3-year old boy with Medulloblastoma
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Short summary
34 month old male has a classical medulloblastoma, probably originating in the vermis. A gross total resection was achieved. He is undergoing a chemotherapy based protocol with autologous stem cell re-infusion.
Patient's questions
Questions posed by the patient’s parents:
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Is the purpose of the chemotherapy to buy time so that the patient can undergo radiation therapy, or is it the main treatment?
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Is the Cancer Institute of Milan, and in particular Dr. Massimino who is treating this child, the best choice or are there other centers of excellence more suited for this condition?
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The tumor has been defined as classic. However, if it were anaplastic, would it be treatable?
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Could the chemotherapy create complications for the child in years to come?
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Is the chemotherapy protocol appropriate, or are there any better protocols?
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Is the chemotherapy connected in any way with the stem cells in this neurooncological pathology?
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Could stem cells be an alternative therapy providing better results?
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According to a medical opinion in country X, approximately halfway through the protocol a very powerful medication will be used. Will this medication be too strong in such a young child?
Medical Background
The onset of symptoms occurred on Jan. 2008 when, at the age of 2 years and 8 months, the patient experienced morning vomiting described as “water and mucous”, which persisted for 10 days. After about a week, the patient’s symptoms became worse, with vomiting no longer limited to the morning, but was protracted throughout the day (the infant would eat and then experience projectile vomiting).
After two weeks, the infant vomited during the day and also displayed symptoms of sleepiness and fatigue, asking to sleep in the afternoon (he would sleep for 13 hours and on waking reported fatigue; he ate, vomited and lost weight and had a sickly complexion).
The patient’s sleeping posture changed (legs astride, on his stomach, no longer in his usual supine position).
The patient was examined by another pediatrician who prescribed various syrups to treat the vomiting, but to no avail.
The patient was taken to hospital where he was given an injection of an unspecified medication, but this was not beneficial.
On Feb. 2008, the patient was taken to hospital again, but he was not admitted due to a shortage of beds.
On the next day, the patient was taken to hospital again and this time was admitted based on evidence of a pupil abnormality and his unsteady gait.
A brain MRI was performed, which showed a “brain mass”. Consequently, an urgent surgical procedure was ordered.
The patient experienced a very severe headache. The severity of this headache caused him to hit his head with his hands and painkillers were not effective.
On Feb. 2008, the patient had an urgent neurosurgical procedure to remove the neoformation in the cerebellum. A sample was sent for histology tests, the results of which were as follows: “Neoplasia characterized by extended necrotic areas containing residual areas of relatively monomorphic cells with medium-sized nuclei, mytotic and apoptotic activity, which were immunohistochemically positive for chromogranine, Synaptophysin and CD 56. Widespread nuclear positivity was observed with the antibody BAF 47 (no deletion INI-1). No immunoreactivity for GFAP. The proliferation index, investigated using the antibody Ki67, was established at approximately 40%.
Diagnosis: Classic medulloblastoma with significant regressive and necrotic phenomena (class IV WHO)”.
On Feb. 2008, an MRI of the cranium was performed (with contrast medium) under anesthesia to follow-up the previous surgical procedure. The results were as follows: “Results of suboccipital craniotomy and removal of expanding subtentorial lesion. A residual surgical cavity is present in the vermian region with a small amount of blood and connecting with ventricle IV. The contrast medium revealed some shaded marginal enhancement areas of the external and basal profile of the cavity likely due to reaction phenomena as a result of the recent surgical procedure. No apparent residual pathology. Subtle enhancement also present around the cerebellar pedicles and pons. These results should be followed-up over time for suspected leptomeningeal spread of the condition.
No further areas of abnormal signal were found in the cerebral parenchyma, cerebellum and encephalic trunk. The ventricular system is within normal limits in terms of morphology and dimensions with a right transtrigonal derivative catheter and extremity in medial homolateral cell.
Slight bihemispheric subdural fluid accumulation, with no significant mass effect on adjacent parenchymal structures, higher intensity signal in liquor in sequences T1w, likely caused by sudden postsurgical liquor drainage.
Normal craniocervical juncture.
Normal pneumatization of paranasal cavities.”
The tumor was vascularized and a blood transfusion was required during the surgical procedure to remove the tumor. Since having the surgical procedure, the patient has not stopped vomiting. The presurgical test of the medulla was negative for cancer involvement.
On Feb. 2008, a second surgical procedure was performed to remove the liquor using method 3 ventriculostomy.
On Feb. 2008 the patient was transferred to the Cancer Institute of Milan to begin chemotherapy, starting on March, 2008 in accordance with the following schedule:
MALIGNANT CEREBRAL NEOPLASIAS IN CHILDREN < 3 YEARS OF AGE
HIGH RISK CONDITION
GENERAL TREATMENT PLAN
PBSC apheresis reinf. PBSC reinf. PBSC
↑ ↓ ↓
HD-MTX --→ HD-VP16 ------→HD-EDX ---→CBDCA1 -------→ HD-TT --------→ HD-TT
+ VCR 1 week 3 weeks + VCR 3 weeks + VCR 4 weeks. 5 weeks
AFTER 4 weeks → possible RADIATION THERAPY (in the event of metastasis or persistence of the condition)
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HD-MTX (methotrexate) 8 g/m2
HD-VP16 (etoposide) 2.4 g/m2
HD-EDX (cyclophosphamide) 4 g/m2
CBDCA1 (carboplatin) 800 mg/m2VCR (vincristine) 1.5 mg/m2
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HD-TT (thiotepa) 300 mg/m2/day x 3 days |
Shortly before this report was sent, tests performed on the liquor were positive for the presence of cancer cells. However, a decision was made to continue the above chemotherapy plan, waiting four weeks before repeating tests on the liquor. If the result is positive again, radio therapy will be added to the current chemotherapy.
Medical opinion
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The purpose of the chemotherapy is both to achieve primary therapy, in the form of killing residual cells that may be left in the site of the primary tumor and in the csf AND to delay irradiation therapy. The use of high dose chemotherapy, that may cause damage to bone marrow cells, is intended to raise the intensity of the chemotherapy sufficiently high that all residual non-detectable cells will be killed. However, if there is spread to the csf, that may be insufficient therapy and thus irradiation will be added. Irradiation is necessary in the vast majority of children with medulloblastoma, and is standard of care. The dose administered varies with whether there is csf involvement.
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The Cancer Institute is a highly regarded cancer center with great expertise in pediatric neurooncology. The doctor is a well known and well published neurooncologist, and the protocol that he is implementing is a recognized and valid protocol for the treatment of infant brain tumors. The Cancer Institute is the equivalent of any other outstanding center for the management of this disease.
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The description of classic refers to the common form of medulloblastoma, and anaplastic is a biologic and morphologic variant. The anaplastic variant has a slightly lower success rate with therapy, but is treatable.
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Could the chemotherapy produce problems for the child in the years to come? Yes, there will be some complications from the chemotherapy. These may include some degree of hearing loss, some risk of infertility. There is some risk of secondary leukemia, but that risk is extremely small. The bigger problems will result from radiation therapy if it is employed, and these have to do with neurocognitive impairment and endocrine abnormalities, including growth hormone deficiency, and other possible endocrine damage, all of which can be handled with replacement hormone therapy.
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This protocol is entirely appropriate. There are many protocols under investigation for the treatment of infants with brain tumors. They are all roughly similar in their composition, all focus on intensive chemotherapy with peripheral blood stem cell harvest, treatment intensification with thiotepa or equivalent drugs, stem cell rescue and an attempt to delay irradiation to minimize the consequences of that irradiation. There are very few differences in outcome.
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There are two different types of stem cells that may be being confused in this question. There are cancer stem cells, that are thought to be involved in the formation of the tumor, and chemotherapy is intended to destroy those stem cells. There are also peripheral blood stem cells and those produce the blood and other related tissues. The chemotherapy maximizes the mobilization of these stem cells, so that they can be harvested and stored for re-infusion. The high dose chemotherapy subsequently administered damages peripheral blood stem cells that have stayed in the body, but those are replaced by the re-infusion.
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The answer in question 6 above should address this question. The stem cells referred to in this question are the peripheral blood stem cells, and they are used as a rescue device to allow high dose chemotherapy that would otherwise have severe side effects. Peripheral blood stem cells are not a treatment on their own, but rather allow maximal treatment intensity using chemotherapy.
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A very powerful drug will be used, as described above. It is given at a dose at which, if peripheral stem cell rescue was not used, would be dangerous. However, the use of these stem cells reduces that danger greatly. The reason for using such powerful and high dose drugs is to attempt to kill the tumor cells. It is used frequently in children with brain tumors, with leukemia and other malignant diseases. While it is powerful and at high dose, it is not too strong for a 34 month old boy.