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\begin{document}

\title{To the editor: Is it possible to achieve long-term survival in relapsed
Intracranial Non-Germinomatous Germ Cell Tumours?}



\author[1]{Mohamed Ahmed}%
\author[2]{Stergios Zacharoulis}%
\author[3]{Istvan Bodi}%
\author[4]{Erika Pace}%
\author[5]{Henry Mandeville}%
\author[1]{Joanna Stone}%
\author[3]{Tony Elias}%
\author[3]{Bassel Zebian}%
\author[6]{Fernando Carceller}%
\affil[1]{Royal Marsden NHS Foundation Trust}%
\affil[2]{Columbia University}%
\affil[3]{King's College Hospital NHS Foundation Trust}%
\affil[4]{Royal Marsden Hospital NHS Trust}%
\affil[5]{The Royal Marsden NHS Foundation Trust}%
\affil[6]{Royal Marsden Hospital Sutton}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\textbf{To the editor: Is it possible to achieve long-term survival in
relapsed Intracranial Non-Germinomatous Germ Cell Tumours?}

\textbf{Authors:}

Mohamed Magdy Ahmed\textsuperscript{1}, Stergios
Zacharoulis\textsuperscript{1,2}, Istvan Bodi\textsuperscript{3}, Erika
Pace\textsuperscript{4}, Henry Mandeville\textsuperscript{5}, Joanna
Stone\textsuperscript{1}, Tony Elias\textsuperscript{6,7}, Bassel
Zebian\textsuperscript{6}, Fernando Carceller\textsuperscript{1,8}

\textbf{Affiliations:}

\textsuperscript{1} Children \& Young People's Unit, The Royal Marsden
NHS Foundation Trust, London, UK.

\textsuperscript{2} Department of Pediatrics, Columbia University,
Irving Medical Center, New York, USA (current address).

\textsuperscript{3} Department of Clinical Neuropathology, Kings College
NHS Foundation trust, London, UK.

\textsuperscript{4} Department of Diagnostic Radiology, The Royal
Marsden NHS Foundation Trust, London, UK.

\textsuperscript{5} Department of Clinical Oncology, The Royal Marsden
NHS Foundation Trust, London, UK

\textsuperscript{6} Department of Neurosurgery, King's College Hospital
NHS Foundation Trust, London, UK.

\textsuperscript{7} Department of Neurosurgery, Brighton \& Sussex
University Hospitals, Brighton, UK (current address).

\textsuperscript{8} Division of Clinical Studies, The Institute of
Cancer Research, London, UK.

\textbf{Corresponding author:}

Name: Dr Fernando Carceller Address: The Royal Marsden NHS Foundation
Trust. Paediatric Offices, Downs Rd. Sutton SM2 5PT United Kingdom
Phone: +44 (0) 208 661 3678 Email: Fernando.Carceller@icr.ac.uk

\textbf{Keywords:}

Relapsed, intracranial, brain, non-germinomatous, germ cell tumor,
survival.

\textbf{To the editor:}

We report a case of an adolescent with relapsed metastatic yolk sac
tumour (YST) of the pineal region who received multimodal treatment and
remains alive and progression-free at 5 years from his last end of
treatment. This encouraging case contributes to the limited existing
body of literature on the management of relapsed non-germinomatous germ
cell tumours of the central nervous system (CNS NG-GCT).

A 12-year-old male presented with a 2-week history of headache, nausea,
vomiting, ataxia and drowsiness. Head CT scan showed a pineal lesion,
subsequently confirmed on Magnetic Resonance (MR) (Supplemental figure
S1). No leptomeningeal spread on MRI. Serum alpha-fetoprotein (AFP)
1,832 ng/ml. Serum beta-human chorionic gonadotropin (\selectlanguage{greek}β-\selectlanguage{english}HCG) 16 IU/L.
Cerebrospinal fluid (CSF) cytology: no malignant cells. AFP in CSF 34.9
ng/ml (\selectlanguage{greek}β-\selectlanguage{english}HCG not available).

An endoscopic third ventriculostomy, stereotactic biopsy of the pineal
lesion, and insertion of a Rickham reservoir were undertaken. The
initial biopsy was inconclusive. A second biopsy was consistent with a
malignant GCT with predominant features of YST.

The child was treated as per SIOP CNS GCT 96 protocol off-trial with 4
cycles of cisplatin, etoposide and ifosfamide (PEI) with partial
response according to Response Evaluation Criteria in Solid Tumors
v1.1\textsuperscript{1}. Serum tumour markers normalized. Subsequently,
he received radical volumetric modulated arc therapy (VMAT) to the
residual tumour (54 Gy in 30 fractions). End of treatment MR scan
revealed a stable subcentimetre tumour residuum with negative serum
tumour markers.

Two years after the end of treatment, routine serum tumour markers
showed AFP 56.6 ng/ml and \selectlanguage{greek}β-\selectlanguage{english}HCG \textless{}2 IU/L. MR brain and spine
demonstrated stable intracranial appearances, with a new solitary plaque
of enhancing tissue over the surface of the spinal cord posteriorly at
the level of T10 disc space (Supplemental figure S1). The child received
alternating carboplatin/etoposide and ifosfamide/etoposide for a total
of 4 cycles as per SIOP CNS GCT II trial (NCT01424839). After 4 cycles
of chemotherapy, the T10 meningeal spinal metastasis shrunk and serum
AFP decreased to 4.8 ng/ml. He then received high dose thiotepa and
etoposide followed by autologous stem cell transplant (ASCT) followed by
craniospinal irradiation -CSI- (30 Gy in 16 fractions) with a boost to
the spinal recurrence (20.8 Gy in 13 fractions). The end of treatment
MRI showed ongoing response and serum AFP was normal. This young man is
currently alive, with normal serum tumour markers and free of recurrence
5 years after treatment.

Whilst most relapsed CNS germinomas can be salvaged, relapsed CNS
NG-GCTs have a much worse prognosis\textsuperscript{2--4}. There is no
international consensus on salvage therapy for relapsed CNS NG-GCT and
there are relatively few published case series with limited and
heterogeneous cases\textsuperscript{5}. Murray et
al.\textsuperscript{6}reported a cohort of 32 relapsed CNS NG-GCT
patients with a 5-year overall survival (OS) of 9\% (95\%CI: 2-26). Of
the 16 patients who received high dose chemotherapy (HDC) and ASCT, 2 of
3 long term survivors had received irradiation after HDC and ASCT.
Similarly, Callec et al.\textsuperscript{5} reported a retrospective
multicenter study of 25 patients with relapsed CNS NG-GCT showing a
5-year OS of 72\% (95\%CI: 46-87) for patients who received HDC versus
29\% (95\%CI: 4-61) for those who didn't (p=0.006). These studies and
others have led the Third International CNS Germ Cell Tumor Symposium to
recommend HDC, surgery, and irradiation, if feasible, for the management
of relapsed CNS NG-GCTs\textsuperscript{7}.

Elevated serum AFP at initial diagnosis (\textgreater{}1000 ng/ml) was
incorporated as a poor prognostic factor in the SIOP CNS GCT II trial
(NCT01424839), following results of the SIOP CNS GCT
96\textsuperscript{8}. This case could receive CSI because he had only
had focal radiotherapy at initial diagnosis. However, cases with
metastatic disease at initial diagnosis who receive CSI upfront would
not have this choice in case of metastatic relapse. Although relapsed
CNS NG-GCTs have a dismal prognosis, this case illustrates the
importance of close surveillance with tumour markers and that long-term
survival is achievable with multimodal treatment, including induction
chemotherapy, high dose chemotherapy with ASCT, and radiotherapy.

\textbf{Conflict of Interest statement}

The Authors declare that there is no conflict of interest.

\textbf{Acknowledgements}

Fernando Carceller is partly funded by The Giant Pledge via the Royal
Marsden Cancer Charity (RMCC). Fernando Carceller also acknowledges
funding from the Hall-Hunter Foundation via the RMCC to support the
Paediatric Neuro-Oncology and Drug Development Units at the Royal
Marsden Hospital.

Erika Pace is supported by The Royal Marsden Cancer Charity.

\textbf{References}

1. EA E, P T, J B, et al. New response evaluation criteria in solid
tumours: revised RECIST guideline (version 1.1). \emph{Eur J Cancer} .
2009;45(2):228-247. doi:10.1016/J.EJCA.2008.10.026

2. Murray MJ, Bailey S, Heinemann K, et al. Treatment and outcomes of UK
and German patients with relapsed intracranial germ cell tumors
following uniform first-line therapy. \emph{Int J Cancer} .
2017;141(3):621-635. doi:10.1002/ijc.30755

3. Modak S, Gardner S, Dunkel IJ, et al. Thiotepa-based high-dose
chemotherapy with autologous stem-cell rescue in patients with recurrent
or progressive CNS germ cell tumors. \emph{J Clin Oncol} .
2004;22(10):1934-1943. doi:10.1200/JCO.2004.11.053

4. Bouffet E. The role of myeloablative chemotherapy with autologous
hematopoietic cell rescue in central nervous system germ cell
tumors.\emph{Pediatr Blood Cancer} . 2010;54(4):644-646.
doi:10.1002/pbc.22376

5. Callec L, Lardy-Cleaud A, Guerrini-Rousseau L, et al. Relapsing
intracranial germ cell tumours warrant retreatment. \emph{Eur J Cancer}
. 2020;136:186-194. doi:10.1016/j.ejca.2020.06.012

6. Murray MJ, Bailey S, Heinemann K, et al. Treatment and outcomes of UK
and German patients with relapsed intracranial germ cell tumors
following uniform first-line therapy. \emph{Int J Cancer} .
2017;141(3):621-635. doi:10.1002/ijc.30755

7. Murray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M,
Nicholson JC. Consensus on the management of intracranial germ-cell
tumours. \emph{Lancet Oncol} . 2015;16(9):e470-e477.
doi:10.1016/S1470-2045(15)00244-2

8. Calaminus G, Frappaz D, Kortmann RD, et al. Outcome of patients with
intracranial non-germinomatous germ cell tumors---lessons from the
SIOP-CNS-GCT-96 trial. \emph{Neuro Oncol} . 2017;19(12):1661-1672.
doi:10.1093/neuonc/nox122

\textbf{Supplemental figure S1:} Series of head (axial T2-weighted turbo
spin echo sequences) and spine (sagittal post-gadolinium T1-weighted
turbo echo sequences) MR examinations. A 12 year-old male presented with
a lobulated neoplastic pineal mass (A1; arrow), biopsy-proven to be a
yolk sac tumour, approximately measuring 4 x 2.5 x 4 cm (ap tr cc/ob),
markedly vascularised but non-high-cellular, and containing a couple of
subcentimetric central cystic foci. This lesion compressed and distorted
the third ventricle causing moderate obstructive hydrocephalus and
exerted mass effect also onto the right dorsal medial thalamic nuclei
and onto the ipsilateral dorsal midbrain along its aqueduct. No
intracranial or spinal metastases at baseline (A2). Favourable response
to chemotherapy and radical VMAT therapy was achieved 7 months after
diagnosis with a minimal cystic residuum (B1; arrow) which has remained
stable over time (C1, D1; arrow). However, 23 months after end of
treatment a millimetric faintly enhancing leptomeningeal deposit
overlying the cord at the level of T10-11 (B2; circle) developed. This
resolved (C2) the following year, after completion of further
chemotherapy, autologous stem cell transplant, and craniospinal
irradiation and has not reoccurred (D2) to date, 5 years off treatment.

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