Low-dose Etoposide Research Articles

Abstract 2145: Elimination of multidrug-resistant glioma cells using unique sequence of high-intensity focused ultrasound and low-dose generic chemotherapeutic

Abstract BACKGROUND Despite medical advances, multidrug-resistant (MDR) gliomas continue to challenge the patients. In this study, I evaluate a new strategy in which the unique sequence of High-Intensity Focused Ultrasound (HIFU) and low-dose generic chemotherapeutic is utilized to attack MDR glioma cells. METHODS This strategy, motivated by recent clinical trials in which HIFU was used to non-invasively disrupt the blood-brain barrier and to treat brain tumors, led to the in vitro study during which human glioma cell line U87 (ATCC), modified for overexpression of epidermal growth factor receptor (EGFR), was paradoxically treated with low-dose Etoposide (VP-16). Day 1: Each data sample consisted of ∼10K cells grown inside a well of 8-well glass slides (Lab-Tek). Each slide was then filled with growth media, sealed, submerged in a 37ºC degassed water bath and secured onto a fixture. The targets for HIFU therapy are the center points of the 4 quadrants of each well's base. The constant HIFU parameters for each slide were acoustic pressure 4.5 MPa, repetition rate 1 Hz, focal-zone depth and 30 sec/sonication/center point while HIFU duty cycle (DC) ranged 0-50% among slides. After HIFU treatment, the slides were incubated for 24h. Day 2: Cell media for each slide was replaced with fresh media containing [VP-16] 0-100 uM prior to repeating the HIFU procedure from day 1. Day 4: After 48h of exposure to VP-16, cell survivability study was performed using cell-count technique to determine the contribution of HIFU-mediated necrosis as well as VP-16-mediated apoptosis. RESULTS Cell survivability decreased by increasing [VP-16] or HIFU DC. In VP-16-only group (HIFU DC 0%), average survivability was 85% (n = 4) at [VP-16] 1 uM. In HIFU-only group ([VP-16] 0 uM), average survivability was 34% (n = 4) at DC 50%. In contrast, average survivability was 12% (n = 4), using [VP-16] 1 uM and DC 50%. CONCLUSION The unique sequence of HIFU and low-dose Etoposide virtually eliminated MDR glioma cells on day 4. in vitro Treatment of Multidrug-Resistant Glioma Cell Line U87 Using HIFU-Etoposide Sequence[Etoposide] = [VP-16], (uM)00.5151050100Average cell survivability (%) ± SD on day 4 (Etoposide only; DC 0%; n = 4)100 ± 47 (control)62 ± 2385 ± 1341 ± 537 ± 725 ± 421 ± 6Average cell survivability (%) ± SD on day 4 (DC 50%; n = 4)34 ± 5 (HIFU only)14 ± 712 ± 66 ± 24 ± 23 ± 14 ± 1Note: The above data suggests that, in principle, drug resistance may be reversible and that the unique sequence of HIFU and a low-dose generic drug may be a promising alternative to current treatments (multidrug regimen, surgery or radiotherapy) against other MDR solid cancers. In addition to high efficacy within a relatively short time, the low cost and the potential absence of drug side effects from using low-dose generic chemotherapeutic are exciting motivations to further investigate this new cancer treatment in animal studies. Citation Format: Howard Q. Vo. Elimination of multidrug-resistant glioma cells using unique sequence of high-intensity focused ultrasound and low-dose generic chemotherapeutic. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2145.

Azacitidine with Oral Cytarabine and Etoposide Induces Immediate Hematological and Cytogenetic Response in Higher Risk Myelodysplastic Syndromes Even in Single Azacitidine Resistance

Background: Although azacitidine (AZA) induces high hematological response and delayed progression to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes (MDSs), its cytotoxic and cytogenetic effects are relatively poor. Moreover, the prognosis of patients at very high risk in the revised international prognostic scoring system (IPSS-R), with poor cytogenetics including complex abnormalities and monosomy 7, and with AZA resistance is extremely poor. Therefore, AZA-based combination therapy with low toxicity is warranted. In the past, effective low-dose etoposide (VP16) and cytarabine ocfosphate (SPAC) combination therapy for refractory MDS and AML was reported. Here, we report 10 higher-risk MDS and AML patients treated with AZA in combination with oral VP16 and SPAC.Patients and methods: AZA (75 mg/m2 daily for 7 days) in combination with SPAC (300 mg daily for 14 days) and VP16 (25 mg daily for 14 days) was administered to 10 patients (median age, 80 years; range, 48 to 90) with newly diagnosed (n=2) and previously AZA-treated (n=8) MDS and AML between December 2013 and April 2015. The diagnoses were RCMD (n=2), RAEB1 (n=2), RAEB2 (n=1), CMML (n=1), and AML-MRC (n=4). IPSS-R categories were low (n=1), intermediate (n=3), high (n=2), and very high (n=4). In 8 AZA-treated patients, its median cycle before this study was 11 (1-30). Results: In the pretreatment period, neutrophil count, platelet count, hemoglobin level, bone marrow blast rate, and WT1 were 805/µl (170-2700), 53.0 (25-222) × 109/l, 8.4 g/dl (7.2-13.5), 6.5% (1.4-30.0), and 1200 (200-31,000) copies/µg RNA, respectively. Five out of 10 had complex karyotype abnormalities. After 1 course of treatment, the overall response rate was 100%. The rate of any hematological improvement (HI) was 90% (9 out of 10) including HI-neutrophil (HI-N) for 67%, HI-platelet (HI-P) for 75%, and HI-erythroid (HI-E) for 0%. Marrow CR (mCR) and cytogenetic response rates were 67% (6 out of 9) and 83% (5 out of 6), respectively. Notably, 3 out of 4 complex abnormalities were also improved. Moreover, WT1 was decreased from 1200 to 60 copies/µg RNA. Interestingly, all (4 out of 4) of the patients with erythroblast hyperplasia or strong erythroid dysplasia exhibited HI-P, HI-N, blast decrease, and at least one log decrease of WT1 copy number. Owing to high marrow suppression including 100% of grade 3 to 4 neutropenia and all patients but 1 with grade 3 to 4 thrombocytopenia, the time to the second course was longer (43 days) than for single AZA. The times to elevation of neutrophils (>500/µl) and platelets (>50×109/L) were 35 and 37.5 days, respectively. Although 70% (7 out of 10) of patients suffered from infection including febrile neutropenia, no other grade 3 to 4 non-hematological adverse events (AEs) resulting in therapy-related death occurred. At present, four of 10 are continuing AZA without disease progression (PD), 2 patients discontinued it due to impaired quality of life (QOL) and the remaining 4 patients had PD (median 6 months). With a median follow-up time of 24 months from starting AZA alone or in combination, median OS was not reached.Conclusion: Our AZA-based combination therapy induced immediate cytotoxicity of malignant MDS clone with poor cytogenetics and single AZA resistance. SPAC, VP16 and AZA might promote effect of each other. However, prolonged marrow suppression resulted in severe infection, impaired QOL and a delayed treatment schedule. Therefore, response duration appeared to be relatively short, resulting in shorter survival. Appropriate dose setting and treatment duration, effective infection control methods such as G-CSF administration, and prophylactic antibiotics were warranted. However, this method did not require an intravenous drip and had good cost performance. Finally, our cohort is very small, so further experience is needed. DisclosuresNo relevant conflicts of interest to declare.

Mortality rate of gestational trophoblastic neoplasia with a FIGO score of ≥13

Gestational trophoblastic diseases include premalignant (partial and complete hydatidiform moles) and malignant entities referred to as gestational trophoblastic neoplasia. Use of the International Federation of Gynecology and Obstetrics prognostic score is encouraged in cases of gestational trophoblastic neoplasia to predict the potential for the development of resistance to single-agent chemotherapy. An International Federation of Gynecology and Obstetrics score of ≥7 defines a high-risk patient and requires combination chemotherapy. Appropriate and rapid diagnosis, treatment by specialized centers, and reduction of early deaths at the time of chemotherapy initiation have led to significant improvements in survival for patients with high-risk gestational trophoblastic neoplasia. There is a crucial need for the early identification of high-risk patients with gestational trophoblastic neoplasia who have an increased death risk to organize their treatment in highly specialized centers. The purpose of this study was to describe cases of gestational trophoblastic neoplasia that have resulted in death, particularly in a subgroup with an International Federation of Gynecology and Obstetrics prognostic score of ≥13, for whom low-dose etoposide and cisplatin induction chemotherapy recently was shown to reduce early death rate. We identified 974 patients from the French Center for Trophoblastic Diseases who had a diagnosis of gestational trophoblastic neoplasia from November 1999 to March 2014. Among 140 patients who were at high risk of resistance to single-agent chemotherapy (International Federation of Gynecology and Obstetrics score, ≥7), 29 patients (21%) had a score of ≥13. Mortality rate was estimated with the use of the Kaplan-Meier method. The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, was 2% for patients with gestational trophoblastic neoplasia (95% confidence interval, 1.25-3.13%). High-risk patients had a 5-year mortality rate of 12% (95% confidence interval, 7.49-18.9%). Patients with an International Federation of Gynecology and Obstetrics score of ≥13 had a higher 5-year mortality rate (38.4%; 95% confidence interval, 23.4-58.6%) and accounted for 52% of the deaths in the entire cohort. Early deaths, defined as those that occur within 4 weeks after treatment initiation, occurred in 8 patients of the entire cohort. Six of them had an International Federation of Gynecology and Obstetrics score of ≥13 at presentation, of whom 5 patients had brain and/or liver metastases. Gestational trophoblastic diseases with an International Federation of Gynecology and Obstetrics score of ≥13 have an increased risk of early death. We suggest that an International Federation of Gynecology and Obstetrics score of ≥13 becomes a consensual criterion for prediction of patients with gestational trophoblastic neoplasia with increased risk of death, particularly early death. These patients justify treatment in highly specialized gestational trophoblastic disease centers and may benefit from the use of induction low-dose etoposide and cisplatin.

Human herpesvirus 8-negative primary effusion lymphoma-like lymphoma with t(8;14)(q24;q32)

Primary effusion lymphoma (PEL) is a large B-cell lymphoma proliferating only in the body cavity effusion. It often occurs in advanced AIDS patients and is associated with human herpesvirus 8 (HHV-8). On the other hand, HHV-8 negative effusion lymphoma, which is different from PEL in many ways, has also been reported and is referred to as HHV8-unrelated PEL-like lymphoma. This lymphoma is very rare and its clinical characteristics have not yet been fully clarified. We therefore report an HIV seronegative elderly patient with HHV8-unrelated PEL-like lymphoma. An 89-year-old woman was admitted to our hospital due to general fatigue and dyspnea. The patient presented with left pleural effusion in the absence of lymphadenopathy and tumor masses. The pathological examination of the pleural effusion showed proliferation of atypical large lymphoid cells, which were positive for CD19, CD20, CD10, CD38, CD7, BCL2 and BCL6 but negative for CD5, CD30, MUM1, surface immunoglobulin, HHV-8 and EBV. Cytogenetic analysis showed a complex karyotype including t(8;14)(q24;q32). The pleural effusion decreased in response to monotherapy with oral low-dose etoposide, but recurrence was detected 7 months later. Rituximab was transiently effective for the recurrent pleural effusion, but the patient died of lymphoma exacerbation 13 months after the diagnosis.

Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer.

Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development.

Analysis of stably expressed genes with low-dose etoposide for toxicological studies in osteosarcoma

Analysis of stably expressed genes with low-dose etoposide for toxicological studies in osteosarcoma

Oral etoposide and oral prednisone for the treatment of castration resistant prostate cancer

Treatment options for patients with castration-resistant prostate cancer (CRPC) are limited. The purpose of our study was to investigate the safety and efficacy in terms of prostate-specific antigen (PSA) response of a low-dose oral combination of etoposide and prednisone in patients with CRPC. Thirty-nine patients with prostate cancer (median age, 77.9 years) with progressive disease after standard hormonal therapy were enrolled. Etoposide (25 mg, twice daily) and prednisone (5 mg, twice daily) were administered orally. Each cycle comprised 21 consecutive days of treatment followed by a 7-day drug holiday. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal prior to entry into the study. A total of 226 cycles were administered with a median of 6.7 cycles per patient (range, 1–18 cycles). Sixteen of 39 patients (41%) with elevated PSA levels at baseline achieved at least a 50% reduction in PSA levels. Median progression-free survival for all patients was 5.9 months (range, 1–17 months). No Grade 4 toxicities were observed. The predominant toxicities were mucositis, nausea, fatigue, and anemia in twelve, nine, eight, and seven patients, respectively. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. The combination of low-dose etoposide and prednisone is an efficacious and reasonably well-tolerated oral regimen in the treatment of elderly patients with CRPC. This regimen can be easily administered in an outpatient setting and does not require frequent patient visits.

Ataxia telangiectasia mutated‐dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor

Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its phosphorylation in an ATM-dependent manner after DNA damage. In vitro kinase assay and site-directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Serine 1512 to Alanine mutation of TOP2A showed increased stability of the protein, retaining TOP2A activity at least with regard to cell survival activity. Ataxia telangiectasia-derived cell lines showed high levels of TOP2A that were associated with hypersensitivity to the TOP2 inhibitor etoposide. These findings suggest that ATM-dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor. In a lymphoblastoid cell line derived from a patient who developed MLL rearrangement, positive infant leukemia, defective ATM expression, and increased TOP2A expression were shown. It was intriguing that hypersensitivity to TOP2 inhibitor and susceptibility to MLL gene rearrangement were shown by low-dose etoposide exposure in this cell line. Thus, our findings have clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment-associated secondary leukemia following exposure to TOP2 inhibitors.

EMA/CO for High-Risk Gestational Trophoblastic Neoplasia: Good Outcomes With Induction Low-Dose Etoposide-Cisplatin and Genetic Analysis

Patients with high-risk (International Federation of Gynecology and Obstetrics score ≥ 7) gestational trophoblastic neoplasia (GTN) frequently receive etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine (EMA/CO). Between 1979 and 1995, overall survival (OS) with this regimen at our institute was 85.4% with a significant proportion of early deaths (< 4 weeks). Here, we determine whether survival rates have improved in a more recent patient cohort (1995 to 2010). Patients receiving EMA/CO were identified using the Charing Cross GTN database. Genetic analysis identified nongestational trophoblastic tumors (nGTTs). The use of induction low-dose etoposide 100 mg/m(2) and cisplatin 20 mg/m(2) (EP; days 1 and 2 every 7 days) since 1995 to reduce early deaths before commencing EMA/CO was noted. Four hundred thirty-eight patients received EMA/CO between 1995 and 2010. Six patients had nGTTs, 140 had high-risk disease, and 250 had relapsed/resistant low-risk GTN. OS was 94.3% in high-risk patients (90.4% including nGTTs) and 99.6% in the low-risk group, with a median follow-up time of 4.2 years. All patients with nGTT and seven patients with high-risk GTNs died as a result of drug-resistant disease. EP induction chemotherapy was given to 23.1% of high-risk patients (33 of 140 patients) with a large disease burden, and the early death rate was only 0.7% (n = 1; 95% CI, 0.1% to 3.7%) compared with 7.2% (n = 11 of 151 patients; 95% CI, 4.1% to 12.6%) in the pre-1995 cohort. OS after EMA/CO for high-risk GTN has increased by nearly 9%. This reflects a more accurate estimate of OS by excluding nGTTs (3.9%) in patients with atypical presentations using genetic diagnosis. Low-dose induction EP in selected individuals also allows near complete elimination of early deaths. The latter should be considered routinely in high-risk GTN.

Efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.

115 Background: The purpose of this study is to determine the efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes. Methods: From June 2008 to April 2012, 22 women with MBC were enrolled and 16 patients were evaluable for toxicity and response. Treatment consisted of capecitabine (1,400 mg/m2 daily, taken in 2 oral doses) on days 1-14 and oral etoposide ( 30 mg/m2 daily ) on days 1-7 . Cycles were repeated every 3 weeks unless disease progression or unacceptable toxicity occurred or patient consent was withdrawn. The primary endpoint was clinical benefit rate (CR + PR + SD≥24 weeks); secondary endpoint was toxicity and time to progression (TTP). Tumor response was evaluated by RECIST criteria, and adverse events were evaluated by NCI-CTC AE v3.0. Results: Sixteen patients were included and received 145 cycles of chemotherapy, with a median of 7 cycles (range, 2-26 cycles). One of the 16 patients had partial response (PR 6.25%), 10 showed stable disease (SD 62.5%) and 5 had progression of disease (PD 31.25%), with a clinical benefit rate of 50% (CR + PR + SD≥24 weeks). Median TTP was 5.0 months (range, 1.5-20 months), and mean TTP was 6.06 months. Adverse effects were mild, and the main adverse effects were leucopenia (13%) and fatigue (13%). All patients are survival till now. Conclusions: An all-oral combination of low-dose etoposide plus capecitabine is a new regimen and has showed effective in treating MBC patients and can be well tolerated. It’s very economic compared with most other schedules today. It is worthy of further study on a large scale, especially in the developing countries.

Primary cutaneous anaplastic large cell lymphoma with subsequent leg involvement

Primary cutaneous anaplastic large cell lymphoma (CALCL) is regarded as an indolent type of cutaneous T-cell lymphoma. However, a few recent publications revealed that C-ALCL patients with initial leg involvement had significantly worse survival than those without initial leg involvement. Herein, we report a case of C-ALCL with subsequent leg involvement, which led to death after chemoradiation therapy. A 75 years old Japanese man presented with multiple erythematous nodules in his left arm and the side of his left chest. Histopathological and immunohistochemical studies led to the diagnosis of primary C-ALCL. At the initial diagnosis, no leg lesion was found. One year after the initial diagnosis, C-ALCL appeared in his right lower thigh and left hip. Radiation therapy, low-dose etoposide and CHOP therapy were performed; however, the patient died of malignant lymphoma 4 years after the initial diagnosis. We speculated that the occurrence of subsequent leg involvement may also be indicative of a worse prognosis, as in the case with initial leg involvement in C-ALCL. Therefore, we propose that C-ALCL patients with initial or subsequent leg involvement should be classified as a distinct clini copathological variant of C-ALCL (“leg -type ” involvement) and that they may require intense therapy.

Successful treatment with low-dose etoposide for hemophagocytic syndrome following reduced-intensity conditioning for cord blood transplantation in a patient with acute myelgenous leukemia

Successful treatment with low-dose etoposide for hemophagocytic syndrome following reduced-intensity conditioning for cord blood transplantation in a patient with acute myelgenous leukemia

Enhanced Antitumor Efficacy of Low-Dose Etoposide with Oncolytic Herpes Simplex Virus in Human Glioblastoma Stem Cell Xenografts

Glioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), has been implicated in this recurrence. The chemotherapeutic agent etoposide is generally reserved for treating recurrent tumors; however, its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low-dose etoposide with an oncolytic HSV to enhance antitumor activity and limit drug toxicity. In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47Δ alone, or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method, and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events, and histologic detection of apoptosis. GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47Δ was similar. Combining G47Δ with low-dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low-dose etoposide with G47Δ significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors. The combination of low-dose etoposide with G47Δ increases survival of mice-bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.

Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children

To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data. Simulations were performed with PK-Sim(®) (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis-Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group. Simulated plasma concentration-time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70ml/min/kg (Cl(observed): 0.70ml/min/kg) versus 0.50ml/min/kg (Cl(observed): 0.60 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated. The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children.

Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome

Allogeneic stem cell transplantation (SCT) offers the best chance of cure and long-term survival for children with myelodysplastic syndromes (MDS). Retrospective analysis of pediatric patients with primary MDS treated with allogeneic SCT at a single institution treated between January 1993 and December 2008. Of 16 consecutive children who received allogeneic SCT for treatment of MDS in our center, 14 patients met the criteria of MDS according WHO I and II criteria. The median age was 4.8 years (range, 1-14 years) and 64% were male. The median time from diagnosis to transplant was 6 months. MDS stage was refractory cytopenia (RC) in 9, refractory anemia with excess blasts (RAEB) in 5. Monosomy 7 was present in 35% of the patients. The majority of patients (11/14) were conditioned with a busulfan-based myeloablative (MA) regimen with addition of low-dose of etoposide (30 mg/kg). All but one received a bone marrow graft. Nine patients achieved complete remission (CR), and seven remain alive. At a median follow-up of 3 years (range, 2-14 years) the OS and EFS was 57% (95%CI, 0.28-0.78). Cumulative EFS at 10 years was 43% (95% CI, 0.14-0.70). Relapse-related mortality was 21.4%; nonrelapse mortality (NRM) was 28.57%. All the survivors had etoposide in their conditioning regimen. Patients younger than 10 years had better survival (P=.001). Children with MDS achieve encouraging OS and EFS following allogeneic SCT. A busulfan-based regimen with a lower dose of etoposide is an effective and less toxic regimen. The outcomes are best in younger patients.

A single-center experience of EMA/CO chemotherapy for high-risk gestational trophoblastic neoplasia: Induction low-dose cisplatin and etoposide chemotherapy improves outcome.

5024 Background: Patients with Gestational Trophoblastic Neoplasia (GTN) classified as high risk, or who fail low risk single agent chemotherapy usually receive etoposide, methotrexate and actinomycin D alternating weekly with cyclophosphamide and vincristine (EMA/CO). At our institute overall survival (OS) after EMA/CO was 87% between 1979-1995. Here we compare a more recent patient cohort (1994-2010) to determine whether survival rates have improved. Methods: The Charing Cross GTD database was screened for patients who received EMA/CO chemotherapy between Jan 1994 and 2010. Patient characteristics and outcomes were recorded. Pathology was centrally reviewed and patients with PSTT or non-gestational tumours were excluded. The introduction in 1994 and use of low-dose etoposide 100mg/m2 and cisplatin 20mg/m2 (EP) on days 1 and 2 repeated weekly as induction chemotherapy for 1-2 weeks before commencing EMA/CO was noted. Results: EMA/CO was given to 442 patients. This was first line therapy for 170 with high risk disease, and second line for 278 failing single agent chemotherapy. OS (median follow-up 4.29 years) was 98% (9 deaths / 442 pts; 95% CI : 96.6-99.3%)in the modern, compared to 87% (95% CI : 81.9 - 90.5%) in our previous cohort. This was not explained by an increase in low-risk patients receiving EMA/CO. EP-induction chemotherapy was given to 21% (35/170) of high risk patients who were significantly more likely to have a high disease burden (FIGO score >8 and > 6 metastases (p<0.01)). Strikingly, this correlated with a reduction in early deaths from 4% (95% CI : 1.9-6.9) in the early pre-EP cohort to 0.2% (95% CI : 0-0.65%) in the current cohort. Of the remaining 8 patients, 7 died due to drug resistance, and one of pulmonary embolism post surgery. Conclusions: Overall survival following EMA/CO for GTN has improved significantly from 87% to 98% in our recent patient cohort. This is partly due to the introduction of low-dose EP-induction chemotherapy for patients with advanced disease. Low dose EP induction chemotherapy should be routinely considered for patients with a FIGO score >8 and metastasis score >6 to minimise the risk of early deaths.

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.

Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy

Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.

Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy

Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.

Intracavitary chemotherapy (Gliadel®) and oral low-dose etoposide for recurrent anaplastic ependymoma

Anaplastic ependymoma is associated with a higher incidence of tumor recurrence and its prognosis still remains unsatisfactory. Consolidated therapy for ependymoma includes surgery followed by focal radiotherapy when resection is incomplete. In the case of relapse treatment, options are limited especially for patients who have already received radiotherapy. We sought to establish the feasibility of administering low-dose oral etoposide (50 mg/m(2)/day for 21 days) in combination with the implantation of intracavitary carmustine (BCNU) wafers (Gliadel) at the gross total resection for achieving synergistic treatment in three children affected by recurrent anaplastic ependymoma. All patients had Karnofsky performance scale (KPS) scores >80%. The therapy was tolerated safely and well in all patients without any post-surgery complications. After BCNU wafer implantation, all patients achieved radiological and clinical stabilization for an average period of 3 months. Two patients relapsed after 4 months as shown in brain MRIs. The other patient went to progression two months after the Gliadel implantation. This multimodal approach was not effective for the treatment of refractory anaplastic ependymoma and further studies are required in order to define the role of the combination of multidrug systemic chemotherapy with BCNU wafer implantation in children with high-risk brain tumors.