Journal of Neuro-Oncology (2022) 156:599–613

https://doi.org/10.1007/s11060-021-03942-0

CLINICAL STUDY

Final results of the Choroid Plexus Tumor study CPT‑SIOP‑2000

Johannes E. Wolff1,2 · Stefaan W. Van Gool3 · Tezer Kutluk4 · Blanca Diez5 · Rejin Kebudi6 ·
Beate Timmermann7 · Miklos Garami8 · Jaroslav Sterba9,10 · Gregory N. Fuller11 · Brigitte Bison12 ·
Uwe R. Kordes13

Received: 9 November 2021 / Accepted: 31 December 2021 / Published online: 8 January 2022
© The Author(s) 2022

Abstract
Introduction Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established.
Methods CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomiza-
tion for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine
(CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC,
incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal
fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incom-
pletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled.
Results For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%,
respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histo-
logical grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event
free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%,
respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with
CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent
prognosticators.
Conclusions Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset
of CPC can be cured without irradiation.

Keywords Choroid plexus tumors · Chemotherapy · Irradiation · Li–Fraumeni syndrome

Introduction pediatric low-risk CPT (CPP/APP) = “pediatric A”,

infratentorial adult low-risk CPT (CPP/APP) = “adult”, and
Choroid plexus tumors (CPT) are rare brain tumors of the supratentorial pediatric high-risk CPT (all CPC, very few
choroid plexus epithelium. The age-standardized incidence APP/CPP) = “pediatric B” [3–6]. CPC is the typical CPT
rate is 1.0 per million, with an incidence peak in the first seen in Li-Fraumeni Syndrome [7].
year of life at 6.1 per million [1]. The WHO classification Treatment recommendations for CPT include multidis-
differentiates between low-grade choroid plexus papilloma ciplinary approaches, with maximal surgical resection for
(CPPCNS WHO grade 1), intermediate-grade atypical cho- all CPT [8–14], followed by chemotherapy [11, 15–21] and
roid plexus papilloma, characterized by increased mitotic radiotherapy [22–24] for high-risk CPT. The prognosis of
activity (APPCNS WHO grade 2), and high-grade choroid CPC remains dismal when tumor resection is the only treat-
plexus carcinoma, which displays frank signs of malignancy ment modality, and the role, sequence, and intensity of pri-
(CPCCNS WHO grade 3) [2]. DNA methylation profiling mary chemotherapy remain debatable [13, 19, 21].
further segregates three distinct subclass: supratentorial We here report the registry results, and the final results of
the first global trial for CPT, which was designed in the late
1990s by an international multidisciplinary pediatric neu-
* Uwe R. Kordes rooncology collaboration following a metaanalysis [22, 25].
[email protected]
Extended author information available on the last page of the article

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The aims were (a) to initiate a registry for the prospec- for patients with metastatic CPC and APP (Supplemental
tive collection of CPT data, (b) to design a multidisciplinary Table 1a, b).
treatment algorithm supporting clinical care by using infor- Feasibility of the study was tested in a pilot phase com-
mation from single cases and small series [22, 23, 26], and pleted in 2005. The primary objective of the trial was Over-
(c) to perform a randomized interventional study compar- all Survival (OS) time (Table 1c). Performance status at
ing six cycles of carboplatin/etoposide/vincristine (CarbEV) diagnosis was graded on a 1–5 level scale (Table 1d). Tox-
versus cyclophosphamide/ etoposide/vincristine (CycEV). icity was documented in a study-specific grading system
(Supplemental Table 2). Statistical analyses were performed
in SPSS version 18 (IBM), and GraphPad Prism version
Methods and materials 7.00 (GraphPad Software, La Jolla, California, USA, www.​
graph​pad.​com). Survival curves were estimated by the
CPT-SIOP-2000 (NCT00500890) was approved by the SIOP Kaplan–Meier method and compared between histologies.
scientific committee, the leading institution ethics commit- Overall survival (OS) was calculated from time of histo-
tee (Regensburg, Germany), local institutional ethics com- logical diagnosis until death. Event free survival (EFS) was
mittees, and the German Cancer Society in 2000. Written calculated from time of histological diagnosis until tumor
informed consent was obtained from patients, parents, or progression, second malignancy, death, or date last seen
appropriate legal guardians in accordance with national (censored). Progression free survival (PFS) was calculated
laws. from time of histological diagnosis to disease progression,
death, or date last seen (censored).

Registry
Results
Patients with histologically-confirmed newly-diagnosed
CPT were eligible for registration, which included all ages, Registry (Consort Diagram 1, Fig. 2a)
performance status, tumor grade and metastatic status (eli-
gibility criteria listed in Table 1a). Central histology and 173 patients were screened from 85 institutions across 23
radiology reviews, as well as Li–Fraumeni syndrome (LFS) countries from 05-Jan-2000 until 22-Jan-2010. The database
testing, were recommended, but not mandatory. Figure 1 was locked for this analysis in 2020. Central review excluded
depicts the algorithm of registry surveillance for low-risk 15 tumors from the analysis as non-CPT (4 ATRT, 2 low-
CPT (non-metastatic CPP and completely resected non- grade glioma, 1 ependymoma, 2 medulloepithelioma, 2 pin-
metastatic APP). Data from patients receiving non-protocol eal non-CPT, 1 cribriform neuroepithelial tumor, 3 undeter-
therapy were also collected. minable). CPT were upgraded in 12 and downgraded in 17
cases. In 3 cases a local non-CPT diagnosis was revised to
Interventional study CPT. After this review, 158 patients (77 females, 81 males)
were included for further analyses, median follow-up for
Patients with either CPC, metastatic disease, or incompletely these were 7.4 (0.2–17) years; pathology central review was
resected APP were eligible for randomized chemotherapy available in 138 patients (further details: Fig. 2a, b).
intervention (Fig. 1; eligibility criteria listed in Table 1b). The median age at diagnosis for all patients was 1.7 years
Open label randomization was provided by the study center. (0.01–45.6); that for patients with CPP (n = 55) was
Six cycles of chemotherapy were repeated every 28 days 2.7 years, for APP (n = 49) 0.7 years, and for CPC (n = 54)
and consisted of etoposide 100 mg/msq on days 1–5, with 2.1 years. Demographical and clinico-pathological vari-
vincristine 1.5 mg/msq on day 1. The third drug was rand- ables are summarized in Table 2. Performance status on the
omized to either carboplatin 350 mg/msq on days 1 and 2 5-level scale was documented in 46 patients: 20% were in
(Supplemental Fig. 1a: CarbEV) or cyclophosphamide 1 g/ level 1, 56% in level 2, 22% in level 3, and 2% in level 4 or
msq on days 1 and 2 (Supplemental Fig. 1b: CycEV). Radio- 5. Values did not correlate with histology or outcome.
therapy was proposed after two cycles of chemotherapy and LFS testing was performed for only 9 patients, which was
restricted to patients that were at least 3 years of age: local prompted by positive family history in three, and detected
fields with 54 Gy administered in 30 fractions (1.8 Gy/frac- pathogenic TP53 mutations in 1 APP (c.743G>A; p.R248Q)
tion) were prescribed for non-metastatic CPC, APP with and 6 CPC (c.818G>A, p.R273H; codon 170 4 bp del lead-
residual tumor and metastatic CPP. Craniospinal fields of ing to stop in codon 173; c.847C>T, p.R283C; c.356C>G,
35.2 Gy in 22 fractions (1.6 Gy/fraction) with a local boost pA119G; c.742C>T, p.R248W; mutation not communicated
of up to a total of 54 Gy for primary tumor and 49.6 Gy in one). LFS was suspected, but not tested, in one patient
for metastases (both with 1.8 Gy/fraction), were prescribed with CPC who developed subsequent glioblastoma and

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Journal of Neuro-Oncology (2022) 156:599–613 601

Table 1  CPT-SIOP-2000 inclusion and exclusion criteria, outcome, performance status

(a) Eligibility Criteria for Registry

Inclusion (1) Local diagnosis of CPT

a. Choroid plexus papilloma (ICD-O 9390/0)
b. Atypical choroid plexus papilloma (ICD-O 9390/1)
c. Choroid plexus carcinoma (ICD-O 9390/3)
(2) Slides sent for pathology reference review
Exclusion (1) Patient or legal guardian does not consent to enrollment with electronic data processing or sending of tumor
slides to the pathology reference center
(b) Eligibility Criteria for Randomized Study Intervention Chemotherapy

Inclusion (1) The first registration on the study was completed

(2) The pathology reference center has confirmed the receipt of histological slides
(3) Postoperative MRI imaging has been performed and the results are available
(4) Any of the High-Risk CPT criteria are met (Fig. 1)
(5) The chemotherapy start c­ riteriaa are met
(6) The agreement of the patient or legal guardian has been documented according to local guidelines
Exclusion (1) Previous irradiation or chemotherapy
(2) Patient or legal guardian does not agree with treatment or randomization
(3) Clinical start criteria for the planned treatment as outlined in treatment modification guidelines are not met
(4) The protocol did not pass the local center required approvals, such as Ethics Committee or scientific review
(5) Previous antiangiogenic therapy
(6) Previous immunotherapy
(c) Objectives and outcome definitions

Survival times
Primary Objective: Overall Survival (OS) Time from histological diagnosis until death, or the date last seen (censored)
Secondary Objective: Progression Free Sur- Time from histological diagnosis to disease progression or death, or the date last seen (censored)
vival (PFS)
Event Free Survival (EFS) Time from histological diagnosis until tumor progression, second malignancy, death, or the date last seen (cen-
sored)
Response evaluation
Complete response (CR) No evidence of tumor
Partial response (PR) Remaining evidence of tumor, with tumor size in cross-sectional area ≤ 50% of pretreatment value in all known
tumor locations;
Stable disease (SD) Tumor size > 50% and ≤ 125%
Progressive disease (PD) Tumor size > 125% of pretreatment value in any individual tumor location or new lesion
(d) Performance status

Level 1 normal activity, no disabilities

Level 2 minor disability, not requiring additional assistance
Level 3 age-related activity greatly reduced
Level 4 bed-ridden, requiring nursing care
Level 5 intensive medical care, moribund

WHO definitions [2]. ∙ Choroid plexus papilloma: Delicate fibrovascular connective tissue fronds are covered by a single layer of uniform cuboi-
dal to columnar epithelial cells with round or oval, basally situated monomorphic nuclei. Mitotic activity is extremely low. Brain invasion, high
cellularity, necrosis, nuclear pleomorphism and focal blurring of the papillary pattern are unusual, but may occur. CPP closely resembles non-
neoplastic choroid plexus, but cells tend to be more crowded, elongated or stratified instead of the normal cobblestone-like surface. ∙ Atypical
choroid plexus papilloma: A choroid plexus papilloma with increased mitotic activity (≥ 1 mitosis/mm2; equating to ≥ 2 mitoses per 10 randomly
selected high power field of each 0.23 ­mm2). Up to two of the following four features may be present, but are not required: increased cellularity,
nuclear pleomorphism, blurring of the papillary pattern, areas of necrosis
Choroid plexus carcinoma: Malignant epithelial neoplasm of the choroid plexus that shows at least four of the following five features: fre-
quent mitoses, increased cellular density, nuclear pleomorphism, blurring of the papillary pattern with poorly structured sheets of tumour cells,
necrotic areas
a
Chemotherapy start criteria White blood cell count: > 2000/μl; platelet count: > 85,000/μl; serum creatinine: in normal range; pregnancy test:
negative (women of childbearing potential); audiology: hearing loss less than 30 dB at 3000 Hz

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Fig. 1  CPT-SIOP-2000 algorithm for surveillance and intervention CarbEV and CycEV (Supplemental Fig. 2) and radiotherapy, with
allocation. The original flow chart shows the overall design of the separate indications for volumes and doses (Supplemental Table 3).
observational registry for low-risk CPT and the interventional chem- The protocol design did not include cross-over between CarbEV and
otherapy study for high-risk CPT. High-risk CPT criteria are listed. CycEV arms for non-responders
These defined the indications for chemotherapy with randomized

malignant hemithorax tumor, and in another patient with kidney in 1 APP patient, and demyelinating disease in 1
APP who had a previous periorbital rhabdomyosarcoma. APP patient.
Sotos syndrome was diagnosed in one patient with Available tumor volumes did not differ amongst the CPT
APP. Other co-morbidities were univentricular heart in 1 subgroups in this cohort (median for all = 53 ml). 80% of all
CPC patient, ureteral duplication in 1 CPP patient, ectopic CPT were located in the lateral ventricles (94% of CPC, 84%

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of APP, 64% of CPP); location in the fourth ventricle was than those which were only partially resected: 34 ­cm3 (range
more common in older patients (15/19 CPT > 3 years versus 0.5–184) versus 76 c­ m3 (range 12–415) (Mann Whitney test:
4/19 CPT ≤ 3 years), and less frequent for high-grade tumors p = 0.003). The prognostic impact of complete resection on
(4% of CPC, 6% of APP, 26% of CPC). Only 1 CPC arose in survival of all CPT appeared significant for EFS and bor-
the third ventricle (Table 2). derline for OS: the five-year EFS and OS rates were 82%
At initial staging, 134 patients had localized disease, (CI95% 72–88) and 89% (CI95% 80–94) versus 64% (CI95%
and 19 had metastatic disease (3 CPP, 5 APP, 11 CPC). Of 50–75) and 81% (CI95% 68–89) after complete resection
the 19 patients with metastatic disease, 2 were identified versus less than total resection. However, these differences
on the basis of positive CSF cytology only, 1 patient had were confounded by the histological grade. When analyz-
intracranial metastases, 8 patients had spinal metastases, ing within each histological group, there was no significant
and 6 patients had generalized leptomeningeal disease. benefit from surgery for PFS, EFS or OS (for CPC: Sup-
For 2 patients with metastatic disease the location was not plemental Fig. 2).
documented. Staging data were not available in 5 patients.
Non-metastatic tumors were more commonly completely Radiotherapy
resected.
Histological grade was the single most prominent prog- Following at least two cycles of chemotherapy, 30 patients
nostic variable (Fig. 3a,b). The 1, 5, and 10 year OS were with CPC and 8 with APP received irradiation. One child
as follows: CPP (n = 55): 100%, 100%, 97%; APP (n = 49): with CPP was irradiated because of a local diagnosis of
100%, 96%, 96%; CPC (n = 54) 83%, 65%, 51%. The 1, CPC. Eleven patients with CPC received craniospinal irra-
5, 10 year EFS were: CPP: 100%, 92%, 92%; APP: 90%, diation plus local boost (median age at irradiation: 5.9 years,
76%, 76%; and CPC: 68%, 41%, 39%. Two patients with range 3–21.2). Nineteen received local radiotherapy (median
CPP experienced malignant progression to CPC and died age 5.6 years, range 1.5–18.6). The 2-year EFS without and
of progressive disease 5.6 and 13.1 years after primary with radiotherapy was 47% (CI95% 27–65) versus 76.5%
diagnosis, respectively. One instance of malignant progres- (CI95% 56.9–88, p = 0.23), respectively. The 2-year OS
sion occurred in an APP patient. APP patients younger than without and with radiotherapy was 55% (CI95% 34–72)
2 years of age at diagnosis had significantly higher higher versus 96.7% (CI95% 78.7–99.5), respectively. This dif-
PFS and OS compared to older APP patients (Fig. 3c, d). ference did not reach statistical significance (Log-rank
For 86 CPT (30 CPP, 25 APP, 31 CPC) a nuclear p53 test: p = 0.052). Among APP patients, for irradiated ver-
labeling index was determined and subsequently correlated sus not irradiated, the 5 year OS/PFS was 75%/63% versus
with grade: 2/30 CPP were positive (index 10%), 6/25 APP 100%/92%, respectively.
were positive (index ≤ 30%), and 19/31 CPC were positive
(index 10–90%). All CPT with a p53 labeling index over Chemotherapy in high‑risk CPT (Consort Diagram 2,
35% were CPC. Nuclear p53 labeling was assessed in 4 of Fig. 2b)
7 patients with LFS: the index was 0% in 2 patients, 10% in
one patient, and 50% in one patient. There was no prognos- Chemotherapy was provided to 87 CPT comprising 8 CPP,
tic relevance of p53 labeling within any of the histological 24 APP, and 55 CPC (including the three CPC arising via
groups. Methylation profiling [3, 5, 6] was available for 36 malignant transformation): 35 CarbEV, 41 CycEV, 11 other
patients, with classification results as follows: pediatric A in (site decision). 6 of 18 CPP/APP with incomplete resection
9 (4 APP, 5 CPP); pediatric B in 25 (3 CPP, 8 APP, 14 CPC); had an OR (CR + PR) after two cycles of chemotherapy. 35
and adult in 2 CPP. One of the three low-grade reference- patients started CarbEV or CycEV after complete resection;
reviewed CPT with subsequent malignant transformation none of these experienced tumor progression during the first
was a CPP that classified into the high-risk pediatric sub- two cycles. Twelve of 33 patients with CPC younger than
group B by methylation profiling. 3 years of age at diagnosis were treated with chemotherapy
only (without radiation) and are alive with a median follow-
Surgery up of 8.52 years (0.86–12.79).

Complete resection was documented in 98 patients, partial Carboplatin versus cyclophosphamide

resection in 56, and biopsy in 4 patients. Extent of surgery randomization
did not correlate with demographic variables or primary
tumor location, but complete resection was achieved less As per intention-to-treat (ITT) 20 CPC were randomized for
frequently in CPC compared to APP and CPP (42% versus CarbEV and 15 for CycEV. The study arms had matching
69% and 77%, respectively: p = 0.0032), and the average clinical values gender (equal), extent of resection (GTR in
size of completely resected tumors was significantly smaller 50% each), metastases (n = 3 in CarbEV, n = 2 in CycEV),

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◂Fig. 2  a Consort Diagram 1: Enrollment, exclusion, and alloca- compared to 53%/36% and 27%/18%, respectively, for
tion to surveillance according to protocol risk stratification (low-risk CycEV (HR 2.6, p = 0.032 for PFS), with six alive (Fig. 4).
versus high-risk CPT) are shown. Out of 173 screened patients 158
were eligible, with reference histology performed in 138 and refer-
ence radiology in 43. 87 patients were allocated to registry surveil- Safety
lance. In three reference-reviewed cases, malignant transformation to
CPC occurred, indicated by the thin blue arrows resulting in trans- Chemotherapy with CarbEV/CycEV was tolerable—within
fer to the intervention allocation; none of these were randomized. 47
of 52 CPP staged M0 underwent surveillance, and 3 events occurred
expected range and without treatment-related deaths. Grade
in this group: 1 malignant transformation, 1 relapsed patient treated 4 toxicity was limited to leukopenia and thrombopenia.
by surgery, and 1 relapsed treated by surgery and off-study second- All adverse event data are summarized in Supplemental
ary chemotherapy. 5 of 52 CPP staged M0 received primary off-study Table 2. Second malignancies were common: 12 subsequent
chemotherapy: 1 to successfully facilitate surgery, 3 at the investiga-
tor’s discretion because of malignant local pathology, and 1 because
neoplasms were documented in 10 patients (Table 2): one
of a concurrent malignant glioma. 25 of the 35 APP staged M0R0 ameloblastoma 10 years after APP; three myeloid malignan-
underwent surveillance; 5 events occurred in this group: 3 local non- cies (2.5, 6 and 3.9 years after CPC), one with an additional
metastatic relapses that received on-study chemotherapy and addi- nephroblastoma; a glioblastoma 4 years after APP, followed
tional focal RT in 1; 1 relapse and malignant transformation treated
with surgery, off-study chemotherapy and csRT; and 1 subsequent
by a soft tissue sarcoma in the same patient (died from glio-
neoplasm (ameloblastoma). 10 of 35 APP staged M0R0 received blastoma); a brainstem astrocytoma with a CPP; one rhabdo-
chemotherapy at the investigator’s discretion because of malignant myosarcoma prior to APP; one epithelioma after CPC (died
local histology; 2 events occurred in this group: 1 secondary GBM, 1 from CPC); one hemangioma after APP; and one skull base
metastatic relapse. APP Atypical Choroid Plexus Papilloma, CarbEV
carboplatin/etoposide/vincristine, CPC Choroid Plexus Carcinoma,
tumor (radiological meningioma/neurinoma) 1.2 years after
CPT Choroid Plexus Tumor, CPP Choroid Plexus Papilloma, csRT CPC. All patients with myeloid malignancies died, two of
craniospinal radiotherapy, CycEV cyclophosphamide/etoposide/vin- these from treatment-related complications after intensive
cristine, dod dead of disease, LFS Li-Fraumeni Syndrome, M+ pres- chemotherapy.
ence of metastasis, M0 no metastasis, pref preference, R+ residual
tumor (partial resection or biopsy), random randomized, R0 no resid-
ual tumor after tumor surgery, RT radiotherapy. b Consort Diagram 2:
Allocation to Intervention. Diagram shows patient allocation to treat- Discussion
ment intervention according to protocol risk stratification. 3 CPP
staged M+ received primary chemotherapy, 2 randomized for CycEV,
1 received off-study CycEV; no events occurred in this group. 9 APP
We report here the largest prospective and the only rand-
were staged M0R+, 3 received study-chemotherapy, with additional omized trial for choroid plexus tumors published to date.
focal RT in one, 1 received off-study chemotherapy; there were no The long median observation time of 7.3 years is one out-
events in this group. 4 APP staged M0R + were observed at the inves- standing feature. Histological grade emerged as the most
tigator’s discretion; there was one local relapse treated with chemo-
therapy alone, and one metastatic relapse treated with chemo and
relevant prognostic factor, and the value of CarbEV was
csRT. 5 APP staged M + were all treated with chemotherapy; three established for choroid plexus carcinoma. Limitations are
received randomized chemo, and two received off-study chemo- incomplete reference review for histology and radiology, and
therapy. Two events occurred in this group (PD). 57 CPC, including incomplete molecular work-up.
three secondary CPC after malignant transformation, were disposi-
tioned to intervention. 1 patient died before chemotherapy; 1 patient
CPP are low-grade tumors with a very high OS; however,
is alive without non-surgical treatment. The intention-to-treat analy- they do not completely follow all characteristics of a benign
sis comprises 35 CPC as-intended (CarbEV 20, CycEV 15). Relevant tumor. While mostly localized, typically in the fourth ven-
demographic variables were distributed homogeneously, as shown in tricle, three were metastatic at the time of diagnosis, two of
the bottom text-box. A total of 9 APP (5 at diagnosis and 3 APP at
relapse in surveillance) were also treated-as-randomized (CarbEV 6,
these confirmed as by reference radiology. All three received
CycEV 3) primary chemotherapy and are alive without event at 8.4, 10
and 14.4 years, with PR, SD, and CR, respectively, after 2
cycles. Two untreated CPP, one with methylation subclass
radiotherapy (60% versus 64%); median age was higher in pediatric B, progressed to CPC, which is a recognized, albeit
CarbEV (3.6 y, 0.22–16) vs CycEV (2.1 y, 0.35–9.4), there rare, event [27]. Both patients received salvage treatment
were 2 cases with LFS in the CarbEV and 4 in the CycEV but died from PD 3.1 and 9.3 years after primary diagnosis.
arm%). After two cycles of chemotherapy the response of In contrast to CPP, half of the patients with CPC died
17 CPC with incomplete resection was 1 CR, 4 PR, 7 SD, 3 despite intensive treatment (Fig. 3a). The study data solid-
PD, and 2 NA; the ORR (CR + PR) here was 55% in CarbEV ify known demographics (Table 1): patients were young
(n = 9) versus 0% in CycEV (n = 8) (p < 0.05, Fisher Exact (median age 2.1 years), without gender predominance, CPC
Test, treated as randomized group), and none of the 15 com- were mostly located in the lateral ventricles, and 3/57 of
pletely resected tumors had recurred. the available family histories were positive for LFS, which
The 5/10 year OS and PFS as per ITT for CarbEV is relevant for counselling and treatment choices [28]. The
was 73%/51% and 62%/47%, respectively, with 12 alive, prevalence of de novo LFS is known to be high in CPC [7],

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Table 2  Patient demographics

Primary histology CPP APP CPC Total

Number of patients 55 49 54 158

Female/male 26/29 24/25 27/27 77/81
Median age at diagnosis in years (range) 2.6 (0.2–46) 0.7 (0.01–13) 2.1 (0.3–18) 1.7 (0.01–46)
Pathogenic germline TP53 variation (LFS) – 1 6 7
Screening for LFS performed – 2 7 9
Sotos syndrome 1
Median tumor volume in ml (range), num- 38 (5–302) 71 (11–231) 50 (12–415) 53 (5–415)
ber of patients 7 16 22 45
Primary location: lateral ventricle, n (%) 35 (64%) 41(84%) 51 (94%) 127 (80%)
IIIrd ventricle, n (%) 4 (7%) 4 (8%) 1 (2%) 9 (6%)
IVth ventricle, n (%) 14 (26%) 3 (6%) 2 (4%) 19 (12%)
Other (IIIrd + IVth; CPA) 2 (3%) 1 (2%) 3 (2%)
Primary metastases, n (%) 3 (6%) 5 (10%) 11 (20%) 19(12%)
Subsequent neoplasms 1 brainstem glioma [0] 1 ameloblastoma [0] 1 AML/MDS [3] 12 in 10 patients
*multiple neoplasm in same patient 1 GBM * & 1 STS * [2] 1 AML/MDS [2]
†
LFS confirmed by testing 1 RMS [2] 1 AML* & 1 nephroblas-
[n] number of treatment exposures prior to 1 hemangioma [0] toma*† [2]
first subsequent neoplasm 1 epithelioma [4]
1 skull base tumor (sus-
pected meningioma/neuri-
noma) [2]

For medium tumor volume calculations, the ellipsoid volume formula was used: 4/3 π [A/2 × B/2 × C/2]), where A, B and C are the maximum
dimensions in the standard planes: axial (cranio-caudal, A), coronal (transverse, B) and sagittal (anteroposterior), results corresponded well with
the abridged ellipsoid formula (1/2 (A × B × C)) as used by the SIOPE Imaging protocol for patients in European SIOP Brain Tumour Studies. In
27 of 45 tumor volumes calculations reference radiology was available
APP Atypical Choroid Plexus Papilloma, CPA cerebellopontine angle, CPC Choroid Plexus Carcinoma, CPP Choroid Plexus Papilloma, GBM
glioblastoma multiforme, LFS Li-Fraumeni Syndrome, STS soft tissue sarcoma, *multiple neoplasms in the same patient, †LFS confirmed by
molecular analysis, [n] number of treatment exposures before first subsequent neoplasm, chemotherapy and radiotherapy are counted separately

but due to limitations of the study this could not be fully tissues of infants, the finding might rather reflect the defini-
addressed. Among the detected TP53-germline mutations, tion of the histological classification, rather than a deep bio-
one novel complex deletion was identified; the others con- logical principle in choroid plexus tumors [20, 31]. Defer-
firmed previous listings in COSMIC and IARC TP53. The ring adjuvant treatment may be justified in select infants
occurrence of an APP in Sotos syndrome described here is a with APP and residual tumor [32].
novel finding, expanding the spectrum of this NSD1-related In contrast to common belief [11, 22, 23], this prospec-
over-growth and tumor-predisposition [29]. tive study did not confirm the impact of complete resection
Staining for p53 in this study correlated with histology: in CPC. This is likely the result of improved non-surgical
all CPT with a labeling index > 30% were CPC. However, treatment, and the data advocate for staged surgery in the
this finding was without independent prognostic relevance, context of comprehensive treatment concepts.
apparently contradicting previous reports [30]. The discrep- The use of chemotherapy in the treatment of choroid
ancy might be explained by the integration of histological plexus tumors has increased since CPT-SIOP-2000 was
grade in this analysis (without the covariate, p53 was a nega- designed [17, 21, 33–40] (Table 3). The treatment intensity
tive prognostic variable in this study as reported in others), of many of these protocols is higher than CPT-SIOP-2000,
or by the laboratory technique. Two CPC with underlying the patient numbers smaller, and the outcome similar [17,
LFS had absent staining for p53. Taken together, the data 35, 39]. There is no FDA-approved pharmacologic agent that
show the limitations of using p53 immunohistochemistry is specific for CPT. A quantitative literature review com-
for informing treatment stratification. paring chemotherapeutic agents suggested benefit of etopo-
This study expands findings from our previous analysis side, carboplatin, cyclophosphamide and vincristine, while
of APP patients [20]. PFS and OS was significantly better similar suggestive evidence was absent for cisplatin, pro-
for APP patients younger than 2 years at diagnosis (Fig. 3c, carbazine and ifosfamide [25]. Since then, methotrexate has
d). However, as mitoses are a primary distinguishing feature been added to the spectrum [19, 33, 34, 37]. CPT-SIOP-2000
for this classification, and mitoses are more common in all adds evidence in support of the use of carboplatin (CarbEV)

13
Journal of Neuro-Oncology (2022) 156:599–613 607

Fig. 3  Overall survival (a)

and event free survival (b) of
all 158 patients registered to
CPT-SIOP-2000 by histology.
Pathology central review was
missing in 20 patients: 5 CPP,
3 APP, 12 CPC. 4 of these
12 non-referenced CPC were
randomized and treated with
CycEV and one was treated
with CarbEV; 1 of 3 non-
referenced APP was randomized
and treated in CarbEV. Three
patients with malignant trans-
formation that was detected at
surgery for relapse are included
here with their histology grad-
ing at primary diagnosis. This
has particular impact on the
CPP curves. Two patients with
an original diagnosis of CPP
had an increase in tumor grade
before treatment was initiated,
and died later. If the curves
were generated taking only the
histology at treatment start into
account, then there would be
no deaths in the CPP curve.
One patient with APP also had
malignant transformation. Age
effect for Overall Survival (c)
and Progression Free Survival
(d) in 49 patients with APP,
pathology central review miss-
ing in 3 APP. APP Atypical
Choroid Plexus Papilloma, CPC
Choroid Plexus Carcinoma;
CPP Choroid Plexus Papilloma,
HR Hazard Ratio, CI Confi-
dence Interval

to achieve superior efficacy (significant for PFS, but not OS) toward longer survival. However, assignment of irradiation
compared to cyclophosphamide (CycEV), however the ran- remains constrained due to the well-known late neuropsy-
domization numbers were low. Long recruitment time and chological sequelae in younger children. Furthermore, par-
small numbers of randomized patients are potential weak- ticularly in the context of LFS, second malignancies remain
ness in the study. a concern. A recent literature review was inconclusive with
The efficacy of irradiation has been suggested in retro- respect to specific indications for chemotherapy and radio-
spective analyses [22, 23]. This study confirmed a trend therapy [13].

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608 Journal of Neuro-Oncology (2022) 156:599–613

Fig. 3  (continued)

Establishing a treatment algorithm as guidance was a Conclusion

major objective of the CPT-SIOP-2000 study, and the algo-
rithm developed was widely followed in the international CPT-SIOP-2000 demonstrates the feasibility of an inter-
pediatric neuro-oncology community. Comparing the overall national randomized clinical trial. CarbEV is effective
outcome of this study to the original literature analysis sug- and tolerable when nested in a multidisciplinary guideline
gests a benefit of a structured algorithm in that the 2-year framework. The robust findings of this study add long-
survival rate in the historical data collection was only half term survival data as a benchmark for future intervention,
of what was found in CPT-SIOP-2000 [15, 19, 21, 23, 25]. and will help design risk-stratified guidelines.
Subsequent guidelines were more detailed and included
response to treatment and LFS status [28, 30].

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Journal of Neuro-Oncology (2022) 156:599–613 609

Fig. 4  Overall survival (a) and

progression free survival (b) by
chemotherapy arm for 35 CPC
patients as per intention-to-treat,
CarbEV-arm (n = 20) or CycEV-
arm (n = 15). Pathology central
review missing in 5 CPC.
Results for treated-as-rand-
omized (CarbEV n = 18; CycEV
n = 14 are very similar)

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610 Journal of Neuro-Oncology (2022) 156:599–613

Table 3  Published studies on CPC and outcome

References n CPC Chemotherapy Outcome Outcome Comments

5y EFS/PFS 5y OS

CPT-SIOP-2000 57 CarbEV/CycEV, and 41% EFS 65% OS (med f/u 6.0 y) 12 alive RT-free; 5 alive with
(this publication) other (including registry RT at relapse; 6 LFS
patients)
Liu (2021) (SJYC07) [17] 13 HDMTX/VCR/Cis/Cy/ 61% PFS 68% 8 alive (3 with RT); 4 LFS
(VBL)
Siegfried (2017) [19] 22 CarbEV/ VEC/ ICE; BB- 25% EFS 64.7% RT in 9; 5 alive RT-free, 1
SFOP XRT at relapse
Bahar (2017); Cleveland 7 SIOP 2009 CarbEV/ 3 relapse 100% (med f/u 5y) 1 adult (transformed CPP),
Clinic [30] CycEV/IT/ HDMTX (all salvaged: med AAD 4.5 y, 2 M + , RT
CSRT and in 5 (3 at relapse)
chemo)
Zaky (2015); 12 HS I-III 38% PFS 62% OS RT in 5 (4 at relapse, 1 focal
HS I-III [31] 5 alive RT-free, 1 RT at RT at relapse)
relapse
Dudley (2015); SEER [6] 95 60% OS (med f/u RT in 16%
40 months) GTR and RRT ns
Koh (2014); Seoul [32] 8 Carb/Cis/Cy/Ifo/VCR/ 2y PFS 0% 2 y OS 42% RT in 4; 3 survived (med f/u
VP16; 4 HDCT 1.5 y)
all HDCT, 2 foc RT
Bettegowda (2012); Johns 7 not detailed 71% (5 of 7 patients 6 chemo, 3 RT
Hopkins [33] survived)
Grundy (2010); UKCCSG 15 Carb/VCR/Cis/MTX 21.7% EFS 21.5% OS ph II trial, 11/14 PD on
[34] chemo;
no RT until PD; 4 alive
RT-free
Lafay-Cousin (2010); Sick- 12 ICE 53.3% PFS 74.1% OS all survivors had GTR/ NTR
kids [15] and RT-free; 1 GTR and
HDCT at relapse)
RT in 3 at relapse/residual
Fouladi (2009) [37] 5 Carbo/Cy/VP16 60% PFS 80% OS ph II, 1 M + , all GTR, RT
for M + or PD; 1 DOD, 1
died SNL
Geyer (2005); CCG 9921 9 VCR/Cis, Cy/VP16; Carb/ 33% 63% (3 y) ph II random
[35] Ifo/VP16; VCR/VP16, 7 PD 4 patients died no upfront RT
Carbo/VP16
Chow (1999); SJCRH [36] 10 Cy/VP16/VCR/Cis, Carbo 3 PD 3 alive with RT RT in 5 (3 at relapse)
2 died

AAD age at diagnosis, Carb carboplatin, Cis cisplatin, csRT craniospinal RT, Cy cyclophosphamide, DOD dead of disease, GTR​ gross total
resection, HDMTX high-dose methotrexate, HS Head Start, ICE ifosfamide, carboplatin, etoposide, Ifo ifosfamide, M + metastatic, med f/u
median follow-up, NTR near total resection; PD progressive disease, RT radiotherapy, SNL secondary neoplasm, VBL vinblastine; VCR vincris-
tine; VEC vinctistine/etoposide/cyclophosphamide; VP16 etoposide, y year

Supplementary Information The online version contains supplemen- Author contributions JEW: Conceptualization, Methodology, Investi-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 11060-0​ 21-0​ 3942-0. gation, Funding Acquisition, Data Curation, Resources (Patients), For-
mal Analysis, Writing Original Draft, Writing Review & Edition, Revi-
Acknowledgements We want to thank the patients, parents and investi- sion. SVG: Participation in Conceptualization, Resources (Patients),
gators for enrolling and providing data (Supplemental Table 4), Brigitte Formal Analysis, Validation, Writing Original Draft, Writing Review
Wrede and Stefan Hartung for managing the study and registry, and & Edition, Revision. TK: Participation in Conceptualization, Resources
Peter Thall and Richard Sposto for statistical support, as well as David (Patients), Writing Review & Edition. BD: Participation in Conceptu-
Ellison, Martin Hasselblatt, Werner Paulus and Torsten Pietsch for alization, Resources (Patients), Writing Review & Edition. RK: Par-
reference neuropathology review. The Choroid Plexus Tumor study ticipation in Conceptualization, Participation in Data Monitoring Com-
was, and the registry currently is, supported by the Deutsche Kinder- mittee, Resources (Patients), Writing Review & Edition. BT: Resources
krebsstiftung DKKS (German childhood Cancer Foundation). Jonathan (Radiation Review), Writing Review & Edition. MG: Participation in
Finlay and Rejin Kebudi were the Data Monitors for this study. The Conceptualization, Resources (Patients), Writing Review & Edition.
European CPT collaboration is ongoing with further registries, as well JS: Participation in Conceptualization, Resources (Patients), Writing
as guidelines. Review & Edition. GNF: Resources (Pathology), Writing Review &

13
Journal of Neuro-Oncology (2022) 156:599–613 611

Edition. BB: Resources (Radiology), Funding Acquisition, Writing Hanggi D, Hans V, Rozsnoki S, Hansford JR, Kohlhof P, Kris-
Review & Edition. URK: Data Curation, Funding Acquisition, Formal tensen BW, Lechner M, Lopes B, Mawrin C, Ketter R, Kulozik
Analysis, Validation, Resources (Patients), Writing—Original Draft, A, Khatib Z, Heppner F, Koch A, Jouvet A, Keohane C, Muh-
Writing—Review & Editing, Visualization, Revision. leisen H, Mueller W, Pohl U, Prinz M, Benner A, Zapatka M,
Gottardo NG, Driever PH, Kramm CM, Muller HL, Rutkowski
Funding Open Access funding enabled and organized by Projekt S, von Hoff K, Fruhwald MC, Gnekow A, Fleischhack G, Tip-
DEAL. The Choroid Plexus Tumor study was (JEW), and the registry pelt S, Calaminus G, Monoranu CM, Perry A, Jones C, Jacques
currently is (BB, UK), supported by the Deutsche Kinderkrebsstiftung TS, Radlwimmer B, Gessi M, Pietsch T, Schramm J, Schackert
DKKS (German childhood Cancer Foundation). G, Westphal M, Reifenberger G, Wesseling P, Weller M, Col-
lins VP, Blumcke I, Bendszus M, Debus J, Huang A, Jabado N,
Northcott PA, Paulus W, Gajjar A, Robinson GW, Taylor MD,
Data availability Not applicable.
Jaunmuktane Z, Ryzhova M, Platten M, Unterberg A, Wick W,
Karajannis MA, Mittelbronn M, Acker T, Hartmann C, Aldape
Declarations K, Schuller U, Buslei R, Lichter P, Kool M, Herold-Mende C,
Ellison DW, Hasselblatt M, Snuderl M, Brandner S, Korshu-
Conflict of interest All authors declare not to have any relevant finan- nov A, von Deimling A, Pfister SM (2018) DNA methylation-
cial or non-financial conflict of interest with this work. based classification of central nervous system tumours. Nature
555:469–474. https://​doi.​org/​10.​1038/​natur​e26000
5. Pienkowska M, Choufani S, Turinsky AL, Guha T, Merino DM,
Open Access This article is licensed under a Creative Commons Attri-
Novokmet A, Brudno M, Weksberg R, Shlien A, Hawkins C,
bution 4.0 International License, which permits use, sharing, adapta-
Bouffet E, Tabori U, Gilbertson RJ, Finlay JL, Jabado N, Thomas
tion, distribution and reproduction in any medium or format, as long
C, Sill M, Capper D, Hasselblatt M, Malkin D (2019) DNA meth-
as you give appropriate credit to the original author(s) and the source,
ylation signature is prognostic of choroid plexus tumor aggres-
provide a link to the Creative Commons licence, and indicate if changes
siveness (vol 11, 117, 2019). Clin Epigenetics. https://​doi.​org/​10.​
were made. The images or other third party material in this article are
1186/​s13148-​019-​0737-7
included in the article's Creative Commons licence, unless indicated
6. Thomas C, Metrock K, Kordes U, Hasselblatt M, Dhall G (2020)
otherwise in a credit line to the material. If material is not included in
Epigenetics impacts upon prognosis and clinical management of
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choroid plexus tumors. J Neurooncol 148:39–45. https://​doi.​org/​
permitted by statutory regulation or exceeds the permitted use, you will
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copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
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Authors and Affiliations

Johannes E. Wolff1,2 · Stefaan W. Van Gool3 · Tezer Kutluk4 · Blanca Diez5 · Rejin Kebudi6 ·
Beate Timmermann7 · Miklos Garami8 · Jaroslav Sterba9,10 · Gregory N. Fuller11 · Brigitte Bison12 ·
Uwe R. Kordes13
4
Johannes E. Wolff Department of Pediatric Oncology, Hacettepe University
[email protected] Medical School and Cancer Institute, Ankara, Turkey
5
Stefaan W. Van Gool Neuro Oncology Program, Institute of Neurological
[email protected] Research, FLENI, Buenos Aires, Argentina
6
Tezer Kutluk Pediatric Hematology‑Oncology, Oncology Institute, Istanbul
[email protected] University, Istanbul, Turkey
7
Blanca Diez Department of Particle Therapy, University Hospital Essen,
[email protected] West German Proton Therapy Centre Essen (WPE), West
German Cancer Center (WTZ), German Cancer Consortium
Rejin Kebudi
(DKTK), Essen, Germany
[email protected]
8
2nd Department of Pediatrics, Semmelweis University,
Beate Timmermann
Budapest, Hungary
[email protected]
9
Department of Pediatric Oncology, University Hospital
Miklos Garami
Brno and Faculty of Medicine, Masaryk University, Brno,
[email protected]
Czech Republic
Jaroslav Sterba 10
International Clinical Research Center, St. Anne’s University
[email protected]
Hospital, Brno, Czech Republic
Gregory N. Fuller 11
Departments of Neuropathology and Neuroradiology, MD
[email protected]
Anderson Cancer Center, Houston, USA
Brigitte Bison 12
Department of Neuroradiology, University Hospital
[email protected]
of Augsburg, Augsburg, Germany
1 13
University of Regensburg, Regensburg, Germany Department of Pediatric Hematology and Oncology,
2 University Medical Center Hamburg, Hamburg, Germany
Present Address: Oncology Development, AbbVie, Chicago,
IL, USA
3
IOZK Immune Oncological Centre Cologne, Cologne,
Germany

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