

A 54-year-old male with relapsed primary cerebral lymphoma and normal renal function was treated with methotrexate (MTX) 3 g/m(2) monthly by intravenous infusion. Throughout treatment the patient self-administered a complementary medicine (Jason Winter's chlorophyll®), which he was advised to cease during methotrexate treatment due to the potential for unknown interactions. For the first four cycles, chlorophyll was ceased two days prior to commencement of methotrexate and withheld until clearance. These cycles were administered without complication, and the methotrexate level reduced to <0.05 µmol/L within three days of each dose. Prior to cycle 5, chlorophyll was not ceased and there were no changes to concomitant medications. A literature search found no documented interactions between methotrexate and chlorophyll and the chemotherapy was administered without a delay in treatment. The methotrexate level three days post-administration was 0.36 µmol/L and did not reduce to <0.05 µmol/L until day 10. Consequently, from cycles 6 to 12, the methotrexate dose was halved, and the patient ceased chlorophyll 48 h prior to methotrexate administration until clearance. There were no further episodes of delayed methotrexate clearance. No impurities were detected in a sample of Jason Winter's chlorophyll®. It is therefore likely that the patient's delayed methotrexate clearance was due to an interaction with chlorophyll. It is recommended that such chlorophyll containing preparations be avoided in patients treated with methotrexate.

Carmustine infusion reactions are more common with rapid administration.

PURPOSE: Carmustine is a nitrosurea alkylating agent predominantly used at Peter MacCallum Cancer Centre as part of the autologous stem cell transplant induction regimens Stanford BCNU and BEAM. Acute infusion reactions were anecdotally reported to be higher than the reported rates of 10%, and it was suggested that the rate of infusion being employed was excessive. Some references suggest maximum infusion rates of 3 mg/m(2)/min for carmustine, a rate which is exceeded in the 2-h infusions used for Stanford BCNU, but not with BEAM. METHODS: A retrospective audit was conducted in 64 patients (57 Stanford BCNU, 7 BEAM) who had received these regimens between January 2009 and November 2010. RESULTS: Rates of infusion reaction to carmustine were higher than literature values, with reactions in Stanford BCNU (94.7%) being significantly higher than for BEAM (28.6%; P = 0.0003). These findings have resulted in a change of administration of carmustine in Stanford BCNU from 2 to 3 h. Further studies plan to compare the incidence of infusion reactions before and after the change in administration rates. CONCLUSION: Patients receiving rapid infusion of carmustine in the Stanford BCNU regimen for stem cell conditioning have a high rate of infusion reaction. A maximum rate of 3 mg/m(2)/min is recommended.

A survey of reimbursement practices of private health insurance companies for pharmaceuticals not covered under the Pharmaceutical Benefits Scheme 2008.

OBJECTIVE: To describe the current practices and policy of Australian private health insurance (PHI) companies with respect to cover for pharmaceuticals not subsidised under the Pharmaceutical Benefits Scheme (PBS). DESIGN, SETTING AND PARTICIPANTS: A 2008 review of web-published policy statements for top-level hospital and comprehensive general treatment insurance, and survey of reimbursement practices by way of questionnaire, of 31 Australian-registered, open-membership PHI companies. MAIN OUTCOME MEASURES(S): Description of the level of pharmaceutical cover and important considerations identified by PHI companies for funding non-PBS pharmaceuticals through benefit entitlements or ex-gratia payments. RESULTS: Nine of thirty-one PHI companies (29%) provided responses accounting for ~60% market share of PHI. The majority of smaller PHI firms either declined participation or did not respond. The maximum limits offered for non-PBS pharmaceuticals, under comprehensive general treatment insurance, varied significantly and typically did not adequately cover high-cost pharmaceuticals. Some companies occasionally offered ex-gratia payments (or discretionary payments in excess of the policyholder's entitlement benefits) for high cost-pharmaceuticals. Factors considered important in their decision to approve or reject ex-gratia requests were provided. All results were de-identified. CONCLUSIONS: There is little consistency across PHI companies in the manner in which they handle requests for high-cost pharmaceuticals in excess of the defined benefit limits. Such information and processes are not transparent to consumers.

Impact of a specialist clinical cancer pharmacist at a multidisciplinary lung cancer clinic.

AIM: Medication misadventure contributes to unplanned hospital admissions. General practitioners (GPs) may lack experience in managing problems involving complex cancer-related medication. A previous survey explored the unmet needs of lung cancer outpatients and highlighted their desire for more medication information. Inpatient clinical pharmacy services positively impact on patient care. This study evaluated the effects of extending this service to outpatients. METHOD: A specialist cancer pharmacist joined the lung cancer clinic team for 6 months. Patients completed assessments of their medication adherence and their satisfaction with the provision of medicine information (at baseline and repeated within 30 days of initial pharmacist review). Following review, a medication list and plan (detailing recommendations/interventions) were provided to patients and their health care providers. Interventions were categorized and graded according to risk avoided. Unplanned admissions and clinic attendance rates were compared with the previous year. GPs' opinion of the service was also evaluated. RESULTS: Forty-eight patients participated in the study. Medication adherence (P = 0.007) and patient satisfaction (P < 0.001) significantly improved. A total of 154 pharmacist interventions were made: 4.5% extreme risk and 43.5% high risk. The mean number of unplanned admissions and clinic attendances per patient decreased from 0.3 to 0.26 (P = 0.265) and from 3.32 to 2.98 (P = 0.004), respectively. Seventy-four percent of surveyed GPs found the service useful. CONCLUSIONS: Adding a specialist cancer pharmacist to the outpatient lung cancer team led to significant improvements in patient medication adherence. Both patients and GPs were highly satisfied with the service. Medication misadventure and clinic attendances were reduced.

Thromboprophylaxis prescribing and thrombotic event rates in multiple myeloma patients treated with lenalidomide or thalidomide at a specialist cancer hospital.

AIM: To assess thromboprophylaxis prescribing patterns against current guidelines and report thromboembolism (TE) incidence in multiple myeloma (MM) patients treated with thalidomide (thal) or lenalidomide (len) at a specialist cancer hospital over a one-year period. METHOD: Dispensing records of thal and len, diagnosis of MM, patients' characteristics, disease status, co-prescribed medicines including thromboprophylaxis and incidence of TE were extracted from patients' records and a patient survey conducted to identify patients who sourced thromboprophylactic medicines outside the hospital. RESULTS: Enoxaparin was most the commonly prescribed thromboprophylactic agent (43%), followed by low-dose aspirin (26%) and therapeutic warfarin (6%). The thromboprophylactic strategy (including no prophylaxis) could not be determined for 22% of patients. TE incidence (with any thromboprophylaxis) was 9.3 and 9.1% in thal-based and len-based regimens, respectively. CONCLUSION: Both aspirin and enoxaparin thromboprophylaxis were prescribed for patients on both low-risk and high-risk immunomodulatory drug-based regimens, deviating from current consensus guidelines. Treatment of comorbidities constituted the rationale for maintenance on therapeutic warfarin. Fixed low-dose warfarin was not prescribed. TE event rates (with any thromboprophylaxis) were consistent with those reported in the literature. Documentation of a chosen strategy was lacking for nearly a quarter of patients, resulting in uncertainty of treatment plan for other members of the multidisciplinary treating team. Centers need to work towards evidence-based institutional guidelines and improving documentation practices for thromboprophylaxis in their MM patients.

A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer.

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of action of therapeutic monoclonal antibodies (mAbs) such as cetuximab, rituximab and trastuzumab. Fc gamma receptors (FcgR) on human white blood cells are an integral part of the ADCC pathway. Differential response to therapeutic mAbs has been reported to correlate with specific polymorphisms in two of these genes: FCGR2A (H131R) and FCGR3A (V158F). These polymorphisms are associated with differential affinity of the receptors for mAbs. This review critically examines the current evidence for genotyping the corresponding single nucleotide polymorphisms (SNPs) to predict response to mAbs in patients with cancer.

Thalidomide thromboprophylaxis in multiple myeloma: a review of current evidence.

Currently multiple antithrombotic agents are used for thalidomide thromboprophylaxis in multiple myeloma patients. Agents used include low-dose aspirin, fixed low-dose and therapeutic warfarin and prophylactic low molecular weight heparin. To evaluate the evidence for the efficacy and safety of aspirin, warfarin and low molecular weight heparin thromboprophylaxis in multiple myeloma patients on thalidomide a literature search was conducted in May and June 2011. Databases searched included the Cochrane Database of Systemic Reviews and the Database of Abstracts of Reviews of Effects, Evidence Based Medicine Reviews and Ovid MEDLINE. The search was restricted to English language articles and limited to articles published from 2005 to 2011. Most studies consisted of small prospective cohort studies not originally designed to assess thromboprophylaxis as an outcome. A single comparative randomized trial, several retrospective review articles, two meta-analyses and two clinical practice guidelines were also identified. Current evidence fails to demonstrate a clear advantage of any particular thromboprophylaxis strategy. Results from the only prospective comparative randomized trial found no significant differences among aspirin, warfarin and low molecular weight heparin. More studies are required that consider not only efficacy and safety, but also costs, lifestyle burden and patient preference.

An unusual case of serotonin syndrome with oxycodone and citalopram.

A 77-year-old female with recurrent non-small-cell lung cancer presented to a hospital outpatient clinic with tremor, weakness, inability to coordinate motor movements, and confusion. It was suspected that the symptoms were due to possible central nervous system metastases; however, a CT scan of her head was unremarkable. The lung clinic liaison pharmacist took a medication history from the patient, complimented by extra information from the patient's community pharmacy. The pharmacist suspected the rare side effect of serotonin syndrome was responsible for the patient's presenting symptoms caused by the combination of oxycodone and citalopram. The patient's symptoms resolved soon after oxycodone was changed to morphine.

Clinical guidance on the perioperative use of targeted agents in solid tumor oncology.

The use of targeted anti-cancer agents is increasing. It is common to utilize a multi-modal treatment approach towards solid tumors, often including surgical resection, and it has become apparent that some targeted agents can impair wound healing or cause an increased risk of perioperative complications. This article reviews targeted agents used in solid tumor oncology with an emphasis on clinically relevant details. Overall, the evidence of targeted agents causing surgical complications is limited. The greatest amount of evidence exists for bevacizumab causing perioperative complications, possibly due to its extended half-life. There are limited data for cetuximab, sorafenib and sunitinib and very little for other solid tumor targeted agents. Our findings suggest that there should be heightened pharmacovigilence around targeted agents with respect to perioperative complications and increased post-surgical support for patients to aid early detection of postoperative complications until definitive data become available.