Actual body weight dosing of temozolomide and overall survival in patients with glioblastoma.

BACKGROUND: Adult glioblastoma patients receiving standard radiation therapy and concurrent temozolomide chemotherapy have a median survival of 14.6 months. Based on the pivotal trial data by Stupp et al., temozolomide doses were calculated based on body surface area. However, no details regarding the weight used to calculate body surface area was included in the study. As a result, temozolomide doses have been variable across the province. METHODS: This retrospective chart review was conducted to determine the correlation between dose of first line temozolomide with overall survival. Patients between January 1st, 2009 and December 31st, 2014 who were newly diagnosed, pathology confirmed glioblastoma treated first line with temozolomide within Alberta Health Services were included in the study. Temozolomide doses above and below determined cut points were compared through the Kaplan-Meier method, then assessed using the log-rank test. RESULTS: A cut point of 97.8% of actual body weight calculated body surface area dosing was determined for concurrent phase temozolomide. At doses above this cut point, there was a statistically significant (p = 0.0158) increase of 0.3 years in median overall survival. As for toxicity concerns, there was a statistically significant increase in the proportion of temozolomide dose reductions due to toxicity in patients dosed above the cut point. CONCLUSION: Temozolomide doses at full actual body weight calculated body surface area dosing during the concurrent phase is required to achieve a similar median OS as seen in the pivotal trial by Stupp et al.

Evaluation of laboratory disturbance risk when adding low-dose cotrimoxazole for PJP prophylaxis to regimens of high-grade glioma patients taking RAAS inhibitors.

BACKGROUND: Cotrimoxazole is associated with the development of hyponatremia, hyperkalemia and elevated serum creatinine, especially when combined with inhibitors of the renin-angiotensin-aldosterone system (RAAS). Pneumocystis jirovecii pneumonia (PJP) prophylaxis is the standard of care for high-grade glioma (HGG) patients receiving temozolomide concurrently with radiotherapy, low-dose cotrimoxazole being the preferred agent. Many of these patients are also taking renin-angiotensin-aldosterone system inhibitors, however the risk of significant laboratory disturbance in these patients remains undescribed. OBJECTIVE: We evaluated whether high-grade glioma patients taking renin-angiotensin-aldosterone system inhibitors receiving low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis are at additional risk of laboratory disturbances in comparison with their non-renin-angiotensin-aldosterone system counterparts. METHODS: We conducted a retrospective chart review of adult neuro-oncology patients treated for WHO Grade III or IV glioma between 2013 and 2016. Patient serum Na, K, creatinine, and eGFR were compared (renin-angiotensin-aldosterone system vs. non-renin-angiotensin-aldosterone system) using the chi-square test. Binary logistic regression analysis was then performed to account for differences between cohorts. RESULTS: Of 63 patients (35 non-renin-angiotensin-aldosterone system, 28 renin-angiotensin-aldosterone system), patients in the renin-angiotensin-aldosterone system cohort were more likely to experience a laboratory disturbance (odds ratio=3.17, p = 0.03). Overall, these disturbances were moderate, but were slightly more common and slightly more severe in the renin-angiotensin-aldosterone system cohort. CONCLUSION: Adding low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis to the regimens of patients with high-grade glioma taking renin-angiotensin-aldosterone system inhibitors increases the risk of laboratory disturbances. While these are generally moderate, some patients are at risk of significant electrolyte abnormalities requiring intervention.

Switch to generic formulation of temozolomide results in statistically significant increase in grade 3 and 4 bone marrow toxicity in glioma patients in the province of Alberta.

Background: Temozolomide (TMZ) is an oral, systemic chemotherapy used chiefly for treating high-grade glioma. Due to the rising costs of systemic chemotherapy, many jurisdictions have replaced brand name with generic formulations. The aim of this study was to determine whether or not there was difference in the incidence of grade 3 or 4 bone marrow toxicity and median overall survival in patients treated with brand name versus generic TMZ in the province of Alberta, Canada. The province suspended the use of generic TMZ based on preliminary data pointing to excess toxicity. Methods: This multicenter, retrospective study included data from patients with newly diagnosed high-grade glioma that received treatment with TMZ in Alberta. Multivariate logistic regression analysis was performed to determine the association between grade 3 or 4 toxicity to generic versus brand name TMZ exposure, ECOG score, and age. Kaplan-Meier survival estimates and log-rank testing were used to determine differences in overall survival between the brand name and generic TMZ cohorts, as well as the cytopenic versus non-cytopenic patients. Furthermore, a screening analysis for grade 3 or 4 bone marrow toxicity was conducted on all de novo glioma patients treated with brand name TMZ after Alberta preemptively stopped generic TMZ. Results: Grade 3 or 4 neutropenia and thrombocytopenia were observed in 15% and 19% of patients treated with generic TMZ (n = 156) as compared to 3% and 5% of patients (n = 100) treated with brand name TMZ-treated patients; P= .003 and .001. A trend toward increased median overall survival in glioblastoma patients treated with generic TMZ (13.7 months) versus brand name (15.8 months, P = .178.) was also observed through meeting statistical significance. Based on these results, the province stopped the use of generic TMZ and reverted to the Merck TMZ. An initial review of all new glioma patients (n = 89) treated with Merck TMZ since the province stopped the generic drug demonstrated 3.4% and 10.1% grade 3 or 4 neutropenia, respectively. Conclusions: The statistically significant difference in toxicity profile has prompted the province of Alberta to replace generic TMZ with brand name TMZ in high-grade glioma patients pending more detailed analysis. Our study provides evidence supporting the importance of conducting prospective studies on long-term safety for generic chemotherapies.