scholarly journals MBCL-34. EFFICACY OF METHOTREXATE (MTX) ACCORDING TO MOLECULAR SUB-TYPE IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii396-iii396
Author(s):  
Claire Mazewski ◽  
Guolian Kang ◽  
Stewart Kellie ◽  
Jeffrey Gossett ◽  
Sarah Leary ◽  
...  
Keyword(s):  
Young Children ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trial ◽  
Stem Cell Rescue ◽  
Group 4 ◽  
Whole Exome ◽  
Group 3 ◽  
Central Pathology ◽  
Survival Differences

Abstract ACNS0334, a Phase 3 trial, compared outcomes of children <36 months treated with intensive chemotherapy +/-high-dose methotrexate. Nodular-desmoplastic M0-stage MB were excluded. Treatment included 3 induction cycles (cyclophosphamide/etoposide/vincristine/cisplatin+/-mtx) and 3 consolidation cycles (carboplatin/thiotepa with stem cell rescue). Radiation (RT) was at physician discretion. Molecular sub-typing was by DNA-methylation. Log-rank testing was used to compare survival differences. Molecular sub-typing of 38 MB identified 11 Sonic Hedgehog (SHH), 25 Group 3 (GP3), 2 Group 4 (GP4). Five-year survival (OS) was 100% for 5 SHH with MTX and 4 SHH without MTX; 80% for 10 GP3 with MTX, 40% for 15 GP3 without MTX (p=0.025). Only 6/14 survivors received RT: 4 for residual following therapy (1 SHH and 3 GP3) and 2 GP3 salvaged after progression. Two GP3 deaths were associated with toxicity; all others were due to disease. Histology among SHH was nodular-desmoplastic (8) or classic (3); GP3 histology was classic (17) or anaplastic (7). Whole-exome sequencing identified 6 somatic PTCH1 and 1 germline SUFU alteration(s) among 9 SHH. Among GP3, no p53 mutations were found; copy-number analysis identified 5/25 with myc-amplification, 5/25 iso17q, 11/25 with 8 loss, 14/25 with loss of 11. Among GP3, 14/19 had no significant germline mutation. ACNS0334 achieved 100% survival for metastatic SHH. Benefit of methotrexate was observed in GP3 MB supporting incorporation of methotrexate into standard therapy for GP3. Upfront central pathology review and molecular sub-typing are critical for future clinical trial risk stratification of young children with embryonal tumors.

scholarly journals MBCL-32. HIGH-DOSE CHEMOTHERAPY WITH STEM CELL RESCUE FOR RECURRENT PREVIOUSLY IRRADIATED MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii395-iii395
Author(s):  
Ekaterina Salnikova ◽  
Irina Vilesova ◽  
Artur Merishavyan ◽  
Alexander Druy ◽  
Ludmila Yasko ◽  
...  
Keyword(s):  
Stem Cell ◽  
Molecular Genetic ◽  
High Dose Chemotherapy ◽  
Local Relapse ◽  
Therapeutic Options ◽  
High Dose ◽  
Genetic Analyses ◽  
Stem Cell Rescue ◽  
Group 4 ◽  
Group 3

Abstract BACKGROUND/OBJECTIVES Relapse of medulloblastoma (MB) is highly lethal in previously irradiated patients. As one of therapeutic options for recurrence MB, high-dose chemotherapy with stem cell rescue (HDSCR) is suggested. The aim of our work was to evaluate the effectiveness of this therapy. DESIGN/METHODS We retrospectively analyzed the data of 8 pts with previously irradiated relapse MB using HDSCR. Initially, M0-stage was verified in 4 cases. Histological diagnoses were desmoplastic (2 pts), classic (2 pts), anaplastic (2 pts) and MB NOS (2 pts). Molecular genetic analyses was performed in 6 cases: Group 3 was verified in 2 cases (1-classic, 1-anaplastic), Group 4 – in 3 cases (1-classic, 1-anaplastic, 1-desmoplastic). Time to first PD was from 15 to 86 months (median=29,4 months). Local relapse was revealed in 1 pt, metastatic – in 5 pts, mixed – in 2 pts. RESULTS All pts were treated according HIT-REZ 2005 (3–5 cycles without/with intraventricular etoposide), with CR achieved in 3 pts and PR in 5 pts. HDCT regimens consisted of carboplatin, etoposide, thiotepa and temozolomide. 2 pts received re-irradiation – focal RT (1) and CSI (1). 7/8 patients died, 1 pt alive with PD. Time from HDCT to death was 5–15 months (median=9,6 months). CONCLUSIONS HDSCR for recurrent previously irradiated MB is ineffective. Use of other methods should be considered in these cases.

scholarly journals ETMR-20. IMPACT OF HIGH DOSE CHEMOTHERAPY WITH AND WITHOUT METHOTREXATE (MTX) ON OUTCOME OF PATIENTS WITH EMBRYONAL TUMORS WITH MULTI-LAYERED ROSETTES (ETMRs): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii327-iii327
Author(s):  
Claire Mazewski ◽  
Guolian Kang ◽  
Stewart Kellie ◽  
Jeffrey Gossett ◽  
Sarah Leary ◽  
...  
Keyword(s):  
Tumor Resection ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Molecular Entity ◽  
High Dose ◽  
Molecular Testing ◽  
Oncology Group ◽  
Embryonal Tumors ◽  
Phase Iii Trial ◽  
Stem Cell Rescue

Abstract Infant embryonal brain tumors comprise a spectrum of histologic and molecular entities including medulloblastoma (MB) and tumors collectively called CNS PNET’s, including supratentorial PNET (sPNET), pineoblastoma and other less common histologic entities. Non-MB embryonal tumors, historically considered high risk disease, were included in ACNS0334, A Children’s Oncology Group prospective phase III trial which compared efficacy of an induction regimen with and without methotrexate combined with high dose chemotherapy and stem cell rescue; no radiation was mandated. Molecular testing performed after ACNS0334 closure identified 14 patients with embryonal tumors with multi-layered rosettes (ETMRs), a new molecular entity previously classified under various diagnostic categories. ETMR patients made up 20% of the molecularly analyzed ACNS0334 cohort and were predominantly females. Tumors were largely non-metastatic (10/14 M0, 1 M1, 3 M2/M3) and originated in the cerebrum (8), cerebellum (3) and pineal gland (3). Gross total tumor resection was achieved in 5/11 patients with M0/M1 disease; 9/14 patients completed full treatment with 5 randomized to MTX induction and 9 to no-MTX. Five of 14 patients progressed on treatment, one had a toxic death. Disease progression was primarily local (88 %). No difference by methotrexate randomization was observed. Four patients are alive without progression 5–10+ years off therapy, none received radiation. No patients received radiation prior to progression. Four were irradiated after progression and died from disease within 3 to 13 months. Our study, a first report on ETMRs prospectively treated on a clinical trial, suggests high dose chemotherapy benefits a portion of ETMR patients.

scholarly journals NCOG-47. CAN YOUNG CHILDREN WITH RELAPSED MEDULLOBLASTOMA BE SALVAGED AFTER INITIAL IRRADIATION-SPARING APPROACHES?

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii139-ii140
Author(s):  
Craig Erker ◽  
Valérie Larouche ◽  
Dolly Aguilera ◽  
Ashley Margol ◽  
Chantel Cacciotti ◽  
...  
Keyword(s):  
Young Children ◽  
Median Time ◽  
High Dose Chemotherapy ◽  
Initial Diagnosis ◽  
Salvage Radiotherapy ◽  
High Dose ◽  
Conventional Chemotherapy ◽  
Curative Intent ◽  
Group 4 ◽  
Group 3

Abstract INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995-2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 66 patients. The median age at initial diagnosis was 27 months (range, 6-72). At diagnosis, 27 patients had metastatic disease. Initial therapy included conventional chemotherapy or with high-dose chemotherapy (HDC) in 30 and 36 patients, respectively. Eight (12.1%) received upfront focal irradiation. Molecular subgrouping was available for 27 (41%) patients. Ten were SHH, five group 3, six group 4 and six others were non-WNT/non-SHH. The median time from initial diagnosis to relapse was 13 months (range, 3-63). Relapse was local, disseminated, or combined in 39%, 32%, and 29%, respectively. The median time to death from relapse was 18 months. Curative intent therapy was given in 53 patients with irradiation (81%), conventional chemotherapy without HDC (40%), and HDC (25%). For patients who received irradiation, 85% received CSI (median dose 33 Gy, 18-41.4) and 15% focal irradiation. Ten patients received chemotherapy without salvage irradiation. The median follow-up time was 44 months (range, 4-255), 33 (62%) patients who underwent curative-intent therapy were alive, including 8/10 SHH, 2/3 group 3, 2/6 group 4, and 4/5 non-WNT/non-SHH. Three of four patients with SHH and treated without salvage radiotherapy are survivors. The 5-year OS for curative intent was 70%. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. A proportion of children with SHH MB can be salvaged without salvage radiotherapy.

A randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2/interferon

2002 ◽  
Vol 3 (1) ◽  
pp. 11-12
Author(s):  
Ken-ryu Han ◽  
Allan J. Pantuck ◽  
Arie S. Belldegrun
Keyword(s):  
Interleukin 2 ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trial

Aprepitant, Granisetron, and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting After High-Dose Melphalan in Autologous Transplantation for Multiple Myeloma: Results of a Randomized, Placebo-Controlled Phase III Trial

2014 ◽  
Vol 32 (30) ◽  
pp. 3413-3420 ◽  
Author(s):  
Thomas Schmitt ◽  
Hartmut Goldschmidt ◽  
Kai Neben ◽  
Anja Freiberger ◽  
Johannes Hüsing ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Rescue Therapy ◽  
Autologous Transplantation ◽  
Nausea And Vomiting ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trial ◽  
End Point

Purpose The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients and Methods Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m2 was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index–Emesis (FLIE) questionnaire on days −1 and 6. Results Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). Conclusion The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life.

Long-term versus short-term androgen deprivation combined with high-dose radiotherapy for localized prostate cancer: A Spanish multicenter phase III trial.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e15036-e15036 ◽  
Author(s):  
A. Zapatero ◽  
A. Guerrero ◽  
X. Maldonado ◽  
A. Alvarez ◽  
C. González San Segundo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
Localized Prostate Cancer ◽  
High Dose ◽  
Short Term ◽  
Phase Iii Trial ◽  
Multicenter Phase

Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
Lawrence E. Flaherty ◽  
James Moon ◽  
Michael B. Atkins ◽  
Ralph Tuthill ◽  
John A. Thompson ◽  
...  
Keyword(s):  
High Risk ◽  
Stage Iv ◽  
Phase Iii ◽  
Stage Iii ◽  
Rank Test ◽  
High Dose ◽  
Phase Iii Trial ◽  
High Risk Melanoma ◽  
Risk Melanoma ◽  
High Dose Interferon

8504 Background: High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts to modify IFN dose or schedule have not improved efficacy. A meta-analysis demonstrated that biochemotherapy (BCT) produced superior response rates compared with chemotherapy in pts with stage IV melanoma (Wheatley et al J Clin Oncol 25:5426, 2007). We sought to determine whether a short course of BCT would be more effective than HDI as adjuvant treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and randomized them to receive either HDI or BCT consisting of dacarbazine 800 mg/m2 day 1, cisplatin 20 mg/m2/ days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2/day continuous IV days 1-4, IFN 5 MU/m2/day sc days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were given every 21 days x 3 cycles (9 weeks total). Pts were stratified for number of involved nodes (1-3 v ≥4), micro v macro metastasis, and ulceration of the primary. Co-primary endpoints were relapse free survival (RFS) and overall survival (OS) using a one-sided log rank test at p= 0.05. Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a median f/up of 6 yrs, BCT improved RFS (p = 0.02, HR 0.77 [90% CI: 0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not different between the two arms (p = 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT provides a statistically significant improvement in RFS compared to HDI, but no discernable difference in OS and more grade IV toxicity. BCT represents a shorter, alternative treatment for pts with HRM, and a potential control arm and basis for future combinations in the adjuvant setting.

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