Managing a patient with diffuse brainstem glioma
A 17-year-old woman with no significant past medical history presented to her primary care physician after having headaches for two weeks. She mentioned a fall during a basketball game, a closed-head, sports-related injury that had been dismissed as a mild concussion. She had begun to notice new-onset, left-sided facial numbness for one week with no associated seizure-like activity or constitutional symptoms. She otherwise had no known genetic abnormalities, nor any history of exposure to any environmental toxins or ionizing radiation.
The patient was subsequently referred to a neurologist for further workup of her headaches and new-onset facial numbness. The patient underwent MRI, and fluid attenuated inversion recovery (FLAIR) imaging (see figure) revealed an expansile mass on the left side of the pons extending exophytically anteriorly into the prepontine cistern. The patient was prescribed high-dose steroids and referred to radiation oncology. At the time of presentation to radiation oncology, her numbness along the distribution of the facial nerve persisted, as well as newly developed gait instability and blurred vision in the left eye. On exam, no other focal neurologic deficits were found.
How will you manage this patient?
A) There is no efficacious therapy — the patient should be placed on
hospice with comfort measures only.
B) The patient should be referred to neurosurgery for a stereotactic biopsy to confirm diagnosis, followed by surgery if possible, in addition to adjuvant chemotherapy and radiation.
C) Though conventional fractionated radiotherapy remains the standard of care, the patient may be a candidate for concurrent chemotherapy and radiation.
D) Radiation is not indicated in this case because the tolerance of the involved organ does not allow radiation dose to effectively treat this disease. Therefore, chemotherapy is the only option.
Which of the following statements is true regarding diffuse pontine glioma?
A) Biopsy is recommended for diagnosis.
B) The incidence of central nervous system dissemination is 75%.
C) It has the worst prognosis of all brainstem gliomas.
D) Radiation doses greater than 60 Gy improve outcome.
Source: L. Dad
This unfortunate case involves an adolescent with diffuse pontine glioma — a diagnosis that may be made in view of clinical symptoms and imaging studies, which does not require pathologic confirmation because histological subtype does not alter the management.
CNS tumors make up 20% to 25% of all childhood malignancies (Halpern, 2007). Though the development of childhood brain tumors has been linked to genetic predispositions including neurofibromatosis types 1 and 2, tuberous sclerosis, adenomatous polyposis syndromes, Li-Fraumeni syndrome and ionizing radiation, the majority of brain tumors arise from no apparent predisposing factor.
Brainstem gliomas represent a heterogeneous group of tumors, conceptually thought to best be divided into focal vs. a more diffuse pattern of disease. With advancements in neuroimaging and the advent of modern neurosurgical techniques, focal brainstem gliomas often times initially are managed surgically (Packer 2005). Focal tumors are those smaller than 2 cm that are well circumscribed, without evidence of infiltration and edema on MRI (Halpern 2007). This case is of a diffuse brainstem glioma with pontine involvement as demonstrated by the imaging seen in the figure.
Diffuse intrinsic brainstem gliomas represent 75% of all brainstem tumors. This category of brainstem glioma tends to arise in the pons and results in diffuse enlargement of the brainstem. Clinically, symptoms on presentation evolve during a short time and are most often of multiple cranial nerve deficits, as seen in our patient. T2-weighted or FLAIR MRI is the imaging modality of choice to make the diagnosis. Surgery has no role in the management of patients with diffuse intrinsic brainstem gliomas. With conventional radiotherapy as the treatment of choice for such tumors, the initial clinical response rate is quite good. However, this type of tumor confers a very poor prognosis, with a median time to progression of less than six months, a median survival of less than one year and a two-year survival rate of less than 20% (Hargrave 2006).
Thus far, all major investigations to improve the outcome for children with diffuse intrinsic tumors have not rendered very much promise (Hargrave 2006). Furthermore, no chemotherapeutic combination has proven any survival advantage to radiation alone for diffuse intrinsic brainstem gliomas (Grill 2007).
In the EORTC randomized study, which compared radiotherapy alone with radiotherapy plus temozolomide (Temodar, Schering) in patients with newly diagnosed glioblastoma, the results demonstrated a significant survival advantage with the addition of chemotherapy (Stupp 2005), thus generating considerable hope in the neuro-oncology community for promising treatment approaches for high-grade gliomas. The role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children was examined in a multi-institutional study (Broniscer 2005). However the addition of temozolomide did not positively affect OS or PFS. The role of concurrent temozolomide with radiotherapy in childhood glioma has yet to be established.
Our patient received a course of concurrent temozolomide and intensity modulated radiation therapy to a total dose of 54 Gy. Her postradiation MRI revealed remarkable decrease in the area of enhancement. Following completion of radiation, the patient was prescribed temozolomide 120 mg daily on a 21-day cycle with seven days off for a 28-day cycle. The patient is currently three months posttreatment and denies any focal neurologic symptoms. She has rejoined her basketball team and has been weaned off all steroids. The current standard of care for diffuse intrinsic brainstem tumors is radiation therapy to the gross tumor volume as seen on T2-weighted or FLAIR MRI with a margin for the clinical target volume of 1 cm to 1.5 cm to a dose of 54 Gy in 30 fractions during six weeks (Perez 2007). The addition of various chemotherapeutic regimens remains experimental.
Luqman Dad, MD, is currently a Resident Physician in the Department of Radiation Medicine at Roswell Park Cancer Institute. He would like to acknowledge his mentor Dr. Dheerendra Prasad and the Neuro-Oncology Team at the Roswell Park Cancer Institute for their continued guidance and support during his residency training.
For more information:
- Broniscer A, Iacono L, Chintagumpala M, et al. Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a multiinstitutional study (SJHG-98). Cancer. 2005;103:133-139.
- Grill J, Bhangoo R. Recent development in chemotherapy of paediatric brain tumors. Curr Opin Oncol. 2007;19:612-615.
- Halpern EC, Brady LW, Perez CA, et al. Perez and Brady's: Principles and practice of radiation oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins: 2007:xii.
- Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol. 2006;7:241-248.
- Packer RJ. Progress and challenges in childhood brain tumors. J Neurooncol. 2005;75:239-242.
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.