Childs Nerv Syst
DOI 10.1007/s00381-017-3352-y
CASE REPORT
Second re-irradiation for DIPG progression, re-considering
Bold strategies^ with new approaches
Andres Morales La Madrid 1,2 & Vicente Santa-María 2 & Ofelia Cruz Martinez 1,2 &
Jaume Mora 2 & Patricia Puerta Roldan 3 & Antonio Guillen Quesada 3 &
Mariona Suñol Capella 4 & Carmen de Torres Gomez-Pallete 5 & Alvaro Lassaletta 6 &
Normand Laperriere 7 & Salvador Villà 8 & Eric Bouffet 6
Received: 2 September 2016 / Accepted: 24 January 2017
# Springer-Verlag Berlin Heidelberg 2017
Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive infiltrative glioma for which no curative therapy is
available. Radiation therapy (RT) is the only potentially effective intervention in delaying tumor progression, but only transiently. At progression, re-irradiation is gaining popularity as
an effective palliative therapy. However, at second progression, exclusive symptomatic treatment is usually offered. Here
we report two patients with DIPG at second progression who
were treated with a second re-irradiation course with good
response. Importantly, treatment was well tolerated with no
irradiation associated acute toxicity identified.
Keywords DIPG . Second re-irradiation
* Andres Morales La Madrid
[email protected]
1
Pediatric Neuro-Oncology, Department of Pediatric Hematology and
Oncology, Hospital Sant Joan de Deu, Passeig Sant Joan de Déu 2,
08950 Barcelona, Spain
2
Pediatric Hematology and Oncology, Hospital Sant Joan de Déu,
Barcelona, Spain
3
Pediatric Neurosurgery, Hospital Sant Joan de Déu, Barcelona, Spain
4
Department of Pathology, Hospital Sant Joan de Déu,
Barcelona, Spain
5
Developmental Tumor Biology Laboratory, Institut de Recerca
Pediàtrica—Hospital Sant Joan de Déu, Esplugues de Llobregat,
Barcelona, Spain
6
Neuro-Oncology Department, Division of Pediatric Hematology/
Oncology, The Hospital for Sick Children, Toronto, Canada
7
Department of Radiation Oncology, Princess Margaret Cancer
Centre, Toronto, Canada
8
Department of Radiation Oncology, Institut Oncològic Teknon and
Institut Català d’Oncologia, Barcelona, Spain
Introduction
Diffuse intrinsic pontine glioma (DIPG) is a lethal infiltrative
glioma centered macroscopically in the pons for which no
therapeutic advance has been achieved for decades (1). Lack
of effective interventions urges for novel therapies, delivery
systems and for re-assessment of current treatment schema
(2). Focal radiation therapy (RT) is the only intervention that
transiently delays tumor progression. At first progression, reirradiation has gained popularity (3, 4), however, at second
progression, most institutions offer full palliative care. We
report two DIPG cases who received a second re-irradiation
course at second tumor progression.
Case 1
A 6-year-old female presented with a 4-week history of headaches and dizziness. Brain MRI showed a large non-contrast
enhancing T1 hypointense/T2 hyperintense mass compatible
with a DIPG (Fig. 1a, b). At diagnosis, parents opted for an
alternative herbal therapy and observation. Follow-up brain
MRI 3 months later showed tumor progression, in concordance with neurologic deterioration. Dexamethasone was
started and shortly after focal RT (54 Gys/30 fractions) was
delivered with rapid improvement. Post-RT brain MRI
showed interval decrease in tumor bulk within the pons
(Fig. 1a, b, c, d). No post-RT therapy was offered and the
patient remained well for 8 months. Thereafter, new neurologic symptoms reappeared. Brain MRI showed significant interval tumor progression. Re-irradiation (30.6 Gys/17 fractions)
was administered with good tolerance and resolution of symptoms. Post re-irradiation MRI showed significant interval decrease in tumor volume (Fig. 1e, f, g, h). After RT, the patient
was kept on the same herbal alternative therapy. Four months
Childs Nerv Syst
Fig. 1 Case 1 diagnosis: a T1 post gad, b T2 FLAIR. Post upfront RT: c T1 post gad, d T2 FLAIR. First progression: e T1 post gad, f T2 FLAIR. Post reRT: G T1 post gad, h T2 FLAIR. Second progression: i T1 post gad, j T2 FLAIR. Post second re-RT: k T1 post gad, l T2 FLAIR
later, new symptoms of progression developed and MRI
showed new interval progression of the lesion with extrapontine lesions identified. A second course of focal re-RT
was administered (21.6 Gys/12 fractions) with good tolerance
and clinical response. Dexamethasone was tapered off by the
end of RT. Post second re-RT brain imaging showed overall
tumor reduction (Fig. 1i, j, k, l). However, the new areas of
tumor infiltration remained unchanged. Three months later,
symptoms reappeared and the patient rapidly deteriorated.
At that point full palliative care was offered and patient died
of disease 1 month later.
Case 2
A 5 year-old male, presented with a 2-week history of right
facial palsy, left hemiparesis, and ataxia. Brain MRI showed a
large pontine T1 hypointense/T2 hyperintense mass compatible with DIPG. Post-gadolinium administration showed heterogeneous contrast enhancement. Focal hypofractionated RT
(39 Gys/13 fractions) was administered with good tolerance
and response. Post-RT imaging showed interval decrease in
tumor bulk and decrease in gadolinium uptake (Fig. 2a, b, c,
d). Thereafter, an oral antiangiogenic regimen as per the
Angiocomb schema was started (5). Eleven months later, clinical and radiologic tumor progression developed. Reirradiation with 20 Gys/10 fractions was administered with
good radiologic and clinical response (Fig. 2e, f , g, h).
Thereafter, irinotecan and rapamycin were started. Eight
months later, new clinical and radiologic progression
established. A second re-irradiation course with 20 Gys/10
fractions with concomitant oral temozolomide was administered with good tolerance and rapid clinical response (Fig. 2i,
j, k, l). Sustained clinical and radiologic response remained for
6 months after second re-RT, when subtle symptoms
reappeared. At this point, patient’s survival was longer than
expected for most patients with DIPG. We proposed to perform a minimally invasive biopsy for molecular characterization of this tumor in the search for potential therapeutic targets.
Parents were in favor of the procedure, knowing it would
Fig. 2 Case 2 diagnosis: a T1 post gad. b T2 FLAIR. post upfront RT: c T1 post gad, d T2 FLAIR. First progression: e T1 post gad, f T2 FLAIR. Post reRT: g T1 post gad, h T2 FLAIR. Second progression: i T1 post gad, j T2 FLAIR. Post second re-RT: k T1 post gad, L T2 FLAIR
Childs Nerv Syst
unlikely change the overall patient’s prognosis. The procedure
was uneventful, however tumor sample was scant. Histologic
review was compatible with a low-grade glioma. Molecular
profiling resulted negative for K27M mutation (both H3.3 and
H3.1 variants), BRAFV600E mutation, and BRAF tandem duplication. One year after second re-RT and 3 months after the
biopsy, clinical and radiologic progression continued, and patient died of disease.
Discussion
DIPG is the most frequent brainstem tumor in children and
diagnosis is usually established on classic clinical and radiologic features (6). A number of dedicated centers have started
to perform diagnostic stereotactic biopsies, showing it to be a
safe procedure when performed by experienced neurosurgical
teams (7, 8). Tissue molecular profiling has shown that DIPG
is a heterogeneous tumor with specific genetic and epigenetic
alterations (i.e., K27M (H3.3 and H3.1), PDGFRA, TP53,
ACVR1, and FGFR1) (9–12). However, this new bulk of
knowledge has not translated yet in better treatments (13).
Focal irradiation is the only intervention that delays tumor
progression transiently in most cases and no drug combination
has changed prognosis significantly (14). Hypo-fractionated
radiotherapy seems to be as effective as standard fractionation,
decreasing the length of therapy by half and with comparable
toxicity (15–17). However, both radiation schemas are still
currently used by treating radiation oncologists.
Unfortunately, most DIPG patients will progress during the
first year after diagnosis. At first progression, re-irradiation
has gained popularity among institutions with some variation
among the total dose to be delivered (3, 4, 18). Responses
obtained are usually short-lasting and patients unequivocally
progress. In this scenario, most centers offer full palliative care
with no antitumor therapy. We opted to offer a second course
of re-irradiation with good tolerance and clinical benefit of
3 months in case 1 and 12 months in case 2. This is the first
report of such approach and although palliative, our intervention showed to be well tolerated and increased the lifespan
while enjoying good quality of life. Of note, case 2 may fall
into the DIPG category of Blong-term^ survivors (19). There
is no molecular data of such cases, thus it is interesting to see
that in spite of having the same radiologic features at diagnosis
and progression, the molecular make up of this tumor is strikingly different to most DIPGs. It is reasonable to hypothesize
that the absence of the classic epigenetic and genetic abnormalities mentioned above make these tumors more Bindolent^
as observed in this case. It is to be seen if other Blong-term^
DIPG survivors show a similar molecular profile.
DIPG is a heterogeneous disease with a group of patients
that may be particularly responsive to radiation therapy. A
second re-irradiation could be proposed in those who show a
good and Bsustained^ response to upfront and re-irradiation.
Importantly, it is to be defined what is a reasonable Bsustained
response^ for this particular disease in order to consider subsequent courses of re-irradiation for it to be beneficial and well
tolerated. In the absence of more efficacious therapies, it is
worth to explore different radiation schemas, both upfront
and at relapse.
There has been no improvement in DIPG prognosis in
more than four decades. We not only need to find more effective therapies, but also we ought to re-think how we use Bold
therapies^ in order to maximize its effectiveness. The Milan
group is currently studying a different upfront radiation schema with separated coursed of radiation; their results may open
new avenues for clinical research at diagnosis and progression. Of note, there was no imaging evidence of radiationrelated necrosis of the surrounding normal nervous structures
in these two cases. Brainstem radiation tolerance, as well as
ethical and safety aspects will have to be reviewed if a feasibility pilot study for a second re-irradiation in DIPG is proposed. Certainly, we need to think Bout of the box^ to improve
the prognosis of this deadly condition.
Compliance with ethical standards
Conflicts of interest The authors declare no conflicts of interest.
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