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\begin{document}

\title{Relapsed neuroblastoma in the central nervous system, a single-center,
retrospective study}



\author[1]{Yutong Zhang}%
\author[1]{Xianmei Jin}%
\author[1]{Chao Zhang}%
\author[1]{Dan Zhong}%
\author[1]{Jian Chang}%
\affil[1]{Jilin University First Hospital}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: The incidence of relapsed neuroblastoma (NB) in the central
nervous system (CNS) is less than 20\%. Here, we presented eleven cases
with CNS relapsed NB to better understand the CNS relapsed NB. Methods:
Medical records from NB patients between January 1st, 2010 and December
31st, 2017 were reviewed to examine those diagnosed with CNS relapsed
NB. The following patient information was extracted, including age,
gender, histological subtyping, tumor stage, risk group, biomarkers,
chemotherapy regimen and dosage, surgery details, treatment outcomes and
follow-up, clinical manifestations of CNS relapsed NB, treatment
protocols for CNS relapsed NB, and patient outcomes (including the cause
of death). Results: From January 1st, 2010 to December 31st, 2017,
eleven NB patients were diagnosed with CNS relapse at our department.
All the eleven patients were classified to have high risk disease. The
median time from the completion of chemotherapy to CNS relapse was 5
months. Five patients did not receive any treatment for the relapsed
disease and finally died of it. Curative treatments were tried in six
patients. At last, two patients with isolated CNS relapsed NB survived.
Conclusions: The median time from the completion of chemotherapy to CNS
relapse is very short in the present retrospective study. It seems that
patients with isolated CNS relapsed disease have better outcomes. We
suggest the temozolomide-topotecan combination as an add-one backbone
for further salvage treatment in children with CNS relapsed NB, even
though this combination is not superior to others in terms of its
efficacy.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Neuroblastoma (NB) is the most common extracranial solid tumor in
children, and over 1/2 NB children develop distant metastasis at the
time of diagnosis. The most common sites of metastasis include bone,
bone marrow, liver, and skin{[}1{]}. With regard to the relapsed
pattern, local foci (8\%), primary metastatic sites (66\%), and primary
site in addition to metastatic sites (26\%) are the major
patterns{[}2{]}. Metastasis in the central nervous system (CNS) is rare
on presentation, let alone the CNS relapsed NB. Little is known on the
clinical characteristics of CNS relapsed NB, and its incidence is less
than 20\%{[}3, 4{]}. Over the past 10 years, our department have
admitted several CNS relapsed NB cases without CNS involvement at the
initial diagnosis. Relapsed CNS NB is associated with poor outcomes,
with a 2-year event-free survival (EFS) of 10\% and a 4-year overall
survival (OS) of 20\%{[}5{]}. Herein, we reported a small case series of
CNS relapsed NB to better understand CNS relapsed NB.

\textbf{Methods}

Our study protocol was approved by the Ethical Institution of our
hospital. Medical records from NB patients between January
1\textsuperscript{st}, 2010 and December 31\textsuperscript{st}, 2017
were reviewed to identify patients diagnosed with CNS relapsed NB.

The diagnosis was made and the stage was assessed according to criteria
of the International Neuroblastoma Staging System (International
Neuroblastoma Staging System, INSS){[}6-8{]}. Typically, a tissue
diagnosis of NB can be made based on conventional histology (with or
without immunohistology and increased urine or serum catecholamines or
metabolites). In addition, a diagnosis can also be made when unequivocal
tumor cells are detected in bone marrow samples and increased urine or
serum catecholamines or metabolites are present{[}9{]}.

The following data were extracted from each patient, namely, age,
gender, histological subtyping, tumor stage, risk group, biomarkers,
chemotherapy regimen and dosage, surgery details, treatment outcomes and
follow-up, clinical manifestations of CNS relapsed NB, treatment
protocols for CNS relapsed NB, and patient outcomes (including the cause
of death). Data collection from the clinical records of patients was
approved by the Institutional Review Boards. Additionally, written
informed consents were obtained from the parents or legal guardians of
all patients before the initiation of treatment.

\textbf{Results}

From January 1\textsuperscript{st}, 2010 to December
31\textsuperscript{st}, 2017, altogether eleven NB patients were
diagnosed with CNS relapse at our department. The median age at
diagnosis was 4 (range, 2-8) years. More details about the
characteristics of these eleven patients are presented in Table 1. Among
these eleven patients, two had stage III disease while nine had stage IV
disease at the initial diagnosis, and all of them were classified to
have high risk disease. The two patients with high-risk stage III disease
showed unfavorable histology, and one patient with stage IV disease was
detected with \emph{MYCN} amplification. Patients investigated in this
study received chemotherapy in accordance with the NB97 trial in
combination with a novel delayed intensification chemotherapy{[}9,
10{]}. If feasible, surgery was performed after the completion of cycle
4 or 6 chemotherapy before initiating the N7 treatment. Gross total
resection of the primary tumor was assessed by computed tomography (CT)
or magnetic resonance imaging (MRI). As for CNS relapsed NB, the
diagnosis was made by enhanced head CT or MRI.

The time to CNS relapse was short, which was no more than 6 months
(range, 1-9 months; median, 5 months) after the completion of delayed
intensification chemotherapy in eight of the eleven (72.7\%) patients.
For patients with CNS relapse, five had relapsed disease in the CNS
alone (including 4 in parenchyma and 1 in leptomeninges), while seven
had systemic bony and marrow disease in CNS relapse. Among these eleven
patients, headache (n=4, 30.8\%) and vomiting (n=4, 30.8\%) were the
most common presentations at relapse, followed by paraparesis (n=2,
15\%.4) and ataxia (n=1, 7.8\%). The cerebrospinal fluid (CSF) cytology
was not routinely tested. CNS relapsed NB was confirmed by pathology in
four patients, and the detailed histological examination excluded the
diagnosis of a second primary CNS malignancy.

Among the eleven patients, five did not receive any treatment at relapse
and finally died of the disease. Curative treatments were tried in six
patients (No.3, No. 4, No. 7, No. 8, No. 9 and No. 11), who received
oral administration of temozolomide at
150mg/m\textsuperscript{2}followed by intravenous injection of topotecan
at 0.75mg/m\textsuperscript{2} for five consecutive days at intervals of
21-28 days. More details about treatments for the six patients are
presented in Table 2. Among these six assessable patients, one (NO.3)
had parenchyma relapse alone, who showed stable disease (SD) after 5
cycles of chemotherapy and withdrew from the treatment. However, he was
alive with tumor at the last follow-up. Unbelievably, he survived for
more than six years. Moreover, another two patients (No. 4, No. 11)
achieved SD either after 4 or 3 cycles of chemotherapy, but they died of
the disease soon after treatment withdrawal. Two patients (No. 7, No. 8)
attained partial remission, underwent surgery after 4 cycles of
chemotherapy, and received 4 cycles of postoperative chemotherapy and
radiation. Patient No.7 with parenchyma relapse showed no evidence of
disease at 19 months. Patient No.8 had relapsed disease again but was
still alive. Patient No. 9 showed progressive disease (PD) after 4
cycles of chemotherapy and died finally.

\textbf{Toxicity}

A total of 32 courses of chemotherapy were administered to the six
patients. On the whole, both topotecan and temozolomide were well
tolerated. No toxicity-related death was reported. All patients
experienced grade 2 or 4 neutropenia in the course of treatment. No
grade 3-4 infection or mucositis was noted. Meanwhile, grade 2 vomiting
was a common presentation in the course of treatment.

\textbf{Discussion}

It should be noted that, due to the lack of experience, imaging
evaluation of disease progression or recurrence in the CNS was not
routinely performed at the early stage of this retrospective study until
two patients (No.5 and No. 6) suffered from CNS relapse immediately
after the completion of delayed intensification chemotherapy at our
institution. Historically, CNS involvement in NB is quite rare, which is
usually a manifestation of end-stage disease because CNS is a sanctuary
site for NB cells, since many chemotherapy and immunotherapy agents can
not cross the blood-brain barrier.{[}1, 11{]}.

The median time from the completion of chemotherapy to CNS relapse was 5
months in the present retrospective study, while that was reported to be
12 months at the Memorial Sloan-Kettering Cancer Center (MSKCC){[}12{]}
and 14 months at the Institut Curie and the Institut
Gustave-Roussy{[}11{]}. Actually, in a larger case series, the median
time from initial diagnosis to CNS relapse was fairly consistent (13
months). However, to our surprise, all the eleven patients had relapsed
disease during the treatment of oral 13-cis retinoic acid. Moreover,
eight of the eleven (72.7\%) patients suffered from relapse within no
more than 6 months after the completion of delayed intensification
chemotherapy. All the eleven patients, except for patients No.5 and No.
6, received head MRI after chemotherapy and clear CNS involvements were
shown. From then on, head MRI was re-examined at intervals of three
months. The precise cause of rapid CNS relapse in these patients
remained unclear. The most probable explanation was that autologous
hematopoietic progenitor cell transplantation was not included in the
standard therapy for high-risk NB patients due to the financial burdens,
and no patient received myeloablative treatment. Besides, anti-GD2
antibody is not available in China, except for Hong Kong. Alternatively,
it is also suggested that, patients diagnosed after 1990 and treated
with the more intensive induction therapies have a higher incidence of
CNS metastasis than those diagnosed earlier{[}12{]}. Also, it is
suggested that the strict monitoring policy facilitates to detect
relapse early, when the tumor burden is still small. Further, it is
hypothesized that, when extensive or bulky disease is involved in
relapse, prolonged survival and even radical cure are less likely.
Undoubtedly, MIBG is the most sensitive surveillance for detecting
high-risk NB relapse{[}2, 13{]}. However, MIBG is not available, which
makes it difficult to surveille CNS relapsed NB.

In some study, CNS involvement in NB may be ascribed to the barrier
action of the dura that protects CNS parenchyma from cell
invasion{[}14{]}. In other opinions, CNS NB may result from the direct
extension of neuroblasts from bone or bone marrow{[}15{]}. In our
series, five of the eleven patients developed isolated CNS relapsed NB.
As reported in literature, the CNS was the first or only site of PD in
several patients{[}3, 14{]}. However, in our study, four of the five
patients with isolated CNS relapse without overlying bony disease
occurred in parenchyma, while the disease in the remaining one patient
took place in leptomeninges. Thus, it is hypothesized that, neuraxis
involvement may occur by the hematologic route during the active disease
period, but the later growth and intra-CNS dissemination via the CSF are
not consistent with our observation. Collectively, it can hardly
determine whether the CNS relapsed NB occurs by breaking down the
blood-brain barrier or by hematogenous spreading.

To the best of our knowledge, no consensus is reached about how to
manage CNS relapse in NB patients so far. A study from MSKCC suggests
that, it is an important part of management to target the entire
neuraxis with craniospinal irradiation (CSI) rather than delivering
focal radiotherapy{[}16{]}. Also, it has been proved that CSI is
effective on CNS relapse, but carries significant long-term morbidity.
Nowadays, MSKCC recommends 18 Gy as the new standard CSI dose for CNS
relapsed NB in conjunction with compartmental radioimmunotherapy (RIT)
and CNS penetrating chemotherapy{[}1{]}. Again, due to the limited
availability of RIT, this treatment regimen is not prevalent.

Among the six patients who received treatment, two with isolated CNS
relapsed NB survived after follow-up for 60 and 19 months, respectively.
Interestingly, patient No.3 received 5 cycles of chemotherapy after
relapse without further treatment, as required by his parents, and he
was alive with tumor for more than 6 years. His young age and non-bone
marrow involvement at diagnosis might be the best explanation for this.
At the same time, the other alive patient had no metastasis disease at
diagnosis; actually, she had stage III disease with unfavorable shimada
classification. Besides, both of these two patients had CNS relapse
alone. It seemed that patients with isolated CNS relapse had superior
outcomes. Furthermore, it was found in our retrospective study that,
temozolomide and topotecan were well tolerated, with the major
treatment-related adverse events of manageable hematologic toxicities.
Typically, it is hard to assess the effectiveness of temozolomide and
topotecan for CNS relapsed NB due to the limited sample size. However,
as shown by a phase II study from SIOP regarding the use of temozolomide
combined with topotecan in treating relapsed or refractory NB, the tumor
control rate (complete response (CR) + partial response (PR) + mixed
response (MR) + SD) is 68\% (95\% confidence interval (CI), 63--90\%).
In the meantime, the 12-month progression-free survival (PFS) and OS are
42\% and 58\%, respectively{[}17{]}. Furthermore, another phase II trial
shows that the overall objective response rate (ORR) is 28\% (95\% CI,
12.7-47.2) in medulloblastoma and 10\% (95\% CI, 0.3-44.5) in primitive
neuroectodermal tumors treated with temozolomide and topotecan{[}18{]}.
Overall, the temozolomide-topotecan combination achieved comparable
therapeutic effect to other combinations on treating children with
heavily pretreated CNS relapsed NB in our retrospective study.
Therefore, this combination may likely be utilized further in front line
or other salvage therapies to treat CNS relapsed NB.

In conclusion, the median time from the completion of chemotherapy to
CNS relapse is very short, as reported in our retrospective study. It
seems that patients with isolated CNS relapsed disease have better
outcomes. We suggest the temozolomide-topotecan combination as an
add-one backbone for further salvage treatment in children with CNS
relapsed NB, although this combination is not superior to others.

\textbf{Conflict of Interest statement} : The authors indicated no
potential conflicts of interest.

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