Infusion Of Etoposide Research Articles

Higher Expressions of PTH Receptor Type 1 and/or 2 in Bone Marrow Is Associated to Longer Survival in Newly Diagnosed Myeloma Patients Enrolled in Total Therapy 3

Higher Expressions of PTH Receptor Type 1 and/or 2 in Bone Marrow is Associated to Longer Survival in Newly Diagnosed Myeloma Patients Enrolled in Total Therapy 3 INTRODUCTIONThe Total Therapy 3 enrolled 303 newly diagnosed multiple myeloma patients at Myeloma Institute for Research and Therapy. Protocol included 2 cycles of VTD-PACE (bortezomib, thalidomide, and dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, and etoposide) as induction and consolidation therapy after melphalan-based tandem transplantation, which is followed by 3 years of intended maintenance with VTD in year 1 and thalidomide/dexamethasone in years 2 and 3. As part of the protocol, gene expression profiling was performed from baseline bone marrow biopsy samples in 178 individuals.We have previously reported the clinical correlation between response to bortezomib and serum parathyroid hormone variations in myeloma patients as well as the interaction between receptor 1 and proteasome inhibitors function in cell line and myeloma mouse model.In this study we examine the PTH receptor 1 and 2 expression levels and their correlation to survival in total therapy 3 enrolled patients. METHODGene expression profiling was performed using Affymetrix U133 plus 2.0 Microarrays (Santa Clara, CA) in baseline bone marrow biopsy samples from 178 patients enrolled on total therapy 3. Of these 178 patients, 108 were male. The overall median age of these patients was 59 years old at enrollment; 10 % of patients were considered to have high risk disease by 70 GEP model. Cox proportional hazards analysis was performed on the MAS5 normalized log 2 expression values of PTH1R and PTH2R using overall survival as the end point. Optimal dichotomous break points were found for PTH1R and PTH2R that corresponded to the maximum log rank test statistic from all cox proportional hazard models examined. To confirm PTH receptor expression in bone marrow, we performed real-time PCR using Taqman probes (PTH1R: Assay ID Hs00174895_m1 and PTH2R: Assay ID Hs00175044_m1) on subset of samples. RESULTSBased on cox proportional hazards regression of PTH1R and PTH2R expression values, patients with higher PTH1R and PTH2R expression demonstrated better survival compared to lower expressing patients. PTH1R expression above optimal break point of 8.92 had a hazard ratio of 0.583 with a 95% confidence interval of (0.351, 0.969) and logrank test p-value of 0.035. PTH2R expression above optimal break point of 6.85 had a hazard ratio of 0.541 with a 95% confidence interval of (0.323, 0.905) and logrank test p-value of 0.018. Furthermore, the patients that were lower expressed in both PTH1R and PTH2R performed significantly poorer in outcome (n= 24 and median survival of 4.52 years logrank p-value+5.71e-05).Real-time PCR using Taqman probes was able to demonstrate relatively high levels of PTH1R and PTHR2 transcripts at bone marrow level. [Display omitted] CONCLUSIONSThis is the first report indicating that PTH receptors type 1 and 2 gene expression levels are positively associated to overall survival in symptomatic multiple myeloma patients. Also we describe the presence of PTH2R at bone marrow level which function appear associated to myeloma control. These data confirm the correlation and close interaction between the survival of multiple myeloma patients and the parathyroid hormone axis. DisclosuresZangari:Norvartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees. van Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity’s Board of Directors or advisory committees; The Binding Site: Membership on an entity’s Board of Directors or advisory committees; MMRF: Membership on an entity’s Board of Directors or advisory committees.

P67 * DEFINING A TARGET INTRA-CEREBROSPINAL FLUID STEADY STATE ETOPOSIDE CONCENTRATION [CSF ETOPOSIDE] FOR PHASE I STUDY IN CHILDREN WITH LEPTOMENINGEAL METASTASIS (LM): INTREPID, A FIRST IN MAN STUDY

INTRODUCTION: Continuous intra-CSF etoposide infusion may optimise etoposide pharmacokinetics by bypassing the blood-brain-barrier and compensating for CSF bulk flow removal, at < 1/340th dose of standard regimens. A 3 + 3 phase I study is proposed, escalating target [CSF etoposide] and infusion durations of intra-CSF etoposide in children with LM. We justify target [CSF etoposide] and infusion durations based upon previously reported clinical and our own preclinical studies. METHOD: AUC24 values were calculated from Fleischhack report of 24 patients receiving intra-ventricular etoposide at 0.25 mg/12h, 0.5 mg/24h or 1 mg/24h, for 5 days, q 2-4 wks (n = 119 cycles), no dose limiting toxicity was reported. The AUC24 values derived from these clinical studies were compared to etoposide cytotoxicity data in human tumour and neural stem cell 3D co-cultures. AUC values were selected to derive target [CSF etoposide], levels 1 & 2 for infusion durations of 7, 10 and 14 days: AUC24= [CSF etoposide] x time (h). RESULTS: Based upon 0.25 mg/12h dose level, the AUC24 25 µg x h/ml (level 1) predicted [CSF etoposide] 1 µg/ml over 24 hours and an AUC7day of 175 µg x h/ml. The cytotoxicity assay [etoposide] of 0.8-1.2 µg/ml resulted in 22% neural stem cell and 8% tumour cell viability, illustrating differential toxicity. Level 1[CSF etoposide] was selected as 0.8 µg/ml as equivalent of AUC24 20, for 7 days (AUC7day 140). Level 2 [CSF etoposide] of 1.2 µg/ml was selected, (AUC7day 210, AUC10days 300; AUC14day 420). CONCLUSION: Target [CSF etoposide] will be 0.8 µg/ml (level 1) to 1.2 µg/ml (level 2), with infusion durations of 7, 10 or 14 day.

Combination of gemcitabine, l-asparaginase, and oxaliplatin (GELOX) is superior to EPOCH or CHOP in the treatment of patients with stage IE/IIE extranodal natural killer/T cell lymphoma: a retrospective study in a cohort of 227 patients with long-term follow-up

Optimal treatment strategies for localized extranodal natural killer/T cell lymphoma (ENKTL) have not been fully defined. We retrospectively compared the efficacy and safety of combined gemcitabine, L-asparaginase, and oxaliplatin (GELOX) (n=38), continuous infusion of etoposide, vincristine and doxorubicin, with cyclophosphamide and prednisone (EPOCH) (n=54), or combined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n=135) as induction chemotherapy in patients who were newly diagnosed with stage I/II ENKTL. After induction chemotherapy, the complete response (CR) rate and overall response rate (ORR) for the GELOX group were significantly higher than those in the EPOCH group (68.4 vs. 42.6%, P=0.011 for CR and 86.8 vs. 68.5%, P=0.038 for ORR). Both EPOCH and GELOX groups can attain much higher CR rates than CHOP group (CR rate was 31.8%, P<0.05). The 3-year overall survival (OS) and progression-free survival (PFS) rate were significantly better in GELOX group than in EPOCH or CHOP group (87.0 vs. 54.0 vs. 54.0% for OS, P<0.05; 72.0 vs. 50.0 vs. 43.0% for PFS, P<0.05). However, no significant differences were found between EPOCH and CHOP groups in OS or PFS (P=0.765 for OS, and 0.421 for PFS). The safety profiles were acceptable in all three groups. In conclusion, GELOX is superior to EPOCH or CHOP in the treatment of patients with stage I/II ENKTL. Further clinical trials of ENKTL should use asparaginase-based regimens as the standard chemotherapy.

VDTPACE As Salvage Therapy For Heavily Pretreated MM Patients

DTPACE is a combination chemotherapy regimen using dexamethasone, thalidomide and a 4-day (d) continuous infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide. It integrates components of CAD (cyclophosphamide, doxorubicin, dexamethasone) and DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), both of which were components of the Arkansas Total Therapy 2 (TT2) approach to multiple myeloma (MM) treatment. Most recently, DTPACE has been combined with bortezomib (VDTPACE) as induction and consolidation after tandem transplantation as part of Total Therapy 3 (TT3). Limited experience suggests that DTPACE, reduces disease burden as a salvage regimen for aggressive MM or plasma cell leukaemia (PCL) resistant to conventional therapies. In heavily pretreated myeloma, DTPACE has advantages as it uses a number of agents to which the typical MM patient has not previously been exposed, some of which penetrate the blood brain barrier and thus may be effective for leptomeningeal myeloma. On the contrary not enough data are available about the role of VDTPACE as salvage therapy in MM patients. To this scope, we identifed a total of 16 patients who received VDTPACE for relapsed/refractory MM. All patients were heavily pretreated (median three prior regimens, range 1-6; prior autologous stem cell transplant [ASCT] 38%). Five of these patients (31%) had developed very aggressive MM complications, such as extramedullary disease. The VDTPACE regimen consisted of high-dose dexamethasone (40 mg orally daily for 4 d) and a 4-d continuous infusion of cisplatin (10 mg/sqm/d), doxorubicin (10 mg/sqm/d), cyclophosphamide (400 mg/sqm/d) and etoposide (40 mg/sqm/d). Bortezomib was administered intravenously at 1.0 mg/sqm (d 1,4,8,11) and thalidomide was given orally at 100 mg daily. A total of 4 cycles of VDTPACE were administered every 4-6 weeks. Response was graded using the International Myeloma Working Group uniform response criteria. Overall response rate was 63% (very-good partial response 7%, partial response 56%) with stable disease in an additional 12% of patients. Median progression-free survival (PFS) was 7 months (95% confdence interval [CI]:4.0 - 9.9). VDTPACE is an intensive regimen which was given in our cohort on an inpatient basis because myelotoxicity is common. The rates of grade 3-4 neutropenia (56%) and febrile neutropenia (56%) were high although GCSF support was used routinely as prophylaxis. The most common non-haematological toxicities were grade 1-2 metabolic abnormalities that were easily corrected. VDTPACE is an effective salvage therapy for heavily pretreated MM patients. In the era of new targeted, biologically active agents against MM, there are now many more options for refractory and relapsed disease. Unfortunately, many of these newer agents are costly and awaiting approval in a number of countries. Consequently, alternative therapies are needed. Although the overall response rate of 63% in this poor prognosis cohort is more than promising, the PFS is short, suggesting the best role for VDTPACE is in bridging to defnitive therapy, such as allo-transplantation.Table 1Patients CharacteristicsVTDPACE 16SexMale10(63%)Female6 (37%)Age of diagnosisMedian age60Range50-66MM SubtypeIgA4IgG11LCD1ISSI7II4III5Stage( Durie and Salmon)I2II1III13KaryotypeNormal10Abnormal6 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

An Exceptional Case of Atrial Fibrillation Arrhythmia Induced by Etoposide

Arrhythmia induced by etoposide is exceedingly rare. There are only a very few individual case histories of arrhythmias during etoposide infusion, including atrial fibrillation. Through this uncommon case, we propose to study the pathophysiology, the diagnosis and the management of this entity. We report a case of a 57-year-old man, without cardiac history, followed for endocrine tumor of the pancreas with liver metastases who had presented atrial fibrillation (AF) after etoposide infusion. It is important to consider cardiac monitoring during etoposide infusion in patients with known cardiac disease or at high risk of cardiac complications.

D(T)PACE as salvage therapy for aggressive or refractory multiple myeloma

Dexamethasone±thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T)PACE] is generally reserved as salvage therapy for aggressive multiple myeloma (MM) or plasma cell leukaemia (PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T)PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona. At time of D(T)PACE, 16 patients had PCL and three patients had leptomeningeal disease. Patients were heavily pretreated (median three prior regimens, range 1-12; prior autologous stem cell transplant [ASCT] 33%). Overall response rate was 49% (very-good partial response 16%, partial response 33%) with stable disease in an additional 36%. Median progression-free survival (PFS) was 5·5months (95% confidence interval [CI]:4·3-9·8); overall survival (OS) 14·0months (95% CI:8·7-19·3). Thirty-five patients proceeded to ASCT or clinical trial, with median PFS for this subset of 13·4months (95% CI:7·7-20·1) and OS 20·5months (95% CI:14·8-63·8). D(T)PACE is an effective salvage therapy for heavily pretreated MM patients. Although the overall response rate of 49% in this poor prognosis cohort is reasonable, the PFS is short, suggesting the best role for D(T)PACE is in bridging to definitive therapy, such as transplantation.

A Case of Systemic Lupus Erythematosus-Associated Hemophagocytic Lymphohistiocytosis Treated Successfully with an Etoposide Infusion

50세 여자 환자를 SLE 연관 HLH로 ì§„ë‹¨í•˜ê³ , ë©´ì—­ì–µì œì¹˜ë£Œì—ë„ í˜¸ì „ë˜ì§€ 않아 etoposide를 주사 후 í˜¸ì „ëœ 증례 1예를 ë³´ê³ í•˜ëŠ” 바이다. 중심 단어: 혈구포식 림프조직구증식증; ì—í† í¬ì‚¬ì´ë“œ; ì „ì‹ í™ë°˜ë£¨í‘¸ìŠ¤

Successful treatment with combined chemotherapy of two adult cases of hemophagocytic lymphohistiocytosis in recipients of umbilical cord blood cell transplantation

Hemophagocytic lymphohistiocytosis (HLH), which occurs during the early period following allogeneic hematopoietic stem cell transplantation (HSCT), is often difficult to diagnose. It is characterized by severe clinical manifestations and high mortality. Despite current therapeutic approaches, outcomes remain poor. Here, we summarize the cases of two patients who experienced engraftment failure and subsequently developed hematopoietic stem cell transplantation-hemophagocytic lymphohistiocytosis (HSCT-HLH). Both patients had high-risk hematological malignancies for which they underwent umbilical cord blood transplantation (UCBT) at our institution. Based on the presence of massive hemophagocytosis in their bone marrow specimens and the results of chimerism analysis, diagnosis of HSCT-HLH was made in both cases. A single infusion of low-dose etoposide was administered immediately to each patient. Four days after the injection, therapeutic efficacy was evaluated. As both cases showed an insufficient response to etoposide, we added vincristine and a medium dose of prednisolone. Clinical symptoms rapidly improved and stable engraftments were observed within a week. The first and second patients were alive 1008 and 232days after UCBT, respectively. The combined use of low-dose etoposide and vincristine plus prednisolone appears to be a promising treatment option for HSCT-HLH, without serious adverse side effects.

Developmental pharmacokinetics of etoposide in 67 children: lack of dexamethasone effect

A randomized clinical trial examined whether dexamethasone administration prior to ondansetron followed by etoposide and carboplatin infusions, and single-nucleotide polymorphisms (SNPs) of CYP3A4, CYP3A5 and MDR1 genes could modify etoposide pharmacokinetics in pediatric patients. Patients, 67 children, aged 14 weeks to 16.7 years, were treated for various malignancies and received either 3- or 5-day courses of etoposide and carboplatin: these two drugs were always administered after ondansetron infusion but combined or not with dexamethasone 5 mg/m²/day 30 min prior to etoposide infusion. Population pharmacokinetics was modeled using a non-linear mixed effect model program (Monolix version 31 s). Etoposide pharmacokinetics was ascribed to a 2-compartment model. The most significant covariate effect was bodyweight (BW), so the parameters were standardized to a 70-kg BW using the allometric ¾ or 1 power model for clearance (CL, Q) or volume terms (V), respectively. The population means for clearance and central volume of distribution were 2.05 l/h/70 kg and 9.21 l/70 kg with the corresponding between-subject variabilities, 0.26 and 0.28. Dexamethasone treatment had no effect on CL, either at the first or at the last administration occasion. CYP3A and MDR1 examined SNPs had no significant effect. Pharmacokinetics of etoposide was influenced by BW on an allometric basis in this pediatric population. Dexamethasone did not influence etoposide pharmacokinetics during these 3-5 days courses. These results should allow a better individualization of etoposide dosing in children.

EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation.

6536 Background: There is no standard chemotherapy regimen for patients (pts) with lymphoid malignancies being considered for reduced intensity allogeneic hematopoietic stem cell transplantation (RI-alloHSCT). The ideal regimen would result in disease control and recipient lymphocyte depletion and have limited toxicity. We developed a novel regimen consisting of continuous infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine ± rituximab, depending on CD20+ expression (EPOCH-FR). Methods: 147 pts, median age 50 yrs (range 21-71), with high-risk lymphoid malignancies (47% with chemo-resistant disease to last regimen, median 3 prior regimens [range 1-13]) were given EPOCH-FR (74% dose-adjusted) prior to RI-alloHSCT. Pts received 1 (48%), 2 (21%), or 3 (31%) cycles of EPOCH- FR until they were lymphodepleted (CD4+ count < 100/μl) or had progressive disease. Results: Overall response rate (RR) was 41% (16% CR, 25% PR); 39% had SD. RR of FCC/CLL>DLBCL/HL>TCL (p = 0.047). More EPOCH-FR cycles were associated with higher RR (17% vs. 33% vs. 84%) (p < 0.0001). 17% of pts with chemo-resistant disease had CR/PR. EPOCH- FR resulted in significant lymphodepletion (pretreatment median CD3+ = 574/μl, CD4+ = 244/μl, and CD8+ = 249/μl vs. posttreatment CD3+ = 184/μl, CD4+ = 97/μl and CD8+ = 68/μl (p < 0.0001). Pts with greater lymphodepletion of CD3+ (p=0.038) and CD4+ (p=0.017) were more likely to achieve CR/PR. Toxicity in 263 cycles included Grade 4 thrombocytopenia in 25%, neutropenia in 65%, and non-heme toxicity in 6%. Of 147 pts, 143 proceeded to RI-alloHSCT. Pts with greater lymphodepletion of CD3+ (p = 0.0007), CD4+ (p = 0.0004), and CD8+ (p = 0.0019) were more likely to achieve full donor lymphoid chimerism by Day +14 post-transplant. Following transplant, pts with CR/PR vs SD/PD to EPOCH-FR had median EFS = 77.4 vs. 4.8 mos (p < 0.0001) and OS = 98.5 vs. 16.2 mos (p = 0.0006) respectively. Conclusions: EPOCH-FR safely provides disease response and lymphodepletion in pts with lymphoid malignancies being considered for RI-alloHSCT. No significant financial relationships to disclose.

Abstract 3596: Comparison of intravenous microdialysis sampling to standard blood sampling to determine free etoposide exposure in non-human primates

Abstract Background: Microdialysis (MD) is a method for continuously sampling small molecules in tissue extracellular fluid in vivo. To determine if free (non-protein bound) drug exposure (AUC) in plasma could be accurately measured by MD under non-steady state conditions, we compared intravenous MD to standard serial plasma sampling during and after a short infusion of etoposide. Methods: CMA IView 64 catheters (10 mm PAES membrane with 20 kD MWT cutoff) were surgically implanted into the external jugular vein of Rhesus monkeys (Macaca mulatta). Catheter inflow and outflow tubing was tunneled subcutaneously from neck to the area on back between shoulder blades, brought through skin and attached to a MD pump (CMA 106 pump with fixed flow rate of 0.3 μL/min). The MD pump was secured in a fitted mesh jacket on the dorsum of the awake animal. Retrodialysis using 10 µM etoposide was used to measure in vivo relative recovery (RR) in each catheter. Following retrodialysis and catheter re-equilibration with normal saline, etoposide (5 mg/kg) was administered IV over 1 h. Serial plasma samples were collected during the infusion and for 8 h post-infusion. Free etoposide was extracted by ultrafiltration. MD samples were collected continuously over a single collection interval (0-9 h) or split into two collection intervals (0-3 h and 3-9 h). Etoposide was quantified using HPLC-electrochemical detection (linear range 0.05 - 10 μM). The etoposide concentration in MD samples was corrected for in vivo RR. The AUC was calculated by the linear trapezoidal method for serial plasma sampling and by summation of the concentration x time intervals for MD. Results: Simultaneous MD and serial plasma sampling was performed in 5 animals. The in vivo RR of etoposide ranged from 86.9 - 99.4%. The mean AUC0-9h for plasma free etoposide was 3.27 (median 3.81, range 2.11 - 5.15) μM·h. The mean AUC0-9h for MD sampling was 2.68 (median 3.02, range 1.75 - 3.65) μM·h. The mean ratio of AUCMD:AUCplasma was 0.81. The mean (95% CI) for the difference in the paired MD and plasma AUC was − 0.7 (−1.94, 0.54) µM·h. Conclusions: Quantitative MD sampling for pharmacokinetic studies is feasible and the in vivo RR of etoposide is high. Free etoposide exposure by MD slightly underestimates the AUC compared to serial plasma sampling. Intravenous MD sampling may be a promising alternative to standard plasma sampling for calculating free etoposide exposure. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3596.

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

AbstractRituximab plus intravenous bolus chemotherapy is a standard treatment for immunocompetent patients with B-cell non-Hodgkin lymphoma (NHL). Some studies have suggested that rituximab is associated with excessive toxicity in HIVassociated NHL, and that infusional chemotherapy may be more effective. We performed a randomized phase 2 trial of rituximab (375 mg/m2) given either concurrently before each infusional etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy cycle or sequentially (weekly for 6 weeks) after completion of all chemotherapy in HIV-associated NHL. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by intravenous bolus cyclophosphamide given every 21 days for 4 to 6 cycles. In the concurrent arm, 35 of 48 evaluable patients (73%; 95% confidence interval, 58%-85%) had a complete response. In the sequential arm, 29 of 53 evaluable patients (55%; 95% confidence interval, 41%-68%) had a complete response. The primary efficacy endpoint was met for the concurrent arm only. Toxicity was comparable in the 2 arms, although patients with a baseline CD4 count less than 50/μL had a high infectious death rate in the concurrent arm. We conclude that concurrent rituximab plus infusional EPOCH is an effective regimen for HIV-associated lymphoma. This study is registered at http://clinicaltrials.gov as NCT00049036.

Cisplatin, Etoposide and Continuous Infusion Bleomycin in Patients with Testicular Germ Cell Tumors: Efficacy and Toxicity Data from a Retrospective Study

We retrospectively reviewed medical charts of 54 patients who underwent orchidectomy for germ cell tumors (GCT) and received a regimen, given every 3 weeks, consisting of cisplatin 100 mg/m2 day 4 intravenous (i.v.), bleomycin 15 Units (U) day 1 i.v. push; bleomycin 10 U days 1-3 24 h i.v. continuous infusion (c.i.) and etoposide 100 mg/m2 days 1-5/i.v. (PEB). 53 of 54 patients achieved a complete remission without adjunctive surgery. At a median follow-up of 48.2 months (95%CI 41.7 - 54.8 months) all patients but one are alive with no evidence of disease recurrence. Patients receiving PEB experienced no pulmonary toxicity, nephrotoxicity nor neurological adverse events. PEB with c.i. bleomycin is an active regimen with a low rate of acute and late toxicity. The main limitations of our study are related to the retrospective analysis, the limited number of patients and the restricted follow-up time. A prolonged follow- up is necessary to evaluate long term toxicity and outcome.

Pharmacokinetic analysis of etoposide distribution after administration directly into the fourth ventricle in a piglet model

We hypothesize that infusion of chemotherapeutic agents directly into the fourth ventricle potentially may play a role in treating malignant posterior fossa brain tumors. Accordingly, we used a piglet model developed in our laboratory to test the safety of etoposide infusions into the fourth ventricle and to study the pharmacokinetics associated with these infusions. In 5 piglets, closed-tip silicone catheters were inserted into the fourth ventricle and lumbar cistern. Five consecutive daily infusions of etoposide (0.5 mg) were administered via the fourth ventricle catheter. Serum and CSF from both catheters were sampled for measurement of etoposide level by reversed-phase high performance liquid chromatography (HPLC). For CSF samples, area under the concentration-time curve (AUC) was calculated. Piglets underwent daily neurological examinations, a 4.7 Tesla MRI scan, and then were sacrificed for post-mortem brain examination. No neurological deficits or signs of meningitis were caused by intraventricular chemotherapy infusions. MRI scans showed catheter placement within the fourth ventricle but no signal changes in the brain stem or cerebellum. In all piglets, the mean fourth ventricular CSF peak etoposide level exceeded the mean peak lumbar etoposide levels by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC were noted at peaks (DeltaAUC = 3384196 ng h/ml with 95%CI: 1758625, 5009767, P = 0.0044) and at all collection time points (DeltaAUC = 1422977 ng h/ml with 95%CI: 732188, 2113766, P = 0.0046) but not at troughs (DeltaAUC = -29546 ng h/ml (95%CI: -147526, 88434.2, P = 0.5251). Serum etoposide was absent at two and four hours after intraventricular infusions in all animals. Pathological analysis demonstrated meningitis, choroid plexitis, and ependymitis in the fourth and occasionally lateral ventricles. Etoposide can be infused directly into the fourth ventricle without clinical or radiographic evidence of damage. Autopsy examination revealed ventriculitis and meningitis which did not have a clinical correlate. Etoposide does not distribute evenly throughout CSF spaces after administration into the fourth ventricle, and higher peak CSF levels are observed in the fourth ventricle than in the lumbar cistern.

G-CSF併用cytarabine, etoposide少量持続点滴療法にて寛解導入し得た,悪性リンパ腫の治療中に発症した治療関連性急性骨髄性白血病

G-CSF併用cytarabine, etoposide少量持続点滴療法にて寛解導入し得た,悪性リンパ腫の治療中に発症した治療関連性急性骨髄性白血病

Outcome of patients with recurrent medulloblastoma or central nervous system germinoma treated with low dose continuous intravenous etoposide along with dose‐intensive chemotherapy followed by autologous hematopoietic stem cell rescue

Adults and children with recurrent malignant central nervous system (CNS) tumors have a poor prognosis despite high dose chemotherapy with a conventional stem cell rescue regimen. In this study we evaluated the results of low dose, continuous infusion etoposide over 21 days added to a conventional high-dose regimen of carboplatin and thiotepa in eight patients with relapsed pediatric CNS tumors. Patients with high risk CNS tumors were treated with etoposide 25 mg/m(2)/day by continuous intravenous (IV) infusion from day -22 to day -2, carboplatin 667 mg/m(2)/dose IV (or area under the curve = 9 mg/ml/min according to the Calvert formula on days -8, -7, and -6, and thiotepa 300 mg/m(2)/dose IV on days -5, -4, and -3, followed by autologous hematopoietic stem cell rescue on day 0. Eight adults and children, with a mean age of 12.9 years (age range 5.6-27.8 years), with relapsed primary CNS tumors (metastatic medulloblastoma (7), germinoma (1)), were enrolled. The mean survival post-transplant was 4.8+ years, (range 8-160+ months). The 2- and 5-year overall survival rates were 75% and 50% respectively. None of the survivors required additional salvage irradiation. The strategy of low dose chronic exposure to a topoisomerase inhibitor along with ablative carboplatin and thiotepa with stem cell rescue showed promising survival outcomes in these relapsed patients. This treatment strategy deserves further evaluation in a larger group of high-risk or relapsed primary CNS tumors.

Chemotherapy administration directly into the fourth ventricle in a new piglet model

The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 microg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.

Distribution of Etoposide in Cerebrospinal Fluid After Infusions Into the Fourth Ventricle in Piglets

Introduction We hypothesize that infusion of chemotherapeutic agents directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. Previous experiments from our laboratory have demonstrated that etoposide can be administered into the fourth ventricle in piglets without causing neurological deficits or radiographic evidence of damage. The objective of this study was to compare etoposide levels in cerebrospinal fluid (CSF) samples from the fourth ventricle to etoposide levels in CSF samples from the lumbar cistern after such infusions. Methods We inserted a closed-tip silicone lumbar drain catheter into the fourth ventricle in 3 piglets via a posterior fossa craniectomy. In the same 3 piglets, we also inserted a catheter into the lumbar cistern via a limited lumbar laminectomy. Five consecutive daily infusions of etoposide (0.5 mg) were administered via the fourth ventricle catheter. CSF was sampled from both catheters for pharmacokinetic analysis by reversed-p...

Continuous drip infusion of low dose cytarabine and etoposide with granulocyte colony‐stimulating factor for elderly patients with acute myeloid leukaemia ineligible for intensive chemotherapy

The optimal strategy for the management of elderly patients with acute myeloid leukaemia (AML) is still controversial. We previously reported the effectiveness of low dose cytarabine (Ara-C) and etoposide (VP-16) (AV therapy) for those elderly AML patients ineligible for intensive chemotherapy. We initiated the present feasibility study to improve the efficacy by using glanulocyte-colony stimulating factor (G-CSF) with AV therapy (AVG therapy). The eligibility for enrolment was AML patients according to the World Health Organization (WHO) criteria who were over 60 years of age and who had difficulty in tolerating intensive chemotherapy due to their poor performance status (PS) or some comorbidities. They were given continuous drip infusion of Ara-C (20 mg/body) and VP-16 (50 mg/body) for 7-14 days, and were also simultaneously administered G-CSF (150 microg/m2) once daily. The median age of consecutively enrolled 25 patients was 73 years. Eighteen (72%) patients achieved complete remission (CR). The 1-year overall survival (OS) and the 3-year OS rates were 69% and 22%, respectively. The 1-year disease free survival (DFS) rate in CR patients was 44%. The major regimen related toxicities of grade 3 or 4 were only febrile neutropenia in 15 patients (60%). No regimen-related mortality was observed. AVG therapy was therefore found to be an effective and well-tolerated regimen for remission induction in elderly AML patients with poor PS or comorbidity.

Retrospective review of DPACE therapy for aggressive, refractory multiple myeloma (MM)

18500 Background: Oral dexamethasone ± thalidomide with a 4-day infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide (DPACE) is an effective induction therapy prior to transplant in patients (pts) with MM. Limited experience also suggests DPACE may reduce disease burden as a salvage regimen for aggressive, refractory MM. Methods: We performed a retrospective review from 1999- 2005 of all MM pts who received DPACE ± thalidomide as a salvage regimen at our center. Results: A total of 39 pts received DPACE at a median 23 mos from diagnosis (range, 10–84). Median age was 53 years (34–70), 51% stage 3 at diagnosis. Plasma cell leukemia had developed in 12 pts and leptomeningeal disease in 4 pts at time of DPACE. Ten of 24 pts (42%) with cytogenetics had del 13q. Pts were heavily pretreated (median 3 prior regimens; prior autotransplant [ASCT] 38%; thalidomide 64%; and bortezomib 10%). Pts received 1–4 cycles as tolerated for refractory (83%) or relapsed (17%) disease. Thalidomide was used in 41% of cycles. Hematologic toxicity was common (grade 3–4 neutropenia 92% and thrombocytopenia 72%). Although G-CSF was used in 71% of cycles, febrile neutropenia was common (53%) and 26% required hospitalization. Overall RR was 36% (14 pts: PR 12, VGPR 2). An additional 8% achieved MR, 23% SD. PD occurred in 15% and 18% died on therapy (4 progressive MM; 2 neutropenic sepsis, 1 GI bleed). No prior ASCT (p=0.04) and &lt;4 prior regimens (p=0.04) predicted for response to DPACE. Eleven pts proceeded to ASCT and one pt to a clinical trial with lenalidomide with a median OS from DPACE of 24.7 mos (95% CI, 11.2–63.6). Those who did not bridge to transplant or trial (n=27) had a short median PFS of 3.0 months (95% CI, 1.2–5.5) and OS of 6.7 mos (95% CI, 1.8–9.7). OS for all 39 pts was 8.7 mos (95% CI, 6.4–12.4). Conclusion: DPACE may be effective salvage therapy for heavily pretreated MM pts. Although the RR of 36% in this poor prognosis cohort is reasonable, the PFS is short and suggests that the best role for this regimen is in bridging to more definitive therapy such as transplantation. [Table: see text]