Diffuse Intra-Axial expansive Lesion of the Enchephalic Trunk not surgically investigated_4
Short Summary

7-year-old boy with prodrome of right-sided and right face weakness, gait ataxia, and intermittent headaches. Head computed tomography demonstrated a tumor at the brainstem/posterior fossa, and then MRI confirmed a diffuse intrinsic pontine glioma (a typical brainstem glioma). Following initiation of dexamethasone (Decadron, steroid for vasogenic edema), the child has started experimental treatment with the medicine nimotuzumab to be followed with conventional radiotherapy.

Patient's Questions
1)         What therapy do you suggest? If you exclude the surgical operation do you share the pharmacologic therapy + diagnosed radiotherapy? Is there the possibility after the diagnosed therapy, that the tumoral mass could decrease allowing later a solving surgical operation?

2)         Do his parents know that the radiotherapy is applicable only once in the same point; afterwards does it exist a follow-up therapy for this kind of tumor that can give long-term and good quality life expectancies?

3)         Now the young patient is taking cortisone that involves an excessive increasing in his appetite compared to his real needs. Is it advisable to regulate the amount and/or to opt for particular types and quality of food? Is it necessary to contact a nutritionist?

4)         What will the pathology course be? Will the symptomatology be very painful?

5)         What are the centres of excellence for the treatment of such pathologies?
Medical Background

7 years old, male.
Diagnosis: DIFFUSE INTRA-AXIAL EXPANSIVE LESION OF THE ENCEPHALIC TRUNK NOT SURGICALLY INVESTIGATED.
Medical history: 
First-born child, he has a younger brother of 5 years old who enjoys a good health. Right-handed child. Not findings of allergies to drugs and food intolerances.
Normal spontaneous delivery. Breastfeeding until six months of age. Psychophysical development within norm limits. He got the vaccinations according to law.
Among the exanthematic diseases: sixth disease when he was 1 and a half year; varicella when he was 5.
No surgical operation in the past and no current home therapy.
Case history:
The clinical symptoms began about one and a half month ago with general asthenia, right hand tremors, state of anxiety and episodes of diffuse headache of short duration, with a frequency of about twice a day with spontaneous remission.
Therefore, he carried out a paediatric visit with evidence of a right asymmetry of the mouth. From 10/2008 repeated vomit episodes occurred, associated with slowing down of the ideomotor functions. On 11/2008 the child was, therefore, brought to the emergency room of the Trento Hospital, where a neurological examination was carried out with finding of a right hand side mouth deviation, uncertain walking, tendency to break up and difficulty in the word articulating activity. A brain CT scan was then performed, with evidence of an expansive lesion on the encephalic trunk that had a swollen appearance. A brain magnetic resonance (MRI) with contrast was then performed, as a further in-depth analysis whose medical report is integrally carried:
“Examination performed as a complement of today’s CAT scan without contrast medium.
We confirm the presence of an expansive lesion of the encephalic trunk, widely infiltrating the pons, the mesencephalon (especially at the right slope), the right cerebellar peduncle, and with an anterior esophitic development with the tendency to wrap the basic artery towards the front.
This formation is characterized by a hyper-intensity in the T2 weighted images, and a hypo-intensity in the T1 weighted images, with nearly absent contrastographic impregnation after Gadolinium (6 ml I.V.) administration: the finding lets hypothesize for a glioma of the encephalic trunk. Nodular enhancement foci are present at clivus level, especially at the right hand side of the median line, likely to be a leptomeningeal dissemination.
Light hyper-intensity of the white peri-ventricular substance close to the frontal and occipital horns in the FLAIR sequence due to an initial subependymal liquor overflow, sign of obstructive hydrocephalus.”
The young patient was, therefore, sent to the Hospital Istituti Ospitalieri of Verona for action.
During this hospitalization it was attempted to carry out a high-field MR imaging (3T), diffusion and spectroscopy, but the child didn’t cooperate for the required time and the procedure was suspended; the neuroradiologists have confirmed what already expressed in the medical report by the colleagues of the Santa Chiara Hospital of Trento, the lesion is, in all probability, a glioma b.g.
For its characteristics of diffuse inherent lesion it is not susceptible of surgery treatment. His parents have consulted a second doctor who has confirmed what it had already been expressed by the colleagues of Trento.
The steroid therapy (Decadron 2 mg x 2 I.V.) has brought about an improvement in the clinical situation at admission.
He was discharged from Verona Hospital on 11/2008 and continued home the current intravenous steroid therapy. Afterwards, on 11/2008, further hospitalization at the National Cancer Institute of Milan, where he is still hospitalized.
With regard to the diagnosed therapy the following elements are reported:
- As for the therapy prescribed to the patient: since 11/08 (date of hospitalization at the Borgo Trento Hospital of Verona, where he remained for three days) the therapy consists of:
Soldesam 0.2% (32 drops in the morning and 16 drops in the afternoon)
Nexium (1 tablet of 20 mg)
- Afterwards, he was moved to the National Cancer Institute of Milan, since 11/08 to the aforesaid drugs the antibody NIMOTUZUMAB (once a week for 12 consecutive times) was added.
The second dosage of NIMOTUZUMAB will be administered on 11/08.
After about another week a third dosage will be administered and to this drug (given once a week for the period of the entire therapy), from the third to the eighth week, a radiotherapy will be combined (5 treatments a week); then 3 further weekly dosages will be administered and they will end the therapy.

Expert's Opinion

have reviewed the MRI, and indeed there is a tumor obscuring the pons within the brainstem, with engulfment of the basilar artery, and extending to the midbrain (mesencephalon) and partly to the medulla. The tumor is hypo- to iso-intense on T1- weighted images, and hyperintense on T2. There is minimal enhancement with gadolinium dye. There is mild hydrocephalus.
 
Following initiation of dexamethasone (Decadron, steroid for vasogenic edema), the child has been treated at the National Cancer Institute of Milan and has started experimental treatment with the medicine nimotuzumab to be followed with conventional radiotherapy. This is a very logical and reasonable approach for this very aggressive, and often refractory malignant brain tumor/cancer. 
 
Questions
(1)       What therapy do you suggest? If you exclude the surgical operation, do you share the pharmacologic therapy + diagnosed radiotherapy? Is there the possibility after the diagnosed therapy, that the tumoral mass could decrease, allowing later a solving surgical operation?
I would strongly suggest the therapeutic approach that has been adopted. In North America, Europe, and South America, the leading, upfront clinical trials for this dreadful tumor have been:
  • nimotuzumab + radiotherapy (a phase II study being performed at selected children’s hospital in Europe, Canada, and the United States)
  • arsenic trioxide + radiotherapy (a I study being performed at selected children’s hospital in the United States)
  • ACNS 0222 gadolinium texaphyrin + radiotherapy (a phase II study conducted by the Children’s Oncology Group at children’s hospitals throughout the United States and Canada; just recently closed)
  • PBTC -021 capecitabine and radiotherapy (a phase I Trial being conducted at 8 centers in the United States)
 
At Stanford, we have been participating in all of the 3 first named studies (nimotuzumab, arsenic trioxide, and gadolinium texaphyrin). While there are no data to indicate any of these experimental treatments are more effective than radiotherapy alone, we would favor either nimotuzumab or arsenic trioxide plus radiotherapy
Any meaningful surgical resection of this tumor is not possible without devastating, catastrophic neurologic injury, or a bad outcome. Tumors such these diffusely infiltrate all the normal tissue of the brainstem, such that the cancer cannot be removed without destroying the normal tissue of the brainstem. 
A limited biopsy could be performed but would not change the treatment plans or outcome in any way.
If the tumor were to grow further after nimotuzumab, we would proceed with bevacizumab plus or minus temozolomide or irinotecan, either on or off an experimental, clinical trial.
(2)       Do his parents know that the radiotherapy is applicable only once in the same point; afterwards does it exist a follow-up therapy for this kind of tumor that can give long-term and good quality life expectancies?
Conventional external beam radiotherapy (photon or less often proton) can be done only once in a lifetime with this tumorWithout any radiation, the average life expectancy is about only 20 weeks. With radiation, the average life expectancy is 1 year, though we would be hopeful that the patient exceeds well that average.
After radiotherapy, we would consider continuing the nimotuzumab or initiating bevacizumab or temozolomide.
(3)       Now the young patient is taking cortisone that involves an excessive increasing in his appetite compared to his real needs. Is it advisable to regulate the amount and/or to opt for particular types and quality of food? Is it necessary to contact a nutritionist?
We would strongly advise trying to minimize the usage of dexamethasone (or cortisone) to the lowest amount tolerable, so as to minimize these many side-effects. Most often we can get children down to a dose of 1 to 2 mg dexamethasone twice a day (along with the Nexium to avoid stomach upset). At the same time, we would make sure that the child is not allowed to eat excessively: he can take regular meals, but then if he is still hungry after meals, he should be offered lowest calorie foods such as carrots or celery without any spreads or dressings. A nutritionist may be helpful for advice.
4)         What will the pathology course be? Will the symptomatology be very painful?
 
These diffuse tumors are all grade II-IV diffuse, non-operable astrocytomas (malignant brain cancers). [Fisher PG et al. A clinicopathologic reappraisal of brainstem tumor classification: identification of pilocytic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 89:1569-1576, 2000]. As the tumor progresses, rarely ever is pain a problem. Instead, children have progressive difficulty with crossed eyes, weak face, difficulty swallowing, and walking. If the tumor is refractory and not responsive to any treatment, the child often lapses into a deep sleep/coma for days or weeks before passing peacefully.
(5)       What are the centres of excellence for the treatment of such pathologies in Italy and Europe?
-       Giorgio Perilongo at University of Padua is an expert Italian neuro-oncologist, well trained in the United States.
-       Jacques Grill is another expert neuro-oncologist in France at Département de Cancérologie de l'Enfant et de l'Adolescent, Institut Gustave Roussy, 39, rue Camille Desmoulins, Villejuif cedex 94805, France.
-       Great Ormond Street Hospital for Children in London is another center of excellence. 

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