Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children's Oncology Group (ACNS1221)

Lucie Lafay-Cousin, Eric Bouffet, Douglas Strother, Vasilisa Rudneva, Cynthia Hawkins, Charles Eberhart, Craig Horbinski, Linda Heier, Mark Souweidane, Chris Williams-Hughes, Arzu Onar-Thomas, Catherine A. Billups, Maryam Fouladi, Paul Northcott, Giles Robinson, Amar Gajjar

Research output: Contribution to journalArticle

Abstract

PURPOSE: Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. PATIENTS AND METHODS: ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. RESULTS: Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse-local (n= 6), distant (n = 3), and combined (n = 3)-at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively (P = .099). CONCLUSION: The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.

Original languageEnglish (US)
Pages (from-to)223-231
Number of pages9
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume38
Issue number3
DOIs
StatePublished - Jan 20 2020

Fingerprint

Medulloblastoma
Disease-Free Survival
Histology
Methotrexate
Recurrence
Survival Rate
Intraventricular Injections
Drug Therapy
Methylation
Neoplasms
Pathology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age : A Report of the Children's Oncology Group (ACNS1221). / Lafay-Cousin, Lucie; Bouffet, Eric; Strother, Douglas; Rudneva, Vasilisa; Hawkins, Cynthia; Eberhart, Charles; Horbinski, Craig; Heier, Linda; Souweidane, Mark; Williams-Hughes, Chris; Onar-Thomas, Arzu; Billups, Catherine A.; Fouladi, Maryam; Northcott, Paul; Robinson, Giles; Gajjar, Amar.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 38, No. 3, 20.01.2020, p. 223-231.

Research output: Contribution to journalArticle

Lafay-Cousin, L, Bouffet, E, Strother, D, Rudneva, V, Hawkins, C, Eberhart, C, Horbinski, C, Heier, L, Souweidane, M, Williams-Hughes, C, Onar-Thomas, A, Billups, CA, Fouladi, M, Northcott, P, Robinson, G & Gajjar, A 2020, 'Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children's Oncology Group (ACNS1221)', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 38, no. 3, pp. 223-231. https://doi.org/10.1200/JCO.19.00845
Lafay-Cousin, Lucie ; Bouffet, Eric ; Strother, Douglas ; Rudneva, Vasilisa ; Hawkins, Cynthia ; Eberhart, Charles ; Horbinski, Craig ; Heier, Linda ; Souweidane, Mark ; Williams-Hughes, Chris ; Onar-Thomas, Arzu ; Billups, Catherine A. ; Fouladi, Maryam ; Northcott, Paul ; Robinson, Giles ; Gajjar, Amar. / Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age : A Report of the Children's Oncology Group (ACNS1221). In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 ; Vol. 38, No. 3. pp. 223-231.
@article{8fa0883785924ff78d4d55ddabbb0d3c,
title = "Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children's Oncology Group (ACNS1221)",
abstract = "PURPOSE: Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. PATIENTS AND METHODS: ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90{\%}) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. RESULTS: Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse-local (n= 6), distant (n = 3), and combined (n = 3)-at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52{\%} (95{\%} CI, 32.4{\%} to 71.6{\%}) and 92{\%} (95{\%} CI, 80.8{\%} to 100.0{\%}) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0{\%} (95{\%} CI, 1.6{\%} to 58.4{\%}) and 66.7{\%} (95{\%} CI, 44.0{\%} to 89.4{\%}), respectively (P = .099). CONCLUSION: The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90{\%}. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.",
author = "Lucie Lafay-Cousin and Eric Bouffet and Douglas Strother and Vasilisa Rudneva and Cynthia Hawkins and Charles Eberhart and Craig Horbinski and Linda Heier and Mark Souweidane and Chris Williams-Hughes and Arzu Onar-Thomas and Billups, {Catherine A.} and Maryam Fouladi and Paul Northcott and Giles Robinson and Amar Gajjar",
year = "2020",
month = "1",
day = "20",
doi = "10.1200/JCO.19.00845",
language = "English (US)",
volume = "38",
pages = "223--231",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "3",

}

TY - JOUR

T1 - Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age

T2 - A Report of the Children's Oncology Group (ACNS1221)

AU - Lafay-Cousin, Lucie

AU - Bouffet, Eric

AU - Strother, Douglas

AU - Rudneva, Vasilisa

AU - Hawkins, Cynthia

AU - Eberhart, Charles

AU - Horbinski, Craig

AU - Heier, Linda

AU - Souweidane, Mark

AU - Williams-Hughes, Chris

AU - Onar-Thomas, Arzu

AU - Billups, Catherine A.

AU - Fouladi, Maryam

AU - Northcott, Paul

AU - Robinson, Giles

AU - Gajjar, Amar

PY - 2020/1/20

Y1 - 2020/1/20

N2 - PURPOSE: Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. PATIENTS AND METHODS: ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. RESULTS: Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse-local (n= 6), distant (n = 3), and combined (n = 3)-at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively (P = .099). CONCLUSION: The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.

AB - PURPOSE: Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. PATIENTS AND METHODS: ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. RESULTS: Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse-local (n= 6), distant (n = 3), and combined (n = 3)-at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively (P = .099). CONCLUSION: The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.

UR - http://www.scopus.com/inward/record.url?scp=85077944487&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85077944487&partnerID=8YFLogxK

U2 - 10.1200/JCO.19.00845

DO - 10.1200/JCO.19.00845

M3 - Article

C2 - 31774708

AN - SCOPUS:85077944487

VL - 38

SP - 223

EP - 231

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 3

ER -