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Thiotepa

"A very toxic alkylating antineoplastic agent also used as an insect sterilant. It causes skin, gastrointestinal, CNS, and bone marrow damage. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), thiotepa may reasonably be anticipated to be a carcinogen (Merck Index, 11th ed)." (MeSH 2013)

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Latest Research Publications

Web Resources: Thiotepa (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Song Q, Zhou X, Yu J, et al.
The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa.
Sci Rep. 2015; 5:16775 [PubMed] Free Access to Full Article Related Publications
This study investigated interactive effects of CYP2B6 genotypes and liver metastasis on the prognosis of metastatic breast cancer patients who received combined chemotherapy of docetaxel and thiotepa. Totally 153 patients were retrospectively genotyped rs8192719 (c.1294 + 53C > T) and rs2279343 (c.785A > G). Kaplan-Meier method and Cox Proportional Hazard Regression model were used to estimate the survival. Patients with liver metastasis had worsen prognosis, conferring a 2.26-fold high risk of progression and 1.93-fold high risk of death (p < 0.05). Both CT/TT genotype of rs8192719 (c.1294 +  3C > T) and AG genotype of rs2279343 (c.785A > G) prolonged survival (p < 0.05). Furthermore, among liver metastatic patients, AG genotype of rs2279343 (c.785A > G) was associated with a 47% reduced risk of death and a 6-month-longer overall survival (p < 0.05). Among non-liver metastatic patients, hazard ratios of CT/TT genotype of rs8192719 (c.1294 + 53C > T) were 0.45 for progression and 0.40 for death; and the corresponding survival was improved by 6 months and 16 months, respectively (p < 0.05). Genotypes of CYP2B6 had an interaction with clinical efficacy of docetaxel and thiotepa on metastatic breast cancer patients; and metastatic sites also affected clinical responses. Further therapies should take into account of chemotherapy regimen, genotypes of metabolizing enzymes and metastatic sites for the particular subpopulation.

Sellner L, Boumendil A, Finel H, et al.
Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT.
Bone Marrow Transplant. 2016; 51(2):212-8 [PubMed] Related Publications
Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B-cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted.

Cho KM, Kim YJ, Kim SH, et al.
Salvage Treatment with Intracerebrospinal Fluid Thiotepa in Patients with Leptomeningeal Metastasis After Failure of Methotrexate-based Treatment.
Anticancer Res. 2015; 35(10):5631-8 [PubMed] Related Publications
AIM: To evaluate the efficacy of intracerebrospinal fluid (intra-CSF) thiotepa in patients with leptomeningeal metastasis (LM) after failure of a methotrexate-based treatment.
PATIENTS AND METHODS: We retrospectively reviewed the medical records of patients with LM who received 10 mg of intra-CSF thiotepa twice a week.
RESULTS: Out of 40 patients, 25 were females (63%), and 31 (78%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Fourteen out of the 30 evaluable patients (47%) had a cytological response to intra-CSF thiotepa. The median overall survival (OS) after treatment with thiotepa was 19.4 weeks (95% confidence interval (CI)=15.3-23.5). Grade 3 toxicities were thrombocytopenia (N=2), bacterial meningitis (N=2), and pneumonia (N=1). According to a multivariate analysis, an ECOG PS ≥2 (hazard ratio (HR)=5.11, 95% CI=1.39-18.80, p=0.014), clinical improvement (HR=0.09, 95% CI=0.03-0.29, p<0.001), and radiation for LM after intra-CSF thiotepa (HR=0.33, 95% CI=0.11-0.97, p=0.043) were independently associated with survival.
CONCLUSION: Intra-CSF thiotepa seems to be a meaningful salvage treatment for patients with LM whose disease progresses after a methotrexate-based treatment.

Zhou X, Wang X, Song Q, et al.
Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.
Int J Clin Pharmacol Ther. 2015; 53(11):914-22 [PubMed] Related Publications
BACKGROUND: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities.
METHODS: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded.
RESULTS: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity.
CONCLUSIONS: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Jahnukainen K, Kallio P, Koivusalo A, Saarinen-Pihkala UM
High-dose Thiotepa as Consolidation Therapy With Autologous Hematopoietic Stem Cell Transplantation for High-risk Ewing Family Tumors: Single-institution Experience.
J Pediatr Hematol Oncol. 2015; 37(7):536-42 [PubMed] Related Publications
High-dose therapy (HDTx) with autologous stem cell rescue has been widely applied in very-poor-risk pediatric solid tumors. Promising data have become available with the use of high-dose busulfan, whereas high-dose (HD) thiotepa is less commonly used. We report retrospectively our single-institution experience from 1986 to 2012 of single and tandem HDTx with special emphasis on HD-thiotepa as the backbone of HD regimen in Ewing family tumors, including all 24 patients in the Helsinki University Hospital referral area in population-based fashion (Ewing sarcoma 9, Askin tumor 9, peripheral neuroectodermal tumor 6). The 10-year overall survival for the entire cohort was 0.73±0.01. Thirteen out of the 24 underwent HDTx (10 single, 3 tandem). The HDTx regimen consisted of HD-thiotepa (900 mg/m), VP16, and carboplatin. Additional HD-melphalan and total body irradiation were used in the tandem regimens. There was no toxic mortality. The 5-year event-free survival was 0.73±0.16 for high-risk cases transplanted in 1CR. In the relapse group, 1 out of the 3 survived. Radiotherapy to axial sites was given safely in combination with HD-thiotepa in all 3 patients. Thiotepa-based HDTx approach resulted in an encouraging outcome without toxic mortality for high-risk patients. HD-thiotepa merits further studies in larger controlled series.

Musso M, Messina G, Marcacci G, et al.
High-Dose Melphalan Plus Thiotepa as Conditioning Regimen before Second Autologous Stem Cell Transplantation for "De Novo" Multiple Myeloma Patients: A Phase II Study.
Biol Blood Marrow Transplant. 2015; 21(11):1932-8 [PubMed] Related Publications
High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m(2)) to high-dose MEL (140 mg/m(2)) before a second ASCT, in a tandem ASCT strategy, in 64 patients with "de novo" MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.

Chahal J, Stopeck A, Clarke K, et al.
Intravenous thiotepa for treatment of breast cancer-related leptomeningeal carcinomatosis: case series.
Neurol Sci. 2015; 36(9):1691-3 [PubMed] Related Publications
Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood-brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution's experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m(2) every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies.

Eder S, Labopin M, Arcese W, et al.
Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
Eur J Haematol. 2016; 96(1):90-7 [PubMed] Related Publications
Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting.

Baronciani D, Depau C, Targhetta C, et al.
Treosulfan-fludarabine-thiotepa conditioning before allogeneic haemopoietic stem cell transplantation for patients with advanced lympho-proliferative disease. A single centre study.
Hematol Oncol. 2016; 34(1):17-21 [PubMed] Related Publications
In recent years, with the aim of reducing transplant-related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan-fludarabine-thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho-proliferative diseases and at high transplant risk. Twenty-seven consecutive patients, median age 43 years (range 19-60), entered this study. All of them were affected by lympho-proliferative disease in advanced phase and have been heavily pre-treated. The median haemopoietic stem cell transplant co-morbidity index was 1 (range 0-3). Twenty-five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non-haematological toxicity was limited. No patient developed veno-occlusive disease. The estimated probability of overall survival and progression-free survival with a median follow-up of 40 months was 52% (95% confidence interval 33-73) and 50% (95% confidence interval 30-70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan-fludarabine-thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow-up and prospective randomized studies are necessary to evaluate this regimen.

Thust SC, Blanco E, Michalski AJ, et al.
MRI abnormalities in children following sequential chemotherapy, hyperfractionated accelerated radiotherapy and high-dose thiotepa for high-risk primitive neuroectodermal tumours of the central nervous system.
J Med Imaging Radiat Oncol. 2014; 58(6):683-90 [PubMed] Related Publications
INTRODUCTION: Intensive postsurgical therapies have improved survival in children with primitive neuroectodermal tumour, but there is concern that the combination of chemotherapy and radiotherapy may result in a compound injury to normal brain. The purposes of this analysis were to characterise what types of imaging abnormalities occur, identify risk factors and explore how treatment-related changes may be distinguished from tumour.
METHOD: One hundred fifty-three MRI studies in 14 children treated with sequential chemotherapy, hyperfractionated accelerated radiotherapy and high-dose thiotepa were retrospectively analysed at a paediatric national referral centre.
RESULTS: We observed 11 episodes of new focal enhancing lesions, 5 of which were transient and judged to be treatment related. In addition, 7/14 (50%) of children demonstrated moderate to severe brain volume loss featuring a leukodystrophy pattern.
CONCLUSION: Treatment-related brain MRI abnormalities occurred frequently in this series with a risk of misdiagnosis as tumour. A proportion of patients suffer generalised white matter injury, which has not been appreciated as a side effect of this particular therapy.

Kokolo MB, Fergusson D, O'Neill J, et al.
Effectiveness and safety of thiotepa as conditioning treatment prior to stem cell transplant in patients with central nervous system lymphoma.
Leuk Lymphoma. 2014; 55(12):2712-20 [PubMed] Related Publications
BACKGROUND: Thiothepa is a cytostatic agent used in managing solid malignancies, and also as conditioning treatment before hematopoietic stem cell transplantation [HSCT]. This systematic review summarizes evidence on its effectiveness and safety, in patients with central nervous system [CNS] lymphoma.
METHODS: We searched 3 databases for clinical studies. When feasible, we performed meta-analyses.
RESULTS: We identified 13 eligible studies, none of which with a priori controls. So data synthesis focused on the 226 patients who received thiotepa. Based on pooled estimates, 75.9% of thiotepa-treated patients achieved a complete remission (95% confidence interval [CI] = 67.5-82.8), and 61.7% had a progression-free survival for up to 125 months post-treatment (95% CI = 49.4-72.7). However, 25.5% relapsed, 24.6% experienced infection, and 13.2% experienced neurotoxicity.
DISCUSSION: Thiotepa-based conditioning followed by HSCT may be effective in most CNS lymphoma patients, with a manageable toxicity profile. But adequately powered randomized trials are needed to better evaluate and isolate the effects of thiotepa.

Comte A, Jdid W, Guilhaume MN, et al.
Survival of breast cancer patients with meningeal carcinomatosis treated by intrathecal thiotepa.
J Neurooncol. 2013; 115(3):445-52 [PubMed] Related Publications
Treatment of breast cancer meningeal carcinomatosis (MC) relies on intrathecal chemotherapy. Thiotepa is one of the few drugs approved in this setting, although no large cohort has been reported. The aim of our retrospective study is to describe survival and prognostic factors of breast cancer patients treated by intrathecal thiotepa. A search in the electronic database of the Institut Curie was performed and retrieved the patients diagnosed with breast cancer MC from 2000 to 2012 and who received at least one intrathecal injection of thiotepa. The standard regimen was intrathecal thiotepa (10 mg) and methylprednisolone (40 mg), repeated every other week. Clinical data were retrieved from the computerized medical file of each patient. Sixty-six patients have been treated with intrathecal thiotepa either as first line or second line of treatment for breast cancer MC. The median overall survival was 4.5 months (range 0.1-50). There was no significant survival difference between patients treated as first or second line. In multivariate analysis, main adverse prognostic factors at diagnosis were performance status >2 (p = 0.001, RR = 3.4, 95 % CI 1.6-7.2) and history of more than 3 previous systemic chemotherapy lines (p = 0.002, RR = 2.90, 95 % CI 1.50-5.65). After start of the treatment, high primary tumor grade, elevated Cyfra 21-1 levels in the cerebrospinal fluid, and lack of clinical improvement were also independent adverse prognostic factors in multivariate analysis. This is the largest retrospective cohort of breast cancer MC treated by intrathecal thiotepa ever reported. The median overall survival was short but some patients clearly benefited from this treatment, even used as second line.

Le Rhun E, Taillibert S, Devos P, et al.
Salvage intracerebrospinal fluid thiotepa in breast cancer-related leptomeningeal metastases: a retrospective case series.
Anticancer Drugs. 2013; 24(10):1093-7 [PubMed] Related Publications
There is currently a paucity of data on salvage intracerebrospinal fluid (intra-CSF) chemotherapy in leptomeningeal metastases (LM). This report is a single-institution experience with salvage treatment in patients with breast cancer (BC) and LM. This retrospective cohort describes 24 consecutive patients with BC selected for a second-line of treatment for LM. The first line of LM treatment consisted of intra-CSF liposomal cytarabine in all patients combined with systemic therapy in 18 cases and radiotherapy in four cases. Second-line (salvage) treatment utilized intra-CSF thiotepa in all and systemic chemotherapy in nine patients. No patient received CNS-directed radiotherapy. The median Eastern Cooperative Oncology Group performance status at initiation of intra-CSF thiotepa treatment was 3 (range 1-4). The median progression-free survival and median survival following intra-CSF thiotepa was 3.1 months (range 3 days-2 years) and 4.0 months (range 6 days-2.5 years), respectively. The median overall survival from LM diagnosis was 9.5 months (range 1.3 months-2.7 years). No grade 3 or higher toxicity was observed. Recognizing the limits of a retrospective study, intra-CSF thiotepa has an acceptable toxicity profile and appears to be a reasonable option for selected BC patients.

Christopoulos P, Schmoor C, Waterhouse M, et al.
Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML.
Bone Marrow Transplant. 2013; 48(7):901-7 [PubMed] Related Publications
A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m(2) and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients ≥ 65 years old who relapsed >12 months after the first allograft (n=20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse.

Saarinen-Pihkala UM, Hovi L, Koivusalo A, et al.
Thiotepa and melphalan based single, tandem, and triple high dose therapy and autologous stem cell transplantation for high risk neuroblastoma.
Pediatr Blood Cancer. 2012; 59(7):1190-7 [PubMed] Related Publications
BACKGROUND: Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations.
METHODS: Thirty six children with high risk NBL, diagnosed 1995-2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987-1994 was updated.
RESULTS: Ten year event-free survival (EFS) from diagnosis was 0.44+/-0.10 of the old and 0.43+/-0.085 of the new cohort. EFS from the last ASCT was 0.53 +/-0.12 and 0.48+/-0.091, respectively. Preoperative HD-melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/-0.15 for single and 0.73+/-0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died.
CONCLUSIONS: Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190-1197. © 2012 Wiley Periodicals, Inc.

Falzetti F, Di Ianni M, Ballanti S, et al.
High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk non-Hodgkin lymphoma.
Clin Exp Med. 2012; 12(3):165-71 [PubMed] Related Publications
High-dose chemotherapy conditioning regimens followed by autologous stem cell transplantation generally provide good results in non-Hodgkin lymphoma. We have evaluated the effects of a high-dose regimen comprising thiotepa, etoposide and carboplatin. After debulking and mobilization with high-dose cyclophosphamide or other schedules, forty-five patients at various disease stages were conditioned with thiotepa, etoposide and carboplatin prior to autologous stem cell transplantation. The overall response rate was 77.8% (30 CR, 66.7%; 5 PR, 11.1%). Ten patients (22.2%) did not respond. Two patients (4.4%) died from transplant-related complications. The mean 5-year overall survival was 71.1%: 12 patients relapsed within the first 5 years of follow-up. The overall response rate and 5-year overall survival were better for patients with an International Prognostic Index (IPI) 1 at diagnosis than for those with IPI 2 and IPI 3 (P<0.005 for all). The thiotepa, etoposide and carboplatin conditioning regimen for autologous stem cell transplantation in non-Hodgkin lymphoma has a good anti-lymphoma effect and provides encouraging results in terms of response to treatment and 5-year overall survival. Its good tolerance and acceptable toxicity suggest that it may a very useful in the management of non-Hodgkin lymphoma.

Lu Z, Jia J, Di L, et al.
DNA methyltransferase inhibitor CDA-2 synergizes with high-dose thiotepa and paclitaxel in killing breast cancer stem cells.
Front Biosci (Elite Ed). 2011; 3:240-9 [PubMed] Related Publications
It has been suggested that breast cancer stem cells (CSCs), which characterized by CD44(+)CD24(-/low), may result in treatment failure in patients with breast cancer. It is possible therefore that that inhibiting such subpopulation might subsequently improve clinical outcome. In the present study, we found that the CD44(+)/CD24(-/low) CSCs, isolated from both human breast cell line MCF-7 and MDA-MB-231, were more resistant to thiotepa, paclitaxel and anthracycline, when compared with the non-breast cancer stem cell subset from the same cell lines, whereas the chemosensitivities were remarkably reversed by higher concentration of thiotepa and paclitaxel except for adriamycin. The percentage of CSCs was significantly decreased with an addition of DNA methyltransferase inhibitor CDA-2 and the expression of Smo, Shh, and Gli-1 of Hedgehog signaling pathway in CSCs was decreased. Of important findings, combination of thiotepa or paclitaxel with CDA-2 could significantly inhibit the proliferation of CSCs regardless of their dosages. These results unveiled that the selection of cytotoxic agents and increasing their dosage might be of great importance in the respect of eliminating CSCs. DNA methyltransferase inhibitor CDA-2 exhibited a synergistic effect with cytotoxic drugs, which might provide a conceptually new therapeutic strategy.

Butturini AM, Jacob M, Aguajo J, et al.
High-dose chemotherapy and autologous hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on outcome.
Cancer. 2009; 115(13):2956-63 [PubMed] Related Publications
BACKGROUND: The role of myeloablative chemotherapy in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors (MB/ST-PNET) is controversial, in particular in patients who develop recurrent disease after craniospinal radiotherapy.
METHODS: In this retrospective analysis, the authors investigated the outcome of children with recurrent MB/ST-PNET who were referred for myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue at Childrens Hospital Los Angeles.
RESULTS: Thirty-three children were referred for myeloablative chemotherapy: Fourteen of those children were never transplanted because of pre-transplant adverse events, and 19, including 6 without and 13 with previous irradiation, underwent transplant. Conditioning regimens included a backbone of thiotepa, which was given either in a single cycle or in multiple sequential cycles. The 3-year post-transplant event-free survival rate in unirradiated versus previously irradiated children was 83% +/- 15% versus 20% +/- 12%, respectively (P = .04). One child who had never been exposed to radiotherapy died of toxicity; the other children received post-transplant radiotherapy and remained disease free. Nine previously irradiated children experienced 4 toxic deaths and 6 tumor recurrences (1 patient had both): An interval of <1 year between initial radiotherapy and myeloablative chemotherapy predicted a greater risk of toxic death (P = .02), whereas a history of meningeal metastases at diagnosis and a poor response to the initial rescue therapy predicted a greater risk of post-transplant recurrence (P = .03 and P = .08, respectively).
CONCLUSIONS: Myeloablative doses of thiotepa-based chemotherapy and radiotherapy were able to cure most children who had radiotherapy-naive, chemoresponsive recurrences. Children who developed recurrences after craniospinal radiotherapy had poorer outcomes; however, cure was possible in those who had good prognostic features at presentation, chemoresponsive recurrences, and a long interval between initial radiotherapy and myeloablative chemotherapy.

Ekhart C, Doodeman VD, Rodenhuis S, et al.
Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa.
Br J Clin Pharmacol. 2009; 67(1):50-60 [PubMed] Free Access to Full Article Related Publications
AIMS: Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa.
METHODS: White patients (n = 124) received a high-dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC-MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (nonmem).
RESULTS: The polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C-69T, G-52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non-inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients.
CONCLUSIONS: This study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa.

Ekhart C, Rodenhuis S, Smits PH, et al.
Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin.
Pharmacogenet Genomics. 2008; 18(11):1009-15 [PubMed] Related Publications
PURPOSE: High-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC) has been developed as a possible curative treatment modality in several solid tumours. However, a large interindividual variability in toxicity is encountered in high-dose chemotherapy. A priori identification of patients at risk for toxicity could be an attractive prospect. Genotyping of genes encoding drug-metabolising enzymes might provide such a tool.
EXPERIMENTAL DESIGN: We assessed 16 selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in CTC metabolism using polymerase chain reaction and DNA sequencing in 113 patients who were treated with high-dose chemotherapy regimens based on CTC.
RESULTS: Patients heterozygous for the ALDH3A1*2 allele (allelic frequency 21.2%) had an increased risk of haemorrhagic cystitis when compared with patients with wild-type alleles [5/38 vs. 1/70; odds ratio (OR): 11.95, 95% confidence interval (CI): 1.18-120.56; P=0.04]. Furthermore, patients heterozygous for the ALDH1A1*2 allele (allelic frequency 5.8%) had an increased risk of liver toxicity when compared with patients with wild-type alleles (6/13 vs. 19/99; OR: 5.13, 95% CI: 1.30-20.30; P=0.02). No other relations reached significance.
CONCLUSION: Patients heterozygous for the ALDH3A1*2 and ALDH1A1*2 allele have an increased risk of haemorrhagic cystitis and liver toxicity, respectively, compared with patients with wild-type alleles when treated with a high-dose chemotherapy combination of CTC. Pharmacogenetic approaches can identify patients who are at risk of experiencing toxic side effects in high-dose chemotherapy.

Cacchione A, LeMaitre A, Couanet DV, et al.
Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen.
Bone Marrow Transplant. 2008; 42(7):449-54 [PubMed] Related Publications
At our Institute, during the last decade, the incidence of hepatic veno-occlusive disease (HVOD) appears to be on the increase among pediatric patients treated with BU-thiotepa (BU-TTP)-conditioning regimen. We thus performed a retrospective analysis to identify the risk factors for HVOD, which could explain such a change. In total, 116 patients treated at Institut Gustave Roussy, between May 1998 and December 2005 were eligible for this study having received BU-TTP as their first high-dose chemotherapy regimen, followed by autologous hematopoietic SCT (AHSCT). According to McDonald's clinical criteria, HVOD was diagnosed in 31% of these children. Demographic, clinical, biological and therapeutic parameters were evaluated in uni- and multivariate analyses that showed a significant correlation between previous carboplatin therapy and risk of developing post transplant HVOD (P=0.028). Comparable results were found for etoposide (P=0.048). In addition, a correlation between HVOD and risk of post transplant death was linked to its association with other types of organ failure (P=0.029). This study demonstrates that previous VPCARBO administration in conventional chemotherapy significantly increases the risk of HVOD among brain tumor patients later consolidated with BU-TTP followed by AHSCT.

Ekhart C, Kerst JM, Rodenhuis S, et al.
Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency.
Cancer Chemother Pharmacol. 2009; 63(2):375-9 [PubMed] Related Publications
PURPOSE: We report a patient with renal insufficiency (creatinine clearance, CL(cr) = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m(2) day(-1)), thiotepa (120 mg/m(2) day(-1)) and carboplatin (AUC = 5 mg min/mL day(-1)) for four consecutive days.
METHODS: Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined.
RESULTS: Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%.
CONCLUSION: These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insufficiency.

Rosman IS, Lloyd BM, Hayashi RJ, Bayliss SJ
Cutaneous effects of thiotepa in pediatric patients receiving high-dose chemotherapy with autologous stem cell transplantation.
J Am Acad Dermatol. 2008; 58(4):575-8 [PubMed] Related Publications
High-dose thiotepa, a polyfunctional alkylating agent used in the treatment of solid tumors in children and adults, has been reported to cause a variety of reactions in the skin, including erythema, blistering, and hyperpigmentation. Reports vary in descriptions of the prevalence, severity, and nature of cutaneous reactions to thiotepa. To further characterize the cutaneous effects of thiotepa in children, we performed a chart review of 38 pediatric patients treated with a thiotepa-based chemotherapy regimen before autologous stem cell transplantation. Although cutaneous symptoms were documented in all patients, a consistent pattern of diffuse erythema with progression to desquamation and hyperpigmentation occurred in nearly 80% of the patients. Intertriginous and occluded areas were often the initial areas to be affected. Recognition of this association will improve the care of this patient population. This study was limited by reliance on chart data and lack of follow-up by a dermatologist.

Grüllich C, Bertz H, Spyridonidis A, et al.
A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation.
Bone Marrow Transplant. 2008; 41(10):845-50 [PubMed] Related Publications
We present a phase II study of fludarabine 5 x 30 mg/m(2), thiotepa 3 x 5 mg/kg as preparative regimen specifically for allogeneic second haematopoietic stem cell transplantation (HCT) after failure of previous HCT. Forty-nine patients (median age 52 years, range 27-68) received an allogeneic second HCT after failed autologous (n=29) or allogeneic (n=20) HCT. Diagnoses were AML (n=18), ALL (n=3), multiple myeloma (n=11), lymphoma (n=16) and CML (n=1). GVHD prophylaxis consisted of CYA and mainly low dose alemtuzumab (40 mg). The median follow-up for patients alive is 528 days (range 217-1344). In 43 of 49 (88%) evaluable patients response rates were CR=19, PR=14 and SD=10 at one month. At one year, the probability (95% confidence interval) of relapse is 55.1 (38.2-72)% and the nonrelapse mortality (NRM) is 29 (14.2-44.4)%. Estimated survival at one year is 42.6 (28.7-56.6)% and event free survival is 38.1 (24.4-51.8)%. Survival was significantly better for patients experiencing relapse beyond one year, than for patients relapsing within one year from first transplantation (51.2 (33.5-68.9)% vs 27 (7-48.5)%; P=0.013). We conclude that this regimen is feasible and well tolerated for allogeneic second HCT.

Spreafico F, Gandola L, Marchianò A, et al.
Brain magnetic resonance imaging after high-dose chemotherapy and radiotherapy for childhood brain tumors.
Int J Radiat Oncol Biol Phys. 2008; 70(4):1011-9 [PubMed] Related Publications
PURPOSE: Brain necrosis or other subacute iatrogenic reactions has been recognized as a potential complication of radiotherapy (RT), although the possible synergistic effects of high-dose chemotherapy and RT might have been underestimated.
METHODS AND MATERIALS: We reviewed the clinical and radiologic data of 49 consecutive children with malignant brain tumors treated with high-dose thiotepa and autologous hematopoietic stem cell rescue, preceded or followed by RT. The patients were assessed for neurocognitive tests to identify any correlation with magnetic resonance imaging (MRI) anomalies.
RESULTS: Of the 49 children, 18 (6 of 25 with high-grade gliomas and 12 of 24 with primitive neuroectodermal tumors) had abnormal brain MRI findings occurring a median of 8 months (range, 2-39 months) after RT and beginning to regress a median of 13 months (range, 2-26 months) after onset. The most common lesion pattern involved multiple pseudonodular, millimeter-size, T1-weighted unevenly enhancing, and T2-weighted hyperintense foci. Four patients with primitive neuroectodermal tumors also had subdural fluid leaks, with meningeal enhancement over the effusion. One-half of the patients had symptoms relating to the new radiographic findings. The MRI lesion-free survival rate was 74%+/-6% at 1 year and 57%+/-8% at 2 years. The number of marrow ablative courses correlated significantly to the incidence of radiographic anomalies. No significant difference was found in intelligent quotient scores between children with and without radiographic changes.
CONCLUSION: Multiple enhancing cerebral lesions were frequently seen on MRI scans soon after high-dose chemotherapy and RT. Such findings pose a major diagnostic challenge in terms of their differential diagnosis vis-à-vis recurrent tumor. Their correlation with neurocognitive results deserves further investigation.

Majolino I, Davoli M, Carnevalli E, et al.
Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma.
Leuk Lymphoma. 2007; 48(4):759-66 [PubMed] Related Publications
Fifty-three patients with multiple myeloma (MM) underwent an allogeneic stem cell transplant (HSCT) from their HLA identical siblings using a reduced-intensity conditioning consisting of thioteopa 5 mg/kg, fludarabine 90 mg/m(2), and melphalan 80 mg/m(2). Their median age was 52 years (range 38 - 68) and the interval from diagnosis 12 months. Forty-three patients (82%) had advanced disease and 33 had previously been treated with high-dose therapy with one (N = 21), or more (N = 12) autologus transplants. Ten (18%) had their allograft programmed after induction chemotherapy. The majority (N = 44) received peripheral blood as stem cell source. Acute graft-versus-host disease (GVHD) grade II - IV developed in 45%, but grade III - IV in only 5%. Cumulative incidence of chronic GVHD was 64%. Sixty-two per cent were in complete remission (CR) following transplantation. Transplant-related mortality was 13%. Relapse incidence was 32%. With a median follow-up of 22 months, 3-year overall survival is 45% and progression free survival (PFS) 37%. The thiotepa, fludarabine, and melphalan conditioning regimen can produce remissions in the majority of MM patients with a limited transplant mortality rate. When used as first line treatment the results of transplantation appear even more encouraging.

Termuhlen AM, Grovas A, Klopfenstein K, et al.
Autologous hematopoietic stem cell transplant with melphalan and thiotepa is safe and feasible in pediatric patients with low normalized glomerular filtration rate.
Pediatr Transplant. 2006; 10(7):830-4 [PubMed] Related Publications
Normalized glomerular filtration rate (nGFR) <60 mL/min/1.73 m(2) often precludes hematopoietic stem cell transplant (HSCT) in pediatric patients. Three patients with nGFR < 60 mL/min/1.73 m(2) enrolled on an institutional phase I trial of HSCT preparative therapy for advanced and recurrent solid tumors with escalating melphalan, ranging from 135 to 180 mg/m(2), thiotepa (600 mg/m(2)), and vincristine (2 mg/m(2)). An additional patient with low nGFR was treated with the same preparative therapy. None of the patients developed acute renal failure, excess toxicities during HSCT or delayed engraftment. These cases demonstrate that it is feasible and safe to perform HSCT in pediatric patients with low nGFR using melphalan- and thiotepa-based preparative therapy.

Fenske TS, Kahl BS, Eickhoff J, et al.
Excessive toxicity of the high dose thiotepa and etoposide regimen when combined with radiation: Long-term autologous transplantation experience in follicular and mantle cell lymphoma.
Leuk Lymphoma. 2005; 46(10):1441-8 [PubMed] Related Publications
We recently described a novel thiotepa plus etoposide high-dose therapy (HDT) conditioning regimen for aggressive histology non-Hodgkin's lymphoma (NHL) that had low regimen-related toxicity (RRT) and an efficacy rate comparable to other NHL HDT regimens. In this report, we describe the UW experience with the addition of total body irradiation (TBI) and pre-transplant involved-field radiation (IFRT) to the thiotepa + etoposide HDT regimen. Between 1992 and 1999, 28 patients with indolent or mantle cell lymphoma were treated on this protocol. With a median follow-up of 64 mo, the median event-free survival (EFS) was 24 months, and the median overall survival (OS) had not been reached. The median number of grade 3 - 4 non-hematologic toxicities was five. There were five deaths (18%) in the first three months after HDT due to RRT. In contrast, the thiotepa + etoposide conditioning regimen (without TBI or IFRT) given to 65 intermediate grade NHL patients resulted in only one treatment-related death and considerably fewer grade 3 - 4 toxicities. Given the relatively short EFS in this cohort of indolent NHL patients, we conclude that the combination of IFRT and TBI plus thiotepa and etoposide resulted in a HDT regimen with excessive toxicity and this protocol was closed at our institution.

Valteau-Couanet D, Fillipini B, Benhamou E, et al.
High-dose busulfan and thiotepa followed by autologous stem cell transplantation (ASCT) in previously irradiated medulloblastoma patients: high toxicity and lack of efficacy.
Bone Marrow Transplant. 2005; 36(11):939-45 [PubMed] Related Publications
We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma.

de Jonge ME, Huitema AD, Holtkamp MJ, et al.
Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism.
Cancer Chemother Pharmacol. 2005; 56(4):370-8 [PubMed] Related Publications
BACKGROUND: Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist aprepitant in addition to standard anti-emetic therapy. As aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of aprepitant in the CTC regimen are reported.
PATIENTS AND METHODS: Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m2/day), thiotepa (120 mg/m2/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without aprepitant. Inhibitory activity of aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes.
RESULTS: In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC50) of aprepitant for inhibition of cyclophosphamide (IC50=1.3 microg/ml) and thiotepa (IC50=0.27 microg/ml) metabolism were within the therapeutic range. Patients receiving aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001).
CONCLUSION: Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy.

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