An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large academic cancer center

Szabatura, Audrea; Cirrone, Frank; Harris, Christy; McDonnell, Anne; Feng, Yang; Voit, Daniel; Neuberg, Donna; Butrynski, James E.; Fisher, David C.

doi:10.1177/1078155214527143

Cited by 51 publications

(68 citation statements)

References 22 publications

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“…Furthermore, CDDP could enhance IFO‐mediated nephrotoxicity . Therefore, it has been speculated that IIE development is likely induced by high levels of metabolites of IFO, including chloroacetaldehyde, owing to renal dysfunction, caused by a combination of multiple drugs with known nephrotoxicity …”

Section: Discussionmentioning

confidence: 99%

Analysis of the clinical characteristics of pediatric patients who experience ifosfamide‐induced encephalopathy

Ide

Yanagisawa

Kubota

et al. 2019

Pediatric Blood & Cancer

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Background Several kinds of pediatric hematological and/or malignant diseases are treated with chemotherapy regimens including ifosfamide (IFO). IFO‐induced encephalopathy (IIE) is one of the serious side effects, but there is not enough evidence regarding the clinical features of IIE in children. Procedure We performed a retrospective study on pediatric patients treated with chemotherapy regimens, including IFO, at a single center. We recorded the clinical characteristics of all patients; we compared the clinical characteristics between patients who developed IIE and those who did not. Results In total, 88 patients received a chemotherapy regimen including IFO. IIE developed in seven patients (8.0%). The median age of patients at the time of IIE development was 4.3 (range 1.4‐6.5) years in the younger population. Six of seven patients with IIE improved with supportive therapy only; however, one patient died due to heart failure. Overall survival was not different between the two groups. Multivariable analysis revealed that the co‐administration of cisplatin (CDDP) or carboplatin (CBDCA) was a significant risk factor associated with IIE. Although there was no significant difference in laboratory data between the groups before chemotherapy, patients who developed IIE showed exacerbation in several laboratory tests, including those for renal and liver functions. Conclusions Renal dysfunction caused by the combination of nephrotoxic agents (IFO and CDDP/CBDCA) seems to be important for the development of pediatric IIE. It was thought to be difficult to predict IIE onset based on laboratory data before the initiation of chemotherapy regimens; however, careful observation of laboratory data during IFO chemotherapy regimens may help predict IIE onset and facilitate early treatment.

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Section: Discussionmentioning

confidence: 99%

Analysis of the clinical characteristics of pediatric patients who experience ifosfamide‐induced encephalopathy

Ide

Yanagisawa

Kubota

et al. 2019

Pediatric Blood & Cancer

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“…22 Ifosfamide-induced encephalopathy is managed by administering methylene blue, an electron acceptor, which acts by regenerating reduced acetylCoA and decreasing fatty acid oxidation by chloroacetaldehyde; moreover, it can inhibit amine oxidases to potentially decrease chloroacetaldehyde formation from chloroethylamine. 10 This difference could be explained by the physicochemical stability of the two formulations of ifosfamide, and in particular by the formation of chloroethylamine in solution.…”

Section: Discussionmentioning

confidence: 99%

“…7 The estimated i ncidence of ifosfamide-induced encephalopathy varies from 10% to 40% in the literature. 10 Aprepitant may also promote ifosfamide-induced encephalopathy by inhibiting CYP 3A4 as described in several case reports. Some variables can increase the risk of ifosfamide-induced encephalopathy.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 98%

“…Symptoms usually manifest during drug administration or within 48 hours, and usually disappear spont aneously 48-72 hours after discontinuation of the infusion. 4,[8][9][10] However, these studies cover a wide r ange of populations and are not very comparable. 7 The estimated i ncidence of ifosfamide-induced encephalopathy varies from 10% to 40% in the literature.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

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Ifosfamide‐induced encephalopathy: Brand‐name (HOLOXAN®) vs generic formulation (IFOSFAMIDE EG®)

et al. 2019

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Summary What is known and Objective Two forms of ifosfamide are commercially available in France: HOLOXAN® (brand‐name drug) and IFOSFAMIDE EG® (generic drug). Following the marketing launch of the generic drug, there has been a significant increase in cases of ifosfamide‐induced encephalopathy reported in France. Our objective is to compare the incidence of ifosfamide‐induced encephalopathy in adult patients treated with HOLOXAN® or IFOSFAMIDE EG®. Methods This is a retrospective study of adult patients treated with ifosfamide in two medical centers from 2013 to 2017, with data analysed from medical records. Comparisons of patients were made, according to the formulation used and according to the occurrence of ifosfamide‐induced encephalopathy. The groups of patients were compared using a chi‐square or Fisher's exact test for qualitative parameters and a Wilcoxon test for quantitative parameters. To include confounding factors in the analysis of the impact of drug formulation on the occurrence of ifosfamide‐induced encephalopathy, a generalized linear model was performed with the occurrence of ifosfamide‐induced encephalopathy as the dependent parameter, and the formulation and the confounding factors as explanatory parameters. Results and Discussion A total of 191 patients were included: 103 patients received HOLOXAN® (53.9%) and 88 patients received IFOSFAMIDE EG® (46.1%). In the HOLOXAN® group, the median infusion time was higher (12 hours vs 3h, P < 0.001) and aprepitant was administered more frequently (78.6% vs 69.7%, P < 0.001) than for the IFOSFAMIDE EG® group. Ifosfamide‐induced encephalopathy occurred in 11 patients (5.8%, CI 95% [2.9%, 10.0%]). In the ifosfamide‐induced encephalopathy group, median infusion time was higher (12 hours [12; 24] vs 3 hours [2; 12] P < 0.001) and a poor performance status was more frequent (54.5% vs 13.9%, P = 0.002) than in the group without ifosfamide‐induced encephalopathy. The frequency of ifosfamide‐induced encephalopathy in the HOLOXAN® group was 1.9% (2/103) against 10.2% (9/88) in the IFOSFAMIDE EG® group (P = 0.014). Multivariate analysis revealed that treatment with IFOSFAMIDE EG® resulted in significantly more ifosfamide‐induced encephalopathies compared to HOLOXAN® (OR and CI 95%:7.4 [1.4; 39.5], P = 0.018). We identified two other risk factors for ifosfamide‐induced encephalopathy: long‐term infusion and a performance status of two or higher. What is New and Conclusion The formation of chloroethylamine in solution could be the cause of more frequent ifosfamide‐induced encephalopathies with IFOSFAMIDE EG® compared to HOLOXAN®. Application of these data could help in the choice of ifosfamide formulation in adult patients to decrease the risk of ifosfamide‐induced encephalopathy, and more specifically for patients with risk factors.

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“…[28] Since aprepitant could inhibit CYP3A4—another metabolizing enzyme for ifosfamide—increasing risk of ifosfamide-induced neurotoxicity has been a concern. A retrospective study suggested a possible risk for ifosfamide-induced neurotoxicity associated with aprepitant use in patients treated with AI, [29] and a case report of a patient with a malignant peripheral nerve sheath tumor treated with ifosfamide, carboplatin, and etoposide showed an ifosfamide-induced neurotoxicity after the addition of aprepitant.…”

Section: Discussionmentioning

confidence: 99%

Efficacy analysis of the aprepitant-combined antiemetic prophylaxis for non-round cell soft-tissue sarcoma patients received adriamycin and ifosfamide therapy

et al. 2016

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Appropriate antiemetic prophylaxis for moderately emetogenic chemotherapy in patients with non-round cell soft-tissue sarcomas (NRC-STS) remains unclear. We retrospectively investigated efficacy and safety of aprepitant-combined antiemetic prophylaxis in patients with NRC-STS receiving adriamycin plus ifosfamide (AI) therapy. Forty NRC-STS patients were enrolled, their median age was 50 years (range 18–74), and 13 (32.5%) were female. Median cycle number of AI therapy was 4. Twenty patients received the doublet antiemetic prophylaxis (5-hydroxytryptamine-3 receptor antagonist and dexamethasone), and 20 received triplet (5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and aprepitant). In the overall period, complete response rate for nausea and emesis in the triplet group was significantly higher than that in the doublet group (70% vs 35%; P = 0.027). Patients with no-emesis in the overall period were more frequently observed in the triplet group than in the doublet group (90% vs 65%; P = 0.058). All toxicities other than emesis were almost equivalent in both the groups. These results suggest that a triplet antiemetic prophylaxis may be optimal in the treatment with AI therapy for NRC-STS.

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An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large academic cancer center

Cited by 51 publications

References 22 publications

Analysis of the clinical characteristics of pediatric patients who experience ifosfamide‐induced encephalopathy

Analysis of the clinical characteristics of pediatric patients who experience ifosfamide‐induced encephalopathy

Ifosfamide‐induced encephalopathy: Brand‐name (HOLOXAN®) vs generic formulation (IFOSFAMIDE EG®)

Efficacy analysis of the aprepitant-combined antiemetic prophylaxis for non-round cell soft-tissue sarcoma patients received adriamycin and ifosfamide therapy

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