A multimodal strategy based on surgery, radiotherapy, ICE regimen and high dose chemotherapy in atypical teratoid/rhabdoid tumours: A single institution experience

Article (PDF Available)inJournal of Neuro-Oncology 92(2):177-183 · April 2009with51 Reads
DOI: 10.1007/s11060-008-9750-y
Purpose Atypical Teratoid/Rhabdoid Tumour is a rare and aggressive childhood tumour. The outcome of a series treated with the same multimodal strategy was reported. Patients The patients were treated with surgery, 2 courses of ifosfamide/carboplatin/etoposide(ICE), 2 courses of cyclophosphamide/etoposide/carboplatino/thiotepa (CECAT) or 2 other ICE courses, high dose chemotherapy (HDC) and radiotherapy. Results Eight patients underwent primary surgery achieving a complete removal in 3. Progressive disease (PD) occurred in 2/8 patients during ICE courses and in 3/4 during CECAT courses. After 4 courses 5 patients presented a PD. HDC was performed in 3 patients followed by local radiotherapy. The Kaplan Meier OS and EFS probability at 5years are, respectively, 50% (CI 11–80%) and 33% (CI 6–66%). Conclusion A strategy based on surgery, including a second surgical look, and on radiotherapy appears the best option. ICE regimen and HDC correlate with good prognosis in some patients but this approach needs further evaluation.
A multimodal strategy based on surgery, radiotherapy, ICE
regimen and high dose chemotherapy in atypical teratoid/
rhabdoid tumours: a single institution experience
Paola Fidani Æ Maria Antonietta De Ioris Æ Annalisa Serra Æ Luigi De Sio Æ
Ilaria Ilari Æ Raffaele Cozza Æ Renata Boldrini Æ Giuseppe Maria Milano Æ
Maria Luisa Garre
Æ Alberto Donfrancesco
Received: 13 August 2008 / Accepted: 17 November 2008 / Published online: 29 November 2008
Ó Springer Science+Business Media, LLC. 2008
Abstract Purpose Atypical Teratoid/Rhabdoid Tumour
is a rare and aggressive childhood tumour. The outcome of
a series treated with the same multimodal strategy was
reported. Patients The patients were treated with surgery, 2
courses of ifosfamide/carboplatin/etoposide(ICE), 2 cour-
ses of cyclophosphamide/etoposide/carboplatino/thiotepa
(CECAT) or 2 other ICE courses, high dose chemotherapy
(HDC) and radiotherapy. Results Eight patients underwent
primary surgery achieving a complete removal in 3. Pro-
gressive disease (PD) occurred in 2/8 patients during ICE
courses and in 3/4 during CECAT courses. After 4 courses
5 patients presented a PD. HDC was performed in 3
patients followed by local radiotherapy. The Kaplan Meier
OS and EFS probability at 5 years are, respectively, 50%
(CI 11–80%) and 33% (CI 6–66%). Conclusion A strategy
based on surgery, including a second surgical look, and on
radiotherapy appears the best option. ICE regimen and
HDC correlate with good prognosis in some patients but
this approach needs further evaluation.
Keywords Atypical teratoid/rhabdoid tumour
Survival ICE regimen High dose chemotherapy
Atypical Teratoid/Rhabdoid Tumour (ATRT) of the Cen-
tral Nervous System (CNS) is a rare disease accounting for
less than 5% of all paediatric CNS tumours. It is most
common before the age of 36 months [1, 2].
ATRT is a malignant embryonal tumour with biological
characteristics and histological features similar to the
malignant rhabdoid tumour of the kidney [3, 4]. In 1987
Rorke [5] named this tumour ‘atypical teratoid/rhabdoid’
to stress the association of different components: rhabdoid,
primitive neuroepithelial, mesenchymal and epithelial, in
analogy with teratomatous tumours.
Molecular cytogenetics has demonstrated deletion of
chromosome 22q11.2 in ATRT tumours; the chromosome
22q11.2 harbours the suppressor gene SMARCB1—also
known as hSNF5/INI1—and a mutation of hSNF/INI gene
has been implicated in peripheral rhabdoid tumours and
atypical teratoid/rhabdoid tumours of the central nervous
system [6, 7].
Recently, immunohistochemical lack of nuclear INI
protein has been described as a characteristic finding in
atypical teratoid/rhabdoid tumours and has been proposed
as a useful maker to distinguish these tumours from other
malignant paediatric central nervous system tumours [8].
The data on outcomes is based almost exclusively on
small, retrospective series: ATRT is a deadly disease with
an overall survival of only 12 months as reported in ret-
rospective studies [2, 9, 10] and only seven long-term
survivors were reported in a 2005 literature review by
Zimmerman [11].
Although ATRT is now recognised as a distinct entity
with well-characterised molecular and cytogenetic aspects,
no specific treatment guidelines for affected patients have
yet been identified, probably, one could surmise, as a result
P. Fidani (&) M. A. De Ioris A. Serra L. De Sio I. Ilari
R. Cozza G. M. Milano A. Donfrancesco
Division of Pediatric Oncology Unit, Ospedale Pediatrico
Bambino Gesu
, Piazza S.Onofrio 4, Rome 00100, Italy
e-mail: fidani@opbg.net
R. Boldrini
Department of Pathology, Ospedale Pediatrico Bambino Gesu
Rome, Italy
M. L. Garre
Division of Pediatric Haematology and Oncology,
Ospedale G.Gaslini, Genoa, Italy
J Neurooncol (2009) 92:177–183
DOI 10.1007/s11060-008-9750-y
of the relative rarity of this tumour. A recent retrospective
series reported that whilst a combination of radiotherapy
and high dose alkylating chemotherapy was associated
with a favourable prognosis in older patients, outcomes for
children aged less than 36 months at diagnosis and for
metastatic patients have always been dismal [12].
Since December 1999, at the Ospedale Pediatrico
Bambino Gesu
(OPBG) a same multimodal strategy has
been used for all ATRT patients, independent of age and
disease status at diagnosis. We now present clinical char-
acteristics and survival rates of our series treated
prospectively with the same intensive treatment strategy.
Patients and methods
From December 1999, all patients with histological proven
diagnosis of ATRT were treated after primary surgery with
four courses of conventional chemotherapy (CT) followed
by high dose chemotherapy (HDC) and at the end of
treatment radiotherapy (RT). Informed consent was
obtained from parents.
The chemotherapy regimen proposed for conventional
CT was 2 courses of ifosfamide/carboplatin/etoposide
(ICE) followed by 2 other courses of ICE or cyclophos-
phamide/etoposide/carboplatino/thiotepa (CECAT). In
ICE courses ifosfamide was administered at a dose of
1800 mg/m
/day for 5 days, carboplatin at 400 mg/m
day for 2 days and etoposide at 100 mg/m
/day for
5 days. When ICE was given for 4 courses, drug dosage
was modified as follows: ifosfamide 2000 mg/m
/day for
3 days, etoposide 150 mg/m
/day for 3 days, whilst car-
boplatin was administered at the same dose (400 mg/m
day for 2 days). In CECAT courses, cyclophosphamide
was administered at 300 mg/m
/day for 2 days; etoposide
at 100 mg/m
/day for 3 days; carboplatin at 500 mg/m
day for 2 days and thiotepa 10 mg/m
/day for 2 days. The
conditioning HDC was based on etoposide 600 mg/m
thiotepa 750 mg/m
and cyclophosphamide 120 mg/kg.
The cumulative dosage of etoposide varied between
2200 mg/m
and 2400 mg/m
in the two different
Disease extent was evaluated by computed tomography
and/or magnetic resonance imaging (MRI) of the brain and
spine at diagnosis and after primary surgery. Response was
evaluated after two and four courses of conventional CT.
Peripheral blood stem cells were collected after ICE
Histology was reviewed by the same pathologist for
morphologic assessment and immunohistochemical analy-
sis. Sections of formalin-fixed and paraffin-embedded
tumour samples were examined with haematoxilin–eosin
routine stains for morphology.
Immunohistochemical studies were performed on sec-
tions from formalin-fixed, paraffin-embedded tissue from
representative blocks of each case. The immunohisto-
chemical procedure included heat-induced epitope
retrieval, standard Peroxidase–antiperoxidase technique
and automated immunostaining with DAKO immuno-
stainer. The following primary antibodies were used: anti-
Vimentin antibody (monoclonal, prediluted Dako), anti-
EMA antibody (monoclonal, prediluted Dako), anti-SM
actin (monoclonal, dilution 1:400 Novo Castra), anti-
cytokeratin (policlonal, prediluted Dako), anti-GFAP (po-
liclonal, prediluted Dako), anti-synaptophisin (policlonal,
prediluted Dako), anti-desmin (monoclonal, dilution 1:20
Dako) and anti-INI1 (BAF 47, monoclonal, dilution 1:100
BD-Transduction Laboratories). DAB was used as chro-
mogen. Appropriate positive and negative controls were
used. In three cases, ultra-structural examination was per-
formed using tissue specimens retrieved from paraffin
blocks, with a 10C Zeiss Electron Microscope.
Overall survival (OS) was defined as the time interval
between the date of diagnosis and the date of death from
any cause or the date of the last follow-up. Progression free
survival (PFS) was defined as the time interval between the
date of diagnosis and the date of first relapse/progression or
the date of the last follow-up. The Kaplan–Meier method
was used for the estimation of survival curves [13]. Anal-
ysis were performed with the Stata 9.0 statistical software
package (StatCorp LP, Texas, USA).
Eight patients, 6 male and 2 female, were treated according
to the proposed protocol. The last patient was enrolled in
February 2008. The median age was 39 months (range 16–
104 months); 4 patients were younger than 36 months at
the time of diagnosis. At admission, vomiting and/or
cephalea were the most frequent symptoms whilst the
tumor was supratentorial in 6 patients and only one patient
presented metastasis. The charachteristics of patients are
resumed in Table 1.
All tumour samples but one were reviewed to confirm the
ATRT diagnosis. In the case of the patient without an
available tumour sample, the diagnosis had been confirmed
by the national pathologist reviewer for paediatric CNS
The morphological elements analysed included the
presence of typical rhabdoid cells with eosinophilic
178 J Neurooncol (2009) 92:177–183
globular cytoplasmic inclusions and eccentric nuclei and
primitive neuroectodermal cells. The mitotic rate was
graded as low (?), moderate (??) or high (???). The
immunohistochemical expression of vimentin, EMA, SMA
actin, GFAP, synaptofisin, desmin, citokeratin and INI1,
and the ultra-structural detection of diagnostic filamentous
whorls were reported. The results of pathology review are
presented in Table 2. In Fig. 1 the histological features of
representative cases are presented.
Treatment and response
Primary surgery was performed in all patients resulting in a
complete resection in 3 patients. Two months after
incomplete surgery, one patient underwent second surgical
look for a early progression; only after the second incom-
plete resection this patient was referred to our Oncology
Unit and started chemotherapy. One patient with complete
resection was referred after 4 ICE courses. Treatment,
response and outcome of patients are resumed in Table 3.
Two ICE courses were administered in all 8 patients:
after the first two ICE courses, 3 out of 5 patients with a
local residual achieved a partial response (PR) and only the
metastatic patient (patient 6) presented a progression at
metastatic site. After the CECAT courses 3 out of the 4
patients presented a PD whilst one of 3 patients progressed
after further ICE courses. Patient 8, with a gross residual
disease after surgery, achived a PR after 2 ICE courses; in
Fig. 2 MRI soon after surgery and after 2 ICE is presented.
At the end of primary chemotherapy 6 out of 8 patients
presented a progressive disease.
Three patients completed the proposed protocol whilst
the later patient is on treatment.
Three patients received HDC based on an ETC regimen
followed by PBSC rescue. Of these, 2 patients had achived
a CR after primary surgery and/or chemotherapy and the
latter patient, relapsed after primary chemotherapy, was in
CR after second surgey. After blood marrow recovery,
radiotherapy was administered at a dose of 45 Gy on the
whole brain with a boost on the primary tumour up to 55–
Table 1 Patients Characteristics
Pt Sex Age at Dx (months) Symptoms Tumour location Metastasis
1 M 104 Cephalea Supratentorial No
2 F 29 Emipalsy Supratentorial No
3 M 19 Vomiting and walk disorder Posterior Fossa No
4 M 42 Cephalea, vomiting Supratentorial No
5 M 91 Seizure Supratentorial No
6 M 16 Vomiting Posterior Fossa Yes, spinal
7 M 36 Seizure Supratentorial No
8 F 44 Cephalea, vomiting, strabismus Supratentorial No
Abbreviations: Pt Patient, Dx Diagnosis, F Female, M Male
Table 2 Morphologic and Immunohistochemical Characteristics
Patients 1 2 3 4 5 6 7 8
Rhabdoid Cells ?? ? ? NK ???
Primitive Neuroectodermic Cells ?? - - NK ??-
Mitosis ?? ??? ??? ?? NK ??? ??? ???
Vimentin ?? ? ? NK ???
EMA ?? - ? NK -??Focal
SMA ?? ? ? NK -?-
Synaptophysin ?? - - NK ??NP
GFAP ?? ?- --??Focal
Desmin -- - - NK ---
CK MNF116 ??Focal ??Focal NK NP NP ? Focal
INI 1 NP NP -- ----
EM:Whorled bundles ?? NP NP NP ? NP NP
Abbreviations: NP Not performed, ? Positive result of immunohistochemical assay and - Negative result (see text for details), NK Not known
For patients 5 histology was performed by outside pathologist
J Neurooncol (2009) 92:177–183 179
60 Gy. The radiotherapy was started at 9, 9 and 10 months,
respectively, after initial diagnosis.
No treatment related deaths occurred during the whole
treatment; haematological and extra-haematological toxic-
ities were manegeable.
In our small series relapse or progression occurred in 6
patients at a median time of 5 months from diagnosis
(range 4–29 months) and in all but one during initial
Of the 8 patients, 4 were still alive at the time of writing,
one is lost to follow-up at 7 months from diagnosis whilst
three had died. The median overall survival was 10 months
(range 5–105 months) whilst the estimated Kaplan–Meier
OS and EFS probability at 5 years are, respectively, 50%
(CI 11–80%) and 33% (CI 6–66%).
Three patients died with PD at 8, 8 and 13 months from
diagnosis, respectively. In these three cases, surgery
achieved a complete resection in only one patient and
chemotherapy was started 25, 42 and 72 days after surgery.
Of the 5 surviving patients, 2 are in CR at 101 and
105 months from diagnosis, one relapsed patient is still
alive in SD at 38 months on palliative treatment with
temozolomide, one relapsed patient was lost to follow-up at
7 months from diagnosis soon after second surgery, and the
last patient is still on treatment in PR after the first 2 ICE
courses. The two surviving patients in CR received radio-
therapy at 9 and 10 months after initial diagnosis,
respectively, and received high dose chemotherapy.
Among the 5 surviving patients surgery led to a complete
resection in one instance.
Of the 4 patients who were below 36 months of age at
the time of initial diagnosis, three experienced an early
relapse whilst of the 4 older patients, 3 patients relapsed
but one is still alive in CR at 101 months from diagnosis.
The ATRT is a rare and aggressive CNS tumour of
childhood, especially of infancy [14]. It was clearly iden-
tified only in 1987 by Rorke et al. before then the tumour
was classified as medulloblastoma or primitive neuroecto-
dermal tumour or choroids plexus tumour [2].
The histological diagnosis of rhabdoid tumor is based on
the recognition of large, rhabdomyoblast-like cells with
vesicular nuclei, prominent nucleoli and characteristic
eosinophilic paranuclear cytoplasmic inclusions. Small,
less differentiated neuroectodermal-like cells are fre-
quently intermingled. Mitotic rate is high and areas of
necrosi are frequent.
Tumor cells express diffusely Vimentin and show vari-
able expression of cytokeratin, neuroectodermal and
myogenous markers whilst INI 1 is invariably negative.
On electron microscopy examination tumor cells contain
characteristic prominent paranuclear spheroidal aggregates
of intermediate filaments in a whorled pattern, largely
displacing nucleus and membranous organelles. Otherwise,
Fig. 1 Pathological features in
Fig. 1a, neoplastic proliferation
is arranged in densely cellular
solid areas of intermediate-sized
cells with high mitotic and
apoptotic rate (HE 109 original
magnification). In Fig. 1b,at
higher magnification, the
rhabdoid-type cells with
eccentrically placed nuclei and
large poligonal, eosinophilic
cytoplasm are intermingled with
smaller cells (HE 409 original
magnification). In Fig. 1c, some
rhabdoid cells show a strong
cytoplasmic expression of
cytokeratin Cytokeratin
MNF116 (609 original
magnification). In Fig. 1d, the
ultrastructural pattern of rhaboid
cells is characterized by nodular
paranuclear aggregation of
densely packed intermediate
filaments organized into whorls
(Uranyl acetate, lead citrate
37,5009 original magnification)
180 J Neurooncol (2009) 92:177–183
the cytoplasm contains little other than a few cysternae of
rough endoplasmic reticulum and mitochondria.
Over the last two decades, a very limited number of
publications reported brief and almost always retrospective
data for different treatment strategies and outcomes. A
recent review suggested a positive impact on outcome
associated with gross total resection of the tumour, the
efficacy of standard and intensified chemotherapy in a
small minority of patients and an association between
survival and early radiotherapy [12]. The survival rate of
ATRT is extremely poor in young children and, as
observed in initial publications, the outcome with con-
ventional treatment is dismal [2, 9, 10, 12]. In a
retrospective study of 37 patients covering a 19-year study
period, Tekautz et al. [12] observed a good prognosis with
a 2-years EFS of 78% in children aged 3 years or older and
a dismal prognosis with only a 2-years EFS of 11% in
younger patients; the patients were treated with various
chemotherapy regimen. Age therefore, seems a major
predictor of survival. In the same study, the combination of
radiotherapy and high dose alkilating chemotherapy seems
a good option for older ATRT patients and the ICE (if-
osfamide, carboplatin and etoposide) regimen was
proposed as salvage therapy.
In our series, all ATRT patients, since 1999, were
treated with the same regimen based on four courses of
conventional chemotherapy, high dose chemotherapy and
local radiotherapy. The two CECAT courses were replaced
by two ICE courses after the fourth patient, given the high
incidence of relapse or progression (3 out of 4) during the
CECAT regimen.
Even if the total number of patients included in this
series is small, the OS probability at 5 years of 50% is
encouraging. As reported by other authors [12], the out-
come for younger children is typically dismal with more
aggressive disease: in our series, an early relapse time of
5 months from diagnosis was observed during chemo-
therapy treatment in younger patients, further confirming
age as a major predictive characteristic.
As suggested by Hilden [1], the quality of surgery
appears to be a significant prognostic factor. Two of the 5
surviving patients achieved a complete resection after
surgery and only one of the 3 deceased patients achieved a
complete resection—in this instance, the 16 month boy
who was metastatic at the time of diagnosis, had a com-
plete removal of the primary lesion. Surgery is a promising
option, even in relapsed patients: in our series one relapsed
patient remains alive after second surgery followed by
HDC an RT.
Radiotherapy plays an important role in the manage-
ment of ATRT patients. In this series, 3 patients received
cranial radiotherapy with 45 Gy with a boost on the pri-
mary tumour up to 55–60 Gy and none presented a spinal
Table 3 Treatment and Outcome
Pt Surgical
Primary CT Response after
2 courses
Disease Status
after primary CT
HDC RT Relapse/
TT after
1 Residual ICE 9 2, CECAT 9 1 SD PD No Yes, at PD Yes 5 RT DOD, 8
2 Residual ICE 9 2, CECAT 9 2 PR CR Yes Yes No 105 NED, 105?
3 Residual ICE 9 2, CECAT 9 2 SD PD No No Yes 5 CDDP/VP16 DOD, 8
4 Complete ICE 9 2, CECAT 9 2 PD Yes, at PD Yes, at PD Yes 4 Surgery/HDC/RT NED,101?
5 Complete ICE 9 4 CR Yes Yes Yes 29 TVD x6/temozolomide AWD, 38?
6 Complete ICE 9 2 PD PD No Yes, at PD Yes 4 Temozolomide DOD, 13
7 Residual ICE 9 4 PR PD No Yes Yes 5 Surgery AWD, 7?
8 Residual ICE 9 2 PR On treatment On treatment On treatment No 5 AWD, 5?
Abbreviations: pt Patient, CT Chemotherapy, ICE Ifosfamide/carboplatin/etoposide, CECAT Cyclophosphamide/etoposide/carboplatino/thiotepa, HDC High dose chemotherapy, RT Radio-
therapy, SD Stable disease, CR Complete response, PR Partial response, PD Progressive disease, PFS Progression free survival, TT Treatment, CDDP Cisplatin, VP16 Vepeside, TVD
Topotecan/vincristine/doxorubicin, DOD Died of disease, NED Non-evidence of disease, AWD Alive with disease
J Neurooncol (2009) 92:177–183 181
relapse. Zimmerman et al. [10] reported four long-term
survivors—median follow-up 37 months—treated with
multimodal strategy including craniospinal radiotherapy.
None of the long-term survivors in our study—101 and
105 months since diagnosis—received spinal radiotherapy
but both received high dose chemotherapy.
The radiotherapy was started at a median time of
9 months and we are not yet in a position to confirm a
relationship between OS and the time interval between
surgery and the start of radiotherapy, as suggested by Chen
[15], owing to the small number of patients who received
RT. We observed that patients who died received RT either
at progression or not at all.
The ICE regimen appears an interesting option for
delaying RT and collecting PBC. There is no evidence of
difference in the response rate between two and four
courses of conventional chemotherapy, and there is no
difference in response between the different modalities of
ICE administration.
The role of high dose and conventional chemotherapy is
not clear. This is in spite of the fact that high dose che-
motherapy was performed in two surviving and in CR
patients, and the conventional chemotherapy achieved a
CR after 4 courses in one patient. We observed a 6 months
progression free survival in one younger boy with meta-
static spread during temozolomide administration. A
protracted temozolomide schedula could be used to delay
radiotherapy in younger patients.
In conclusion, we suggest a multimodal strategy for the
treatment of all ATRT patients.
Our experience confirms an important role of surgery
and radiotherapy in the treatment of ATRT patients. The
positive impact of ICE courses and/or high dose
chemotherapy which also demonstrated efficacy in some
patients needs further evaluation. In younger patients a
strategy based on conventional and high dose chemother-
apy appears to be the only option for controlling local and
metastatic progression prior to RT will be possible. In older
patients, surgery and early radiotherapy seem to be a valid
therapeutic option.
Acknowledgements The authors would like to thank G. Izzi MD
who referred one patient after conventional chemotherapy and F.
Giangaspero MD who reviewed the histology of the same patient. The
authors would also like to thank L. Rava
PhD for statistical support
and R. Trenchard PhD for editing the manuscript.
1. Hilden JM, Meerbaum S, Burger P et al (2004) Central nervous
system atypical teratoid/rhabdoid tumor: results of therapy in
children enrolled in a registry. J Clin Oncol 22(14):2877–2884.
2. Lefkowity IB, Rorke LB, Packer RJ et al (1987) Atypical teratoid
tumor of infancy: definition of an entity. Ann Neurol 22:448–449
3. Packer RJ, Biegel JA, Blaney S et al (2002) Atypical teratoid/
rhabdoid tumor of the central nervous system: report on work-
shop. J Pediatr Hematol Oncol 24:337–342. doi:10.1097/00043
4. Kleihues P, Louis DN, Scheithauer BW et al (2002) The WHO
classification of tumours of the nervous system. J Neuropathol
Exp Neurol 61:215–225
5. Parwani AV, Stelow EB, Pambuccian SE et al (2005) Atypical
teratoid/rhabdoid tumor of the brain: cytopathologic characteris-
tics and differential diagnosis. Cancer 25(105):65–70. doi:
6. Biegel JA, Fogelgren B, Zhou JY et al (2000) Mutations of the
INI1 rhabdoid tumor suppressor gene in medulloblastomas and
primitive neuroectodermal tumours of the central nervous system.
Clin Cancer Res 6:2759–2763
Fig. 2 MRI of patient 8 soon
after primary surgery and after 2
course of conventional
chemotherapy. The patient
presents a gross residual disease
after surgery (Fig. 2a). After 2
ICE courses, she achived a PR
(Fig. 2b)
182 J Neurooncol (2009) 92:177–183
7. Biegel JA, Tan L, Zhang F et al (2002) Alterations of the hSNF5/
INI1 gene in central nervous system atypical teratoid/rhabdoid
tumours and renal and extrarenal rhabdoid tumours. Clin Cancer
Res 8:3461–3467
8. Haberler C, Laggner U, Slavc I, Czech T, Ambros I, Ambros P,
Budka H, Hainfellner JA (2006) Immunohistochemical analysis
of INI1 protein in malignant pediatric CNS tumours and in a
fraction of primitive neuroectodermal tumours without rhabdoid
phenotype. Am J Surg Pathol 30:1462–1468. doi:10.1097/01.pas.
9. Burger PC, Yu IT, Tihan T et al (1998) Atypical teratoid/rhab-
doid tumor of the central nervous system: a highly malignant
tumor of infancy and childhood frequently mistaken for medul-
loblastoma: a pediatric oncology group study. Am J Surg Pathol
22:1083–1092. doi:10.1097/00000478-199809000-00007
10. Rorke LB, Packer RJ, Biegel JA (1996) Central nervous system
atypical teratoid/rhabdoid tumours of infancy and childhood:
definition of an entity. J Neurosurg 85:56–65
11. Zimmerman MA, Goumnerova LC, Proctor M, Scott RM, Mar-
cus K, Pomeroy SL, Turner CD, Chi SN, Chordas C, Kieran MW
(2005) Continuous remission of newly diagnosed and relapsed
central nervous system atypical teratoid/rhabdoid tumor. J Neu-
rooncol Mar 72:77–84
12. Tekautz TM, Fuller CE, Blaney S et al (2005) Atypical teratoid/
rhabdoid tumours (ATRT): improved survival in children 3 years
of age and older with radiation therapy and high-dose alkylator-
based chemotherapy. J Clin Oncol 23:1491–1499. doi:10.1200/
13. Kaplan EL, Meier P (1959) Nonparametric estimation from
incomplete observation. J Am Stat Assoc 53:457–481. doi:
14. Reddy AT (2005) Atypical teratoid/rhabdoid tumours of the
central nervous system. J Neurooncol 75:309–313. doi:10.1007/
15. Chen YW, Wong TT, Ho DM et al (2006) Impact of radiotherapy
for pediatric CNS atypical teratoid/rhabdoid tumor (single insti-
tute experience). Int J Radiat Oncol Biol Phys 64:1038–1043. doi:
J Neurooncol (2009) 92:177–183 183
    • "The second cycle consisting of cyclophosphamide and vincristine, while myelosuppressive, is usually well tolerated if infection is prevented. Regarding PEI or ICE-type chemotherapy several previous reports suggested that a combination of cisplatin, ifosfamide, and etoposide is efficacious in patients with ATRTs [11, 34]. This is in accordance with our own observation. "
    [Show abstract] [Hide abstract] ABSTRACT: Atypical teratoid rhabdoid tumors (ATRTs) are recently defined highly aggressive embryonal central nervous system tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease-specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy. From 1992 to 2012, nine patients initially diagnosed correctly as ATRT (cohort A, median age 24 months) were treated according to an intensive multimodal regimen (MUV-ATRT) consisting of three 9-week courses of a dose-dense regimen including doxorubicin, cyclophosphamide, vincristine, ifosfamide, cisplatin, etoposide, and methotrexate augmented with intrathecal therapy, followed by high-dose chemotherapy (HDCT) and completed with local radiotherapy. Thirteen patients were treated differently (cohort B, median age 30 months) most of whom according to protocols in use for their respective diagnoses. As of July 2013, 5-year overall survival (OS) and event-free survival (EFS) for all 22 consecutive patients was 56.3 ± 11.3% and 52.9 ± 11.0%, respectively. For MUV-ATRT regimen-treated patients (cohort A) 5-year OS was 100% and EFS was 88.9 ± 10.5%. For patients treated differently (cohort B) 5-year OS and EFS were 28.8 ± 13.1%. All nine MUV-ATRT regimen-treated patients are alive for a median of 76 months (range: 16–197), eight in first complete remission. Our results compare favorably to previously published data. The drug combination and sequence used in the proposed MUV-ATRT regimen appear to be efficacious in preventing early relapses also in young children with M1–M3 stage disease allowing postponement of radiotherapy until after HDCT.
    Full-text · Article · Feb 2014
    • "Although this analysis may show a possible benefit to the use of methotrexate and further supports better outcomes with more complete resection, the 3-year estimated EFS is comparable to that achieved with other therapeutic approaches. A group from Italy reported eight patients treated on a clinical trial that included radiotherapy; ifosfamide, carboplatin, and etoposide (ICE); and HDC (Fidani et al., 2009 ). They had originally included cyclophosphamide, etoposide, carboplatin, and thiotepa, but after three of four patients had progressive disease on this therapy, they decided to exclude these courses and replace them with additional ICE. "
    [Show abstract] [Hide abstract] ABSTRACT: Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1-2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases. ATRT is characterized by loss of the long arm of chromosome 22 which results in loss of the hSNF5/INI-1 gene. INI1, a member of the SWI/SNF chromatin remodeling complex, is important in maintenance of the mitotic spindle and cell cycle control. Overall survival in ATRT is poor with median survival around 17 months. Radiation is an effective component of therapy but is avoided in patients younger than 3 years of age due to long term neurocognitive sequelae. Most long term survivors undergo radiation therapy as a part of their upfront or salvage therapy, and there is a suggestion that sequencing the radiation earlier in therapy may improve outcome. There is no standard curative chemotherapeutic regimen, but anecdotal reports advocate the use of intensive therapy with alkylating agents, high-dose methotrexate, or therapy that includes high-dose chemotherapy with stem cell rescue. Due to the rarity of this tumor and the lack of randomized controlled trials it has been challenging to define optimal therapy and advance treatment. Recent laboratory investigations have identified aberrant function and/or regulation of cyclin D1, aurora kinase, and insulin-like growth factor pathways in ATRT. There has been significant interest in identifying and testing therapeutic agents that target these pathways.
    Full-text · Article · Sep 2012
    • "Most reports have suggested a slight male predominance (29). Despite multimodal treatment, including intensive chemotherapy, surgery and at times radiation, prognosis is very poor and most patients fail to survive 1 year after diagnosis (2, 11, 14, 15, 21, 34, 43). The " teratoid " component of ATRTs is derived from histologic evidence of divergent differentiation along mesenchymal, neuroectodermal and epithelial lines (7, 29, 36). "
    [Show abstract] [Hide abstract] ABSTRACT: As "atypical teratoid rhabdoid tumors" (ATRTs) may mimic "small round blue cell tumors" (SRBCT), we reexamined our ATRT experience focusing upon INI-1 immunohistochemistry (IHC). All high-grade pediatric brain tumors occurring from 1986-2006 at our institution underwent INI-1 IHC. Clinicopathologic data from each INI-1 immunonegative case were reviewed. Additional genetic, epigenetic and IHC analyses (including interrogation of INI-1 and CLDN6) were performed on a subset of the INI-1 immunonegative cases. Twelve INI-1 IHC negative tumors were identified retrospectively, of which only two previously carried the diagnosis of ATRT. Overall, the clinicopathologic and genetic data supported the assertion that all 12 cases represented ATRT. Unexpectedly, three long-term survivors (4.2, 7.0 and 8.5 years) were identified. As hypothesized, "teratoid" and "rhabdoid" histologic features were relatively infrequent despite gross total resections in some cases. Methylation specific polymer chain reaction (PCR) (MSP) revealed a uniform methylation pattern across all cases and gene promoters tested (ie, MGMT, HIC1, MLH3 and RASSF1); notably, all cases demonstrated unmethylated MGMT promoters. Our data demonstate that a primitive non-rhabdoid histophenotype is common among ATRTs and highlights the diagnostic importance of INI-1 IHC. Epigenetically, the MGMT promoter is usually unmethylated in ATRT, suggesting that potential temozolomide-based chemotherapy may be of limited efficacy.
    Full-text · Article · Dec 2011
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