Child's Nervous System

, Volume 33, Issue 5, pp 849–852 | Cite as

Second re-irradiation for DIPG progression, re-considering “old strategies” with new approaches

  • Andres Morales La Madrid
  • Vicente Santa-María
  • Ofelia Cruz Martinez
  • Jaume Mora
  • Patricia Puerta Roldan
  • Antonio Guillen Quesada
  • Mariona Suñol Capella
  • Carmen de Torres Gomez-Pallete
  • Alvaro Lassaletta
  • Normand Laperriere
  • Salvador Villà
  • Eric Bouffet
Case Report


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.


DIPG Second re-irradiation 


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, re-irradiation 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 later, new symptoms of progression developed and MRI showed new interval progression of the lesion with extra-pontine 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.
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 re-RT: 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

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. Re-irradiation 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 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.
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 re-RT: 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


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, 10, 11, 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, 16, 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 “long-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 “indolent” as observed in this case. It is to be seen if other “long-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 “sustained” response to upfront and re-irradiation. Importantly, it is to be defined what is a reasonable “sustained 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 “old 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 radiation-related 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 “out 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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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • 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
  1. 1.Pediatric Neuro-Oncology, Department of Pediatric Hematology and OncologyHospital Sant Joan de DeuBarcelonaSpain
  2. 2.Pediatric Hematology and OncologyHospital Sant Joan de DéuBarcelonaSpain
  3. 3.Pediatric NeurosurgeryHospital Sant Joan de DéuBarcelonaSpain
  4. 4.Department of PathologyHospital Sant Joan de DéuBarcelonaSpain
  5. 5.Developmental Tumor Biology LaboratoryInstitut de Recerca Pediàtrica—Hospital Sant Joan de DéuBarcelonaSpain
  6. 6.Neuro-Oncology Department, Division of Pediatric Hematology/OncologyThe Hospital for Sick ChildrenTorontoCanada
  7. 7.Department of Radiation OncologyPrincess Margaret Cancer CentreTorontoCanada
  8. 8.Department of Radiation OncologyInstitut Oncològic Teknon and Institut Català d’OncologiaBarcelonaSpain

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