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Atypical Teratoid/Rhabdoid Tumors (ATRT): Improved Survival in Children 3 Years of Age and Older With Radiation Therapy and High-Dose Alkylator-Based Chemotherapy Tanya M. Tekautz, Christine E. Fuller, Susan Blaney, Maryam Fouladi, Alberto Broniscer, Thomas E. Merchant, Matthew Krasin, James Dalton, Gregory Hale, Larry E. Kun, Dana Wallace, Richard J. Gilbertson, and Amar Gajjar

A B S T R A C T

Purpose To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children’s Research Hospital (SJCRH).

Patients and Methods Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed.

Results Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% � 14%; OS, 89% � 11%) were significantly better than those for younger patients (EFS, 11% � 6%; OS, 17% � 8%); EFS, P � .009 and OS, P � .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy.

Conclusion Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

INTRODUCTION

Atypical teratoid/rhabdoid tumor (ATRT) is a malignant embryonal tumor of the CNS that is composed of rhabdoid cells, with or without fields resembling classical primitive

neuroectodermal tumor.1 Although ATRT is a relatively rare disease, accounting for less than 5% of all pediatric CNS tumors, up to 20% of malignant CNS tumors diagnosed before the patient is 3 years old are ATRTs.2-4 ATRT has been reported in

From the Department of Hematology- Oncology, Department of Pathology, Department of Radiological Sciences, Department of Biostatistics, and Depart- ment of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN; Texas Children’s Hospital, Houston TX.

Submitted May 28, 2004; accepted December 6, 2004.

Supported by the Cancer Center (CORE) Support Grant CA 21765 from the National Institutes of Health and by the American Lebanese Syrian Associ- ated Charities (ALSAC).

Authors’ disclosures of potential con- flicts of interest are found at the end of this article.

Address reprint requests to Amar Gajjar, MD, Department of Hematology- Oncology, Mail Stop 260, St Jude Children’s Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; e-mail: [email protected].

0732-183X/05/2307-1491/$20.00

DOI: 10.1200/JCO.2005.05.187

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adults; it is exceedingly rare, however, with only eight cases reported in the literature to date.5-7

The diagnosis of ATRT relies predominantly on morphologic and immunohistochemical criteria (IHC).8

Chromosome 22q11 abnormalities are frequently seen in ATRT and have proved valuable for diagnostic purposes. Chromosome 22q11.2 harbors the putative tumor suppressor gene SMARCB1 (also known as hSNF5/INI1), a component of an SWI/SNF ATP-dependent chromatin-remodeling com- plex that likely controls the expression of certain target genes involved in cell cycle regulation.9-11 Seventy-five percent of ATRTs contain homozygous deletions of SMARCB1, or loss of one allele and mutation of the other copy of the gene.12-15

Published series of ATRT report an overall 2-year survival rate of less than 15% for children aged younger than 3 years at diagnosis. Therapeutic approaches to treatment of ATRT have included a variety of postoperative chemotherapy regimens with or without radiation therapy (RT).2,3,16 Although RT appears most effective when administered early in the treat- ment of ATRT,2 the unacceptable sequelae associated with cranial irradiation in infants and young children precludes the use of this modality in most patients with this disease.2 For the first time we present the clinical characteristics and survival correlates from our institutional series of patients with newly diagnosed ATRT and compare the infants and young children (� 3 years) with older children (� 3 years).

PATIENTS AND METHODS

Tumor Registry Review

With institutional review board approval, we reviewed the medical records of all patients younger than 22 years, who were diagnosed with ATRT at St Jude Children’s Research Hospital (SJCRH) between July 1984 and June 2003. The subjects were retro- spectively identified through survey of our institutional database.

Clinical Review

Once patients with the diagnosis of ATRT were identified, a detailed review of the clinical data was performed to ascertain the presenting features, degree of surgical resection, chemotherapy regimen, RT dose, and volume.

Pathology, Immunohistochemistry, and Fluorescence

In Situ Hybridization

All available tumor material from patients receiving an insti- tutional diagnosis of ATRT between July 1984 and June 2003 was reviewed by a single neuropathologist (C.F.). Histopathologic re- view included morphologic assessment of ATRT characteristics according to WHO criteria and immunohistochemical (IHC) analysis. IHC was performed using a panel of six antibodies in- cluding epithelial membrane antigen (EMA), smooth muscle actin (SMA), vimentin, glial fibrillary acidic protein (GFAP), keratin, and synaptophysin. The specific immunohistochemical stain(s) employed for a given tumor varied and was dependent on the histologic appearance of the tumor and amount of tissue available.

Tissue microarrays (TMA) were constructed from formalin- fixed, paraffin-embedded archival tissue blocks using a tissue ar-

rayer (Beecher Instruments, Silver Spring, MD). Two to 4 tissue cores (1.0-mm diameter) from histologically representative areas of tumor were included from each case. Five micrometer-thick sections were then cut from the TMA and mounted on poly-L-lysine-coated slides for dual-color fluorescence in situ hybridization (FISH) exper- iments as previously reported.9 Bacterial artificial chromosome (BAC)– derived probes targeting SMARCB1 (22q11.23; contiguous gene sequence of CTD-2034E7 and CTD-2355C2, Invitrogen, Huntsville, AL) and PANX2 (control for chromosome 22 ploidy- 22q13.3; RPCI3-402G11, Children’s Hospital Oakland Research In- stitute, Oakland, CA) were labeled in rhodamine and fluorescein, respectively, and diluted 1:50 in DenHyb hybridization buffer (Insitus Laboratories, Albuquerque, NM) for dual-target hybridization. The probe and target were simultaneously denatured at 90°C for 13 min- utes, followed by overnight hybridization at 37°C in a humidified chamber. DAPI (1.0 �g/mL; Insitus Laboratories) was used as a nuclear counterstain, and the sections were viewed under a Nikon E800 fluorescent microscope with appropriate filters (Nikon Instru- ments, Melville, NY).

Sections showing sufficient hybridization efficiency were considered informative, and 100 to 200 intact nonoverlapping nuclei were scored for the number of fluorescent signals by two reviewers (C.F., J.D.). Cutoffs for abnormalities and/or deletions were based on counts from non-neoplastic control specimens (nor- mal brain from autopsy cases) for each probe. Interpretation of dele- tion required more than 37% of tumor nuclei containing 1 (hemizygous) or zero (homozygous) red SMARCB1 signals (mean � 3 SDs in controls); all cases showing homozygous deletion retained demonstrable SMARCB1 signals within normal tissue components (endothelial cells). As nuclei with more than two signals were rarely seen in non-neoplastic controls, polysomies (gains) were arbitrarily defined as more than 5% nuclei containing three or more signals.

Images were captured using a high-resolution black and white COHU CCD camera and the CytoVision basic workstation (Applied Imaging, Santa Clara, CA). A Z-stack motor allowed for sequential DAPI (one level), FITC (16 levels), and rhodamine (16 levels) filter settings to be captured, and the resulting images were reconstructed with blue, green, and red pseudocolors.

Statistical Analysis

Overall survival (OS) was measured from the date of initial diagnosis of ATRT to the date of death or last contact. Event-free survival (EFS) was measured from the date of diagnosis to the first date of progressive disease for those who progressed, to the date of death for those patients who died without progressive disease or to the date of last contact for children who survived in the absence of treatment failure. Distributions of EFS and OS were estimated using the method of Kaplan and Meier.17 Associated SEs were calculated as suggested by Peto et al.18 Differences in OS and EFS distributions in relation to age at diagnosis were assessed by exact log-rank tests.19 In comparison with survival estimates in relation to other risk factors, stratification was based on age at diagnosis; stratified exact log-rank tests were also used. Only two-sided P val- ues are reported. Exact tests were performed using the StatXact software package (Cytel Software Corp, Cambridge, MA).

RESULTS

From July 1984 through June 2003, an ATRT was diag- nosed in 37 of the 1,387 patients (2.7%) evaluated for CNS

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neoplasm at SJCRH. Of these 37 patients, pathology review confirmed the diagnosis of ATRT in 36. Tumor in one patient was excluded from the analysis because it was deter- mined to be a high-grade glioma. Five additional patients were not included in the analysis for the following reasons: three patients were treated at other centers with alternate diagnoses before the diagnosis of ATRT was made at our facility; one patient with a history of a renal rhabdoid tumor presented in extremis and died before therapy was initiated; and one patient’s family declined treatment. Hence, 31 patients with confirmed histologic diagnosis of ATRT were included for analysis of clinical management and outcome.

Pathology and Molecular Review

There was a broad range of histopathologic and immu- nohistochemical features present in the tumors from this

patient cohort. In addition to a primitive neuroectodermal component composed of generally patternless sheets of round blue cells, tumor samples from all patients harbored variable numbers of “rhabdoid cells” with abundant cyto- plasm often containing eosinophilic filamentous inclu- sions, eccentrically situated nuclei with open chromatin, and large nucleoli. IHC analysis of 31 ATRTs demonstrated strong cytoplasmic positivity with EMA, the majority addi- tionally showing polyphenotypic immunoprofiles consis- tent with ATRT including positivity for SMA, vimentin, GFAP, keratin, and synaptophysin, in decreasing order of frequency (Table 1).8,9,20

Twenty-one tumor samples from 20 patients were available for FISH analysis (Table 1). Sixteen cases (76%) contained deletion of SMARCB1. Homozygous SMARCB1

Table 1. Immunohistochemical and Molecular Characteristics of ATRTs

Patient EMA SMA Vimentin GFAP Keratin Synaptophysin FISH for

SMARCB1

Age at diagnosis � 3 years old

1 ND� ND ND ND ND ND ND 2 � ND � � � ND ND 3 ND ND � � � � ND 4 � ND � � � � Homo del 5 � ND � � � � Deleted�

6 � ND � � � � Deleted 7 � ND � � � � Normal 8 � � � � � � ND 9 � ND ND ND ND ND ND

10 � � � � � � Deleted 11 ND � � � � ND Monosomy 12 � ND � � � � ND 13 � � � � � � ND 14 � ND � � � � ND 15 � � � � � � Deleted 16 � � � � � � Monosomy 17 � ND � � � � Deleted 18 � ND ND � � � Deleted 19 � � � � � � Normal 20 � ND ND � � � Homo del 21 � ND ND ND ND ND Deleted 22 � ND � � � � Normal

� 3 years old 23 ND ND � � � ND ND 24 � ND � � � ND ND 25 � � � � � � Normal 26 � � � � � ND Homo del 27 � � � ND � ND ND 28 � � � � � � Homo del 29 � � � � � � Homo del 30 � � � � � � Monosomy 31 � � � � � � Deleted

Abbreviations: ATRT, atypical teratoid/rhabdoid tumor; EMA, epithelial membrane antigen; SMA, smooth muscle actin; GFAP, glial fibrillary acidic protein; FISH, fluorescence in situ hybridization; ND, not determined; �, positive result of immunohistochemical assay; �, negative result; monosomy, monosomy 22; deleted, single copy INI1 deletion; homo del, homozygous INI1 deletion.

�Done on original patient sample and subsequent biopsy sample for this patient. Initial results indicated no SMARCB1 was present however, the second specimen demonstrated a deletion of SMARCB1. The discrepant results were attributed to tumor variability, not acquisition of this lesion.

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deletion was detected in five cases (24%); the average per- centage of cells showing homozygous deletion in these five samples was 84% (range, 67% to 92%). All five tumors that displayed homozygous deletion also displayed evidence of concomitant monosomy 22, with only a single PANX2 sig- nal per cell (average percentage of cells, 51%; range, 34% to 80%). These data suggest that in these cases homozygous de- letion occurred as a result of monosomy 22 and associated interstitial deletion of the second SMARCB1 allele. Eight cases (38%) showed deletion of a single copy of SMARCB1/ hemizygous deletion (average percentage of cells, 52%; range, 39% to 93%). A significant proportion of these cases showed a larger region of loss on chromosome 22; up to 63% (range, 50% to 71%) of INI1-deleted cells displaying single red and green signals (monosomy) and a lesser percentage had only hemizygous loss of INI1 (single red INI1 and two green PANX2 signals per cell). Monosomy 22 alone was the predom- inant alteration in three cases (14%) with the majority of tumor cells involved (average, 82%; range, 76% to 86%). Only five cases (24%) had no demonstrable alterations of chromo- some 22 detected by the current FISH assay. In one patient (patient 5), FISH analysis on tumor obtained at diagnosis did not detect any INI1 abnormality. The child subsequently de- veloped recurrent disease; evaluation of the recurrent tumor demonstrated an INI1 hemizygous deletion by FISH.

ATRT Patient Cohort: Demographic/

Clinical Features

Twenty-two patients (71%) were younger than 3 years at diagnosis with a median age of 1 year (range, 0.2 to 2.7 years). Sixteen patients younger than 3 years old at diagnoses were male; 16 were white, four were African-American, and two were Hispanic. The median age at diagnosis of patients 3 years and older was 3.9 years (range, 3.3 to 7.4 years) and included three males; six were white, two were African Amer- icans, and one was Hispanic.

Disease extent was evaluated by computed tomogra- phy and/or magnetic resonance (MR) imaging of the brain and spine after tumor resection and, Tc99 bone scintigra- phy. CSF cytology was examined in all cases.

RT was delivered either to the entire neuraxis or locally. The dose of craniospinal irradiation (CSI) administered was determined by the patient’s age, postoperative residual disease, and the presence of metastatic disease. Patients 3 years or older with less than 1.5 cm2 postoperative residual disease and no evidence of neuraxis dissemination received 2,340 cGy to the neuraxis whereas all other patients 3 years or older were treated to a neuraxis dose of 3,600 cGy. The primary site of disease or tumor bed was treated to a dose of 5,580 cGy using image-guided techniques.21 Patients who were treated with local-only RT had image-guided delivery of their treatment to cumulative doses selected by the treating physicians.

Primary tumors originated from the posterior fossa (n � 14, 45%), the supratentorial region (n � 16; 52%), and spine (n � 1). Posterior fossa was the most common primary tumor site among patients younger than 3 years (n � 12; 55%). In contrast, supratentorial primary tumors were predominant in the older patients (n � 7; 78%); only two (22%) tumors originated in the posterior fossa. Meta- static disease was present in six patients (27%) at diagnosis (M1 � 2, M2 � 2, M3 � 2); one patient (patient 17) was found to have an asymptomatic renal rhabdoid tumor. All patients with initial metastatic disease were younger than 3 years at diagnosis (Table 2).

Treatment for all patients included surgical resection of the tumor (Table 2). Of the 31 patients, 21 (68%) with ATRT underwent gross total or near total tumor resection (GTR/NTR); 14 of these patients were younger than 3 years. Ten patients (32%) had subtotal resections (STR), eight patients were younger than 3 years at diagnosis. Treatment administered after surgical excision varied depending on patient age (Table 3). All patients younger than 3 years were treated with chemotherapy, three also received RT or CSI. Seven of the nine patients 3 years or older were treated with RT and chemotherapy as outlined in Tables 3 and 4.

Therapeutic Response and Survival

No chemotherapy-related deaths occurred. Of the 22 patients younger than 3 years at diagnosis, 18 experienced recurrent or progressive disease at a median of 0.4 years from diagnosis (range, 0.1 to 0.7 years). Recurrence was local in 13 (72%), distant in 3 (17%), and both local and

Table 2. Clinical and Molecular Features in Pediatric Patients With ATRT

No. of Patients %

� 3 Years Old

22 9 71 29 Tumor location�

Supratentorial 9 7 41 78 Posterior fossa 12 2 55 22 Spine 1 4

Metastasis M0 16 9 73 100 M� 6 0 27 0

Resection GTR/NTR 14 7 64 78 STR 8 2 36 22

Alterations in chromosome 22 No 3 1 14 11 Yes 11 5 50 56 Not done 8 3 36 33

Abbreviations: ATRT, atypical teratoid/rhabdoid tumor; M0, no metasta- sis; M�, positive results of cerebrospinal fluid analysis; GTR/NTR, gross total/near total resection; STR, subtotal resection.

�One patient with a primary spinal ATRT was omitted from the EFS by location analysis.

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distant in 2 (11%). Thirteen of the 18 patients with relapsed disease were treated with chemotherapy (n � 4), RT (n � 4), or a combination of chemotherapy and RT (n � 5; Table 3). The five patients who did not receive further treatment experienced a median survival of 0.3 years (range, 0 to 0.3 years). Salvage treatment consisting of chemotherapy only was administered to four patients. Treatment included alkylator-based chemotherapy (cyclophosphamide/cisplatin/ vincristine/etoposide; carboplatin/ifosfamide/etopside (ICE); high-dose cyclophosphamide and topotecan followed by au- tologous hematopoietic stem-cell reconstitution; and oxalipla- tin/topotecan). The median survival was 0.3 years (range, 0.3 to 0.5 years).

Radiation only was employed in the treatment of four patients with recurrent disease, three of four patients had CSI (3,300 to 3,960 cGy), one received local RT (2,100 cGy). The median survival of these patients was 0.4 years (range, 0 to 0.8 years). Finally, five patients were treated with RT and chemotherapy after recurrence was detected. Radiation was administered before the chemotherapy in four of these chil- dren. Two were treated with CSI (2,500 and 3,960 cGy) and three received local RT (5,040 to 5,580 cGy). Chemotherapy in this group included two patients who received high-dose chemotherapy with autologous hematopoietic stem cell reconstitution (one of whom was treated with intrathecal methotrexate) in combination with an alkylator-based

Table 3. Treatment and Outcome in Pediatric Patients With ATRT

Patient Chemotherapy RT (cGy) Response Time to

Relapse (years) Salvage Therapy Status

� 3 years old 1 MOPP 0 PD-L 0.1 Chtx/RT DOD 2 CNS3 0 PD-L 0.7 RT DOD 3 CNS14 0 PD-L 0.4 Rxn/Chtx DOD 4 P9233 0 PD-L 0.5 Rxn/Chtx DOD 5 P9233 0 PD-L 0.3 Rxn/Chtx/RT DOD 6 CYCLO/CDDP/VCR Local CR NA NA NED 7 BB98 CSI CR NA NA NED 8 BB98 0 PD-L 0.5 Rxn DOD 9 BB98 0 PD-L�D 0.3 Rxn DOD 10 BB98 0 PD-L 0.4 RT DOD 11 BB98 0 PD-D 0.1 Chtx DOD 12 BB98 0 PD-L 0.5 None DOD 13 BB98 0 PD-D 0.2 None DOD 14 PBTC-001 0 PD-L 0.4 Rxn/Chtx/RT DOD 15 ICE Local PD-L 0.3 None DOD 16 PBTC-001 0 SD NA NA DOC 17 CYCLO/CDDP/DOX/

DACTINO/VP/IT MTX 0 PD-L 0.5 Rxn/Chtx/RT DOD

18 PBTC-001 0 CR NA NA NED 19 CCG9921 0 PD-L�D 0.5 Chtx DOD 20 PBTC-001 0 PD-L 0.3 Rxn/Chtx/RT NED 21 PBTC-001 0 PD-D 0.5 RT AWD 22 PBTC-001 0 PD-L 0.3 None DOD

� 3 years old 23 ICE 0 PD-L 0.2 RT DOD 24 None 0 PD-L�D 0.3 Rxn/RT NED 25 SJMB96 CSI: AR PD-L 3.8 Rxn/Chtx NED 26 SJMB96 CSI: HR CR NA NA NED 27 SJMB96 CSI: AR CR NA NA NED 28 SJMB96 CSI: HR PD-L�D 2.2 Rxn/Chtx/RT AWD 29 SJMB96 CSI: AR CR NA NA NED 30 SJMB96 CSI: AR CR NA NA NED 31 SJMB96 CSI: AR CR NA NA NED

NOTE. For a description of the specific chemotherapeutic regimens listed, see Table 4. Abbreviations: ATRT, atypical teratoid/rhabdoid tumor; MOPP, nitrogen mustard/vincristine/procarbazine/prednisone; CSI, craniospinal radiation; AR, average

risk; HR, high risk; PD-L, progressive disease locally; Chtx, chemotherapy; RT, radiation; DOD, dead of disease; CNS3, cisplatin/cyclophosphamide/etoposide/ vincristine; CNS14, cyclophosphamide/carboplatinum/etoposide; P9233, cisplatin/cyclophosphamide/etoposide/vincristine; Rxn, surgical resection; NA, not applicable; CYCLO, cyclophosphamide; CDDP, cisplatin; VCR, vincristine; BB98, cisplatin/cyclophosphamide/vincristine/oral etoposide/intrathecal mafos- amide; NED, no evidence of disease; PD-L�D, progressive disease local and distant sites; PD-D, progressive disease at distant sites; CR, complete response; SD, stable disease; DACTINO, actinomycin D; DOX, doxorubicin; VP, etoposide; IT MTX, intrathecal methotrexate; DOC, dead of other causes unrelated to tumor progression; AWD, alive with disease.

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chemotherapy regimen. One patient received cisplatin and etoposide, and one patient was treated with a topoisomer- ase I inhibitor. The median survival in this group was 0.6 years (range, 0.3 to 1.4 years). All patients younger than 3 years with recurrent disease died within 1.5 years of pro- gression with a median survival of 0.4 years (range, 0.06 to1.4 years).

Four of the 22 patients in the younger cohort did not develop recurrent or progressive disease. One patient (pa- tient 16) died of respiratory failure (secondary to complica- tions of surgery at the time of tumor resection) 2.5 months from diagnosis without evidence of progressive disease. The remaining three patients are alive without recurrent disease. One patient (patient 18) who received chemotherapy only electively terminated treatment at 6 months from diagnosis and is without evidence of disease 10 months from diagno- sis. Two patients were treated with surgical resection, che- motherapy, and RT; they are alive 4.8 and 5.8 years from diagnosis (patients 7 and 6, respectively).

In contrast, of the nine patients 3 years of age or older at diagnosis, five remain free of disease at a median of 2.2 years (range, 0.8 to 4.1 years) from diagnosis. Four have experi- enced disease recurrence at a median of 1.2 years from diagnosis (range, 0.2 to 3.9 years; Table 3); recurrence was local in two and both local and distant in two. Two of these patients (patients 23 and 24) did not receive any RT as part of their initial therapy. Three of the four patients who experienced disease recurrence are alive (two with no evi- dence of disease; one alive with disease) at 0.6, 1.5, and 9.5 years after five to eight cycles of ifosphamide, carboplatin, etoposide, and RT in two of the three (local, 1; CSI, 1).

EFS and OS estimates for the entire cohort of 31 pa- tients at 2 years were 31% � 9% and 40% � 10%, respec-

tively. The median length of follow-up for the group younger than 3 years was 0.7 years (range, 0.2 to 5.8 years), and their 2-year EFS and OS estimates were 11% � 6% and 17% � 8%, respectively (Figs 1A and B). For the group 3 years and older at diagnosis, the median length of follow-up was 2.8 years (range, 0.5 to 9.8 years); the 2-year EFS esti- mate was 78% � 14%, and the 2-year OS estimate was

Table 4. Treatment Protocols for Pediatric CNS Tumors

Regimen or Protocol Chemotherapy

Radiation

Dose to Primary Site (cGy)

Dose to Neuraxis (cGy)

� 3 years old MOPP1 Nitrogen mustard/vincristine/procarbazine/prednisone CNS3 Cisplatin/cyclophosphamide/etoposide/vincristine CNS14 Cyclophosphamide/carboplatinum/etoposide CCG9921 Carboplatin/ifosfamide/etoposide/vincristine v

cisplatin/cyclophosphamide/vincristine/etoposide ICE Carboplatin/ifosfamide/etoposide P9233 Cisplatin/cyclophosphamide/etoposide/vincristine BB98 Cisplatin/cyclophosphamide/vincristine/oral etoposide/IT mafosfamide PBTC-001 Cisplatin/cyclophosphamide/vincristine/oral etoposide/IT mafosfamide

� 3 years old SJMB96 Topotecan window (HR only)/cisplatin/HD-cyclophosphamide/vincristine � aBMT AR 5,580 2,340

HR 5,580 3,600 ICE Carboplatin/ifosfamide/etoposide 0 0

Abbreviations: CNS, central nervous system; IT, intrathecal; HR, high risk; HD, high dose; aBMT, autologous bone marrow transplant or autologous peripheral blood stem cell reconstitution; AR, average risk.

Fig 1. Event-free (A) and overall survival (B) estimates for patients with ATRT: solid line indicates patients younger than 3 years old at diagnosis, dashed line those 3 years old or older. The exact log-rank test was used to compare survival estimates for the two groups. P values are based on the true distribution of the test statistic, not on a large-sample assumption.

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89% � 11% (Figs 1A and 1B). Given the striking association between age and EFS (P � .009; Fig 1A) and OS (P � .0001; Fig 1B), further analyses were stratified based on age at diagnosis. Primary tumor location was not predictive of EFS (P � .41). Similarly, EFS was not correlated with M-stage at diagnosis (P � .95), extent of the initial tumor resection (P � .096), or abnormalities in chromosome 22 (P � .82). Separate analysis of the two age groups, how- ever, suggested an association between the extent of surgi- cal resection (GTR/NTR v STR) and OS estimates (P � 0.053; data not shown).

Survival estimates for those patients initially treated with chemotherapy alone were compared with those for patients treated with chemotherapy and RT. In this analysis, we did not consider the chemotherapeutic agents used or doses administered, the extent and dose of RT, or the se- quence in which these treatments were given. For the 21 patients treated with chemotherapy, the 1-year EFS esti- mate was 0%, the 1-year OS estimate was 42% � 11%, and a 2-year OS estimate was 12% � 7% (Figs 2A and 2B). In contrast, the 2-year EFS and OS estimates for the 10 patients treated with chemotherapy and RT (three from the younger group and seven from the older group) were both 90% � 10% (Figs 2A and 2B). The correlation between treatment administered and EFS (P � .0003) and OS (P � .007) in our patient cohort with RT associated with improved survival.

Therapy received was dependant on age, disease location, and disease extent, and thus the survival differences ob- served are likely attributable to multiple confounding fac- tors. It is notable, however, only two long-term survivors (� 24 months from diagnosis) in children younger than 3 years at diagnosis from the current cohort both received RT as part of their up-front therapy, before the development of progressive disease.

DISCUSSION

ATRT is a rare aggressive CNS tumor of unclear histo- genesis.2,22,23 The diagnosis is challenging, as there may be significant microscopic overlap with other embryonal tu- mors.12,24 Effective therapy for patients with ATRT has remained elusive. Occasional anecdotal reports of success- ful treatment are noted; however, no regimen appears to be consistently curative with this disease. At a National Cancer Institute (NCI) -sponsored multi-institutional workshop2

data were presented that demonstrated infants have a poor prognosis. Preliminary data for children 3 years and older suggested that they might have a better survival rate. The current series confirms the preliminary findings from the NCI workshop and includes an expanded cohort of older children.

Molecular and cytogenetic analysis initially implicated abnormalities of 22q11.2 in the pathogenesis of both ATRT and malignant rhabdoid tumor (MRT)12,13 and subse- quently, the SMARCB1 gene was identified in this region.10

As part of the SWI/SNF chromatin remodeling complex, SMARCB1 functions as a DNA-binding protein, facilitating SWI/SNF-mediated cotransactivation of genes involved in cell cycle regulation.13,25,26 Homozygous deletions or trun- cation mutations of the SMARCB1 gene abrogate SWI/ SNF-imposed cell-cycle arrest11,13 and have been identified in up to 75% of ATRTs evaluated.9,13,27,28 The majority (76%) of ATRTs in the current study likewise had demon- strable losses of material from chromosome 22, including the SMARCB1 locus by FISH analysis.

Similar to Biegel et al,14 approximately one quarter of our ATRTs harbored homozygous deletions of SMARCB1. It is interesting to note that all of these cases, as well as the majority of those showing hemizygous SMARCB1 dele- tions, had much larger regions of loss involving chromo- some 22. A high proportion of cells in these cases showed loss of both SMARCB1 (22q11.2) and a subtelomeric target, PANX2 (22q13.3), indicative of monosomy 22. Apart from the observations by Burger et al22 in a study that describes frequent monosomy 22 in ATRTs using a chromosome 22 paint probe, little comment has been made on the fre- quency of monosomy 22 in these tumors detectable by modern molecular techniques, particularly FISH. In most

Fig 2. Event-free (A) and overall survival estimates (B) for patients treated with chemotherapy (solid line) and chemotherapy/RT (dashed line). Stratified exact log-rank test was used to assess differences in survival estimates relative to other risk factors. Age at diagnosis was the basis of stratification. P values are based on true distribution of the test statistic, not a large- sample assumption.

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cases, locus-specific probes targeting the 22q11.2 region were paired with probes to nearby genes such as NF2 and EWS,9,11,28 which did not allow assessment of the distant subtelomeric region of chromosome 22 as was the case in the current study. Likewise, LOH and sequencing studies limit their focus to only SMARCB1.11,13,24 It would appear then that our findings and those of Burger et al22 indicate that monosomy 22, as opposed to smaller deletions limited to SMARCB1, may account for the significant proportion of the structural losses involving chromosome 22 in ATRT.

We found that in children 3 years or older at diagnosis of ATRT, treatment with high-dose alkylator-based chemo- therapy and RT resulted in outcomes that are consistently superior to infants; eight of nine patients were alive at a median of 2.2 years from diagnosis. Disease recurrence developed in four patients in this cohort. Three patients are currently free of disease at 0.6, 1.5, and 9.5 years from diagnosis after therapy with ICE chemotherapy and with or without RT, suggesting that this combination may be a potential useful salvage therapy for this patient cohort.

Prognosis for infants and young children younger than 3 years at diagnosis of ATRT remains dismal. Our observa- tions and those of others indicate younger patients are more likely to have disseminated disease at diagnosis and tend to develop disease progression and/or recurrence with higher frequency and earlier in the course of therapy than older patients. Further, in contrast to the older children, recur- rent and/or progressive ATRT in children 3 years or younger appears refractory to salvage therapy.

Objective comparison of treatment efficacy between the two patient groups was problematic because of the heterogeneity in chemotherapeutic regimens administered and variability in the use of up-front RT. Disease progres- sion occurred in 18 patients (82%) in the younger patient group and was seen early in the course of treatment. In all cases, recurrent disease occurred at the same time patients

were receiving chemotherapy. None of the 18 patients was receiving concomitant RT, and only one patient (patient 15) had undergone prior RT. Further attempts at curative therapy after disease progression in this group were uni- formly unsuccessful; all patients experienced a rapidly fatal course irrespective of the treatment (or lack thereof) ren- dered. Review of the literature demonstrates similar sur- vival rates.29-31

RT has been associated with prolonged survival of older children and adults with ATRT. Hence, it is not sur- prising that in the current series the only long-term survi- vors in the younger patient cohort received RT early in the course of their treatment. Of the 18 young children with recurrent disease in our study, 15 experienced recurrence within 26 weeks of diagnosis, similar to other previous reports of brief progression-free intervals averaging 5 months (median, 4 months).2,20,22,29,31 It is notable that the only two long-term survivors (� 24 months from diagno- sis) in our younger patient cohort both received RT as part of their up-front therapy. Additionally, the only patient in the older cohort who died was not treated with up-front RT. This prompts one to consider the utility of early focal RT for infants and young children with ATRT as the majority of patients develop progressive disease early, within 20 to 24 weeks of diagnosis.

■ ■ ■

Acknowledgment

We thank Julia Cay Jones for her editorial assistance and Jana Freeman for data management. We also thank the physicians and nursing staff who provided outstanding clinical care for the patients in this study.

Authors’ Disclosures of Potential

Conflicts of Interest

The authors indicated no potential conflicts of interest.

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