scholarly journals High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008

2019 ◽  
Vol 37 (34) ◽  
pp. 3192-3202 ◽  
Author(s):  
Uta Dirksen ◽  
Bernadette Brennan ◽  
Marie-Cécile Le Deley ◽  
Nathalie Cozic ◽  
Henk van den Berg ◽  
...  

PURPOSE The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 672-672 ◽  
Author(s):  
A. R. Zander ◽  
N. Kroeger ◽  
C. Schmoor ◽  
W. Krueger ◽  
V. Moebus ◽  
...  

672 Background: Investigation of high dose chemotherapy (HD-CT) supported by autologous hematopoietic stem cell transplantation compared with standard dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more axillary lymph nodes. Methods: Between November 1993 and September 2000 307 patients were randomized to receive the following cycles of Epirubicin (90 mg/m2), Cyclophosphamide (600 mg/m2) intervenously (every 21 days) either HD-CT of Cyclophosphamide (1500 mg/m2), Thiotepa (150 mg/m2) and Mitoxantrone (10 mg/m2) intervenously for 4 consecutive days followed by stem cell transplantation or standard dose chemotherapy SDCT in 3 cycles of Cyclophosphamide (500 mg/m2), Methotrexate (40 mg/m2) and Fluoruracil (600 mg/m2) intervenously on days 1 and 8 every 28 days. The primary end points were event-free survival and overall survival. Results: After a median follow-up of 6.1 years 166 events with respect to event-free survival (SD-CT: 91, HD-CT: 75) and 123 with respect to overall survival (SD-CT: 66 and HD-CT: 57) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0,80, p = 0,15. The hazard ratio for overall survival for high dose chemotherapy versus standard dose chemotherapy is estimated as 0,84, p = 0,33. Analysing the effect of treatment on event-free survival premenopausal patients, patients with tumor grade III and ER-positive patients had a better outcome with HD-CT with an interactive effect of 2.5 and 1.4. The significance was only shown in grade III patients in favour of HD-CT, (p = 0,049). The interactive effect of HD-CT with prognostic factors did not reach significance for overall survival. Conclusion: Even with a follow-up of 6.1 years there was only a trend in favour of high dose chemotherapy with respect to overall survival but without a statistical significance. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients which might benefit from this treatment approach. No significant financial relationships to disclose.


2020 ◽  
Author(s):  
Jie Jiang ◽  
Chong Liu ◽  
Guoyong Xu ◽  
Tuo Liang ◽  
Chaojie Yu ◽  
...  

Abstract Background: Ewing's sarcoma (ES) is the second most prevalent malignancy among bone tissue tumors, and there is no adequate prognosis biomarker. The protein encoded by CCT6A is a molecular chaperone. Early studies have suggested that CCT6A is involved in the development of many cancers, however, there is no clear evidence of a role for CCT6A in ES.Methods: In this study, we performed a bioinformatics analysis of 32 Ewing sarcoma specimens from the GSE17618 dataset for differences in gene expression and overall survival, event-free survival, and gene expression in different subgroups. Results: After three screenings, we identified CCT6A as highly correlated with Ewing's sarcoma prognosis. Survival analysis showed low overall survival (OS) for CCT6A high expression (P=0.024). On the other hand, Cox regression analysis showed that CCT6A expression, event-free survival (EFS), and age were strongly associated with the prognosis of Ewing sarcoma, identified as independent poor prognostic biomarkers. (CCT6A: P=0.015; Age: P-value=0.026; EFS: P-value=0.001). Conclusion: The expression level of CCT6A is strongly associated with the prognosis of Ewing's sarcoma. High expression of the CCT6A gene may serve as a biomarker for poor prognosis in patients with Ewing's sarcoma.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2966-2966
Author(s):  
Cornelia Becker ◽  
Rainer Krahl ◽  
Antje Schulze ◽  
Georg Maschmeyer ◽  
Christian Junghanß ◽  
...  

Abstract Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) > 109/l and median platelets (plt) > 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p<10−6) and for EFS (p<10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (>1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p<10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.


Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2540-2544 ◽  
Author(s):  
Catherine Sebban ◽  
Nicolas Mounier ◽  
Nicole Brousse ◽  
Coralie Belanger ◽  
Pauline Brice ◽  
...  

AbstractThe purpose of this study is to compare our standard chemotherapy regimen (CHVP [cyclophosphamide, doxorubicin, teniposide, and prednisone]) plus interferon with 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) in treatment-naive patients with advanced follicular lymphoma. Four hundred one patients were included from July 1994 to March 2001: 209 received 12 cycles of CHVP plus interferon α for 18 months (CHVP-I arm) and 192 received 4 cycles of CHOP followed by high-dose therapy (HDT) with total body irradiation and ASCT (CHOP-HDT arm). Overall response rates were similar in both groups (79% and 78% after induction chemotherapy, respectively). One hundred thirty-one of the 150 patients eligible for HDT underwent transplantation (87%). Intent-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the 2 arms for overall survival (P = .53) or event-free survival (P = .11). Patients with a complete response at the end of the induction therapy had a statistically longer event-free survival and overall survival (P = .02 and < .001, respectively). After long-term follow-up, our study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with follicular lymphoma. High-dose therapy should be reserved for relapsing patients.


2020 ◽  
Author(s):  
Jie Jiang ◽  
Chong Liu ◽  
Guoyong Xu ◽  
Tuo Liang ◽  
Chaojie Yu ◽  
...  

Abstract Background Ewing's sarcoma (ES) is the second most prevalent malignancy among bone tissue tumors, and there is no adequate prognosis biomarker. The protein encoded by CCT6A is a molecular chaperone. Early studies have suggested that CCT6A is involved in the development of many cancers, however, there is no clear evidence of a role for CCT6A in ES. Methods In this study, we performed a bioinformatics analysis of 32 Ewing sarcoma specimens from the GSE17618 dataset for differences in gene expression and overall survival, event-free survival, and gene expression in different subgroups. Results After three screenings, we identified CCT6A as highly correlated with Ewing's sarcoma prognosis. Survival analysis showed low overall survival (OS) for CCT6A high expression (P = 0.024). On the other hand, Cox regression analysis showed that CCT6A expression, event-free survival (EFS), and age were strongly associated with the prognosis of Ewing sarcoma, identified as independent poor prognostic biomarkers. (CCT6A: P = 0.015; Age: P-value = 0.026; EFS: P-value = 0.001). Conclusion The expression level of CCT6A is strongly associated with the prognosis of Ewing's sarcoma. High expression of the CCT6A gene may serve as a biomarker for poor prognosis in patients with Ewing's sarcoma.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5432-5432
Author(s):  
Ambuj Kumar ◽  
Benjamin Djulbegovic ◽  
Heloisa P. Soares

Abstract Background: Hodgkin disease (HD) is a potentially curable lymphoma with overall survival exceeding 60% at 10 years. However, patients with relapsed Hodgkin’s disease have a dismal prognosis when treated with conventional salvage chemotherapy. The primary objective of our systematic review/meta-analysis was to evaluate the efficacy of high-dose chemotherapy and autologous stem-cell transplant (HSCT) versus conventional chemotherapy in patients with relapsed Hodgkin’s disease which has not been done before. Methods: Data search of published studies included Medline (1966–2006), Cochrane library and hand search of references. Studies were included if they were randomized controlled trials of HSCT versus conventional chemotherapy only. Data were extracted on benefits as well as harms (overall survival, event-free survival, and treatment related mortality). All data extraction was done in duplicate independently. Results: Out of 47 identified studies only 2 met the inclusion criteria of the current systematic review. Overall survival was similar for HSCT and conventional chemotherapy arms (see figure 1) with a pooled hazard ratio (HR) of 0.69 (95%CI 0.40, 1.18, p=0.2). However, the event-free survival was better in the HSCT arm than the conventional chemotherapy alone group (HR = 0.59, 95%CI 0.41, 0.85, p=0.005). Treatment related mortality was similar in both groups. (HR = 0.40, 95%CI 0.11, 1.44, p=0.2). Conclusion: Results from our meta-analysis indicate that treatment with HSCT compared with conventional chemotherapy only improves event free survival without excessive toxicity. However, overall survival was not affected by the HSCT therapy. In summary patients with relapsed Hodgkin’s disease should be offered HSCT therapy. Role of transplant in relapsed or resistant hodgkin’s disease Role of transplant in relapsed or resistant hodgkin’s disease


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 79-79 ◽  
Author(s):  
Jacques Delaunay ◽  
Christian Recher ◽  
Arnaud Pigneux ◽  
Francis Witz ◽  
Norbert Vey ◽  
...  

Abstract Abstract 79 The prognosis of acute myeloblastic leukemia (AML) with intermediate-risk cytogenetics is refined further by testing the mutational status of NPM1,FLT3 and CEBPa genes. Patients with a NPM1mut\FLT3wt and CEBPa double mutation are now classified in a separate favorable group of the new ELN classification. Conversely, all other molecular profiles including these 3 genes, considered as carrying a worse prognosis, are included in ELN intermediate groups 1 and 2. Nevetheless the therapy of AML has remained unchanged since many years and needs improvement even in this subset of patients. The GOELAMS has tested the association of gemtuzumab ozozgamycin (GO), a monoclonal anti-CD33 antibody conjugated with chalicheamycin to standard chemotherapy in a phase III prospective randomized trial focusing on such patients with intermediate cytogenetics. Methods: Between 2007 and 2010, 254 patients aged between 18 to 60 years with de novo AML and intermediate karyotype have been included. The molecular status for NPM1, FLT3 and CEBPa mutations was determined at diagnosis. After 1/1 randomization, GO 6m/m2 was added to standard 3+7 induction and to a first MidAc intensive consolidation course (Mitoxantrone and intermediate doses of cytarabine). Patients in the ELN favorable molecular group received a second MidAc course followed by an autologous bone marrow transplant (BMT). Patients in the ELN intermediate 1 or 2 groups were considered for geno or phenoidentical allogeneic transplant. Patients 50 years of age or lower, received either standard allo-BMT preceded by a single course of chemotherapy or a reduced intensity chemotherapy (RIC) regimen after the two courses of intensive consolidation. In this sub-group, patients with no donor received autologous BMT after the two randomized courses of consolidation. Results: Two hundred and thirty-eight patients were analyzed with a median follow-up of 20 months. Their median age was 50 years old (18–60). There was no significant difference between the two arms according to age, WBC, % of circulating and % of marrow blasts, FAB subtypes, cytogenetics (normal vs abnormal) and molecular subgroups (favorable versus intermediate 1 and 2 ELN groups). In the GO group, the complete remission (CR) rate was 91.6% versus 86.5% (P=NS), early death(ED) was 10% versus 4.5% (P=NS). Major toxicity was observed in the GO arm during induction phase with 4 cases of veno-occlusive liver disease (VOD) and overall more toxic grade III/IV hepatic toxicities (23% versus 13%, p=0.031). No significant difference was observed between the two arms for grade III/IV hematological toxicity. No difference was observed either at 3 years for event free survival (EFS) at 51% in the GO arm and 33% in the other arm, nor for overall survival (OS) at respectively 53% and 46%. In the subset of patients who could not receive an allogeneic transplant, EFS was significantly higher in the GO group (53.7% vs 27%, p=0.0308) while there was no difference for OS. This better outcome was mostly observed in the group of patients classified ELN intermediate 1 or 2 (p=0.0126). Conclusion: In the subset of patients with intermediate cytogenetics AML, the adjunction of GO to standard chemotherapy failed to improved OS, yet a better EFS was observed with the addition of GO for patients who could not receive an allogeneic SCT. More detailed results will be presented. Disclosures: No relevant conflicts of interest to declare.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii396-iii397
Author(s):  
Jonathan Finlay ◽  
Martin Mynarek ◽  
Girish Dhall ◽  
Claire Mazewski ◽  
Richard Grundy ◽  
...  

Abstract BACKGROUND/OBJECTIVE The introduction of German regimens, supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), report encouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young children with ClMB or A/LCMB. DESIGN/ METHODS Data from 12 prospective multi-center trials published between 2005 and 2019 for children &lt;six-years-old with ClMB or A/LCMB were reviewed; survivals were compared. RESULTS COG-9921, UKCCSG-CNS9204, COG-P9934 and SJYCO7 employing standard chemotherapy with either no or risk-based irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/-28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87, HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HIT-SSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%, 50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13% (HS-III). Finally, 5-year overall survivals for ACNS0334, without or with induction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB combined. CONCLUSIONS A trend towards better outcomes for young children with ClMB and A/LCMB is observed in trials including either HD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.


2020 ◽  
Vol 7 ◽  
Author(s):  
Timur Koca ◽  
Aylin Fidan Korcum ◽  
Yasemin Şengün ◽  
Melek Gamze Aksu ◽  
Mine Genç

Aim: In this study, we aimed to evaluate the overall and progression-free survival, the radiotherapy process and the early and late adverse effects in patients who underwent radiotherapy (RT) for primary nervous system lymphoma in our clinic.Method: Between January 2010 and September 2019, 16 patients who received radiotherapy due to primary central nervous system lymphoma in our clinic were examined according to their statistically significant differences in terms of survival and side effects.Results: The median disease-free survival of the patients was 6 months, and the median overall survival was 12.5 months. 18.75% of the patients could not receive chemotherapy but only radiotherapy. Radiotherapy doses were range from 2600 to 5000 cGy. When patients were evaluated in terms of radiotherapy dose, field size and chemotherapy, no statistically significant difference in overall survival was detected. Cognitive disorders were observed as the most common late side effects while the most common acute side effects in patients were headaches.Conclusion: In the treatment of primary central nervous system lymphoma, changes in radiotherapy portals and radiotherapy doses can be predicted in patients who received high-dose methotrexate chemotherapy or not. Furthermore, it has been considered that more comprehensive studies are needed to increase the success of treatment and provide standardization in treatment, especially in patients with elderly and comorbid diseases.


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