Brain Neoplasms and Malignancies

The American Brain Tumor Association reports that American clinicians will diagnose more than 79,000 diverse primary brain tumors in 2017.¹ Approximately one-third will be malignant.

The most common primary tumors—originating in the meninges—account for 37% of cases.¹ Meningiomas are usually benign, grow slowly, and rarely recur after removal. Neoplasms that originate from connective tissue are referred to collectively as “gliomas” and represent 25% of total lesions but 75% of malignancies.^1,2 Other brain lesions include primary central nervous system lymphomas, nerve sheath tumors, pituitary tumors, and metastases. This article focuses on malignant tumors that require pharmacotherapy in addition to surgery.

INITIAL SYMPTOMS

Tumor headaches are most common with posterior fossa tumors and in pediatric patients.² They are unaffected by time of day, Valsalva maneuvers, or posture changes. When increased intracranial pressure causes pain that resembles tension-type headache, its location may suggest the side involved.^3-5

Although headache is the most common presenting symptom for meningiomas, malignant tumors usually start with other symptoms.^2,6 Gliomas typically create generalized symptoms that develop slowly as the tumor grows, although ventricular obstruction or bleeding may cause an acute onset. TABLE 1^2,7 highlights nonspecific symptoms as opposed to symptoms that may indicate progressed or localized disease.⁷

Physical findings alone cannot confirm a brain mass.² Magnetic resonance imaging (MRI) with contrast is the gold standard for identifying and monitoring lesions2; however, computed tomography (CT) scans are appropriate during preliminary diagnosis, or when MRI is contraindicated (eg, patient has implanted devices or is claustrophobic). Clinicians must consider the patient’s renal status and allergy history before administering contrast media (TABLE 2^8-11).^8,9

CONCERNS AT DIAGNOSIS

The multidisciplinary team—a neurosurgeon, an oncologist, a radiologist, a radiation therapy expert, and a pharmacist—will consider the tumor origin, location, and comorbid conditions.² Once a neoplasm is confirmed, corticosteroids address cerebral edema. Dexamethasone’s high potency and low association with salt retention make it the drug of choice.⁷ Patients should receive the following:

• 10 mg intravenous as soon as possible

• 4 mg intramuscularly every 6 hours until cerebral edema subsides

• Decreasing doses over 5 to 7 days¹²

Dexamethasone may be discontinued once acute control is achieved, but some patients will require oral maintenance doses every 8 to 12 hours while they start definitive therapy.^7,12

Seizures are common in glioma patients, but studies discourage prophylactic use of anti-epileptic drugs (AEDs) in patients lacking seizure histories or in patients undergoing neurosurgery.² When AEDs are necessary, clinicians should select noninducers (eg, levetiracetam, topiramate, valproic acid) to avoid possible drug interactions with chemotherapy.

COMBINED TREATMENT COMMON

Patients may receive surgery, radiation, or chemotherapies. Surgical treatments include biopsy, debulking, or total removal; ventricular shunt placement; or drug-impregnated wafers.² Targeted radiation therapy (RT) decreases healthy cells’ exposure, but diffuse disease often requires whole brain radiation.²

When treating malignant gliomas, cellular origin and level of disease progression dictate treatment. Gliomas are classified as astrocytoma or oligodendroglioma, which are typically low-grade tumors and can become anaplastic when cells lose their normal differentiation.^1,2 Highly vascular and necrotic, glioblastoma is the highest grade malignancy.² A biopsy confirms diagnosis in low-grade glioma, and surgeons will resect the tumor, if possible, to delay or prevent progression.² After surgery, patients may receive RT immediately or wait until disease progression. Study results suggest that immediate RT increases time to disease progression with no significant effect on overall survival. TABLE 3^3,13 lists factors that clinicians consider to categorize risk and determine how aggressively to manage the disease.² Although chemotherapy is not a mainstay for gliomas, low-grade gliomas can behave aggressively in high-risk patients, who will then require adjuvant RT or chemotherapy. ONLINE TABLE 4² highlights chemotherapy used to treat gliomas.

TABLE 4: CHEMOTHERAPY USED TO TREAT GLIOMAS^2,14

Classification

Chemo Regimens

Pharmacist Considerations

Low-grade gliomas

First-line:

• Temozolomide
• PCV

Alternatives:

• Lomustine
• Carmustine
• Platinum-based therapies

Chemotherapy usually reserved for high-risk patients or recurrent disease

Tumors with 1p/19q respond well to preferred agents

Anaplastic gliomas

First-line:

• Temozolomide
• PCV
• Temozolomide + PCV

Alternatives:

• Cyclophosphamide
• Platinum regimens
• Irinotecan
• Etoposide
• Bevacizumab

Tumors with 1p/19q respond well to preferred agents

When indicated, start chemotherapy after RT to improve tolerability

Elderly or frail patients may respond to chemotherapy alone

Glioblastoma

Concurrent and adjuvant temozolomide is recommended for at least 6 months

Tumors with low MGMT expression are more sensitive to alkylating agents, such as temozolomide

MGMT = methylguanine-DNA methyltransferase; PCV = procarbazine, carmustine, vincristine; RT = radiation therapy.

Clinicians treat anaplastic or glioblastoma tumors based on the patient’s performance status and age and on the tumor’s genetic profile. Surgical resection may include placement of carmustine wafers. Clinicians may be concerned about carmustine wafers’ safety when used with adjunct temozolomide, but the combination appears safe.^15-17

Traditionally, oncologists relied on fractionated RT after surgery for high-grade gliomas. Recently, chemoradiation is preferred in patients with 1p/19q co-deletions and KPS &shy;60, and who are younger than 70 years.⁸ For these patients, adjuvant PCV (procarbazine, carmustine, vincristine) or temozolomide after RT is more tolerable than concurrent therapy.² When 1p/19q co-deletions are absent, RT is still standard, but PCV or temozolomide may be less beneficial. Patients with a low performance score (<60) may be managed with RT, chemotherapy, or palliative care.

Glioblastoma patients younger than 70 years with good performance scores should receive concurrent chemoradiation, whereas patients older than 70 are best treated with hypofractionated RT alone, where a standard dose of radiation is given over fewer treatment sessions. Other options include standard RT with concurrent and adjuvant chemotherapy.2 Patients with poor performance scores may receive RT, chemotherapy, or palliative care. For additional recommendations, refer to the National Comprehensive Cancer Network guidelines at nccn. org/professionals/physician_gls/f_guidelines.asp#cns.

DYLAN GIRARDI is a 2017 PharmD candidate.

JEANNETTE Y. WICK, RPH, MBA, is a visiting professor at the University of Connecticut School of Pharmacy.

References

1. Brain tumor statistics. American Brain Tumor Association website. abta.org/about-us/news/brain-tumor-statistics/?referrer. Accessed February 9, 2017.

2. NCNN guidelines. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/f_guidelines.asp#cns. Accessed February 10, 2017.

3. Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology. 1993;43(9):1678-1683.

4. Purdy RA, Kirby S. Headaches and brain tumors. Neurol Clin. 2004;22(1):39-53.

5. Tabatabai RR, Swadron SP. Headache in the emergency department: avoiding misdiagnosis of dangerous secondary causes. Emerg Med Clin North Am. 2016;34(4):695-716. doi: 10.1016/j.emc.2016.06.003.

6. Cancer Facts & Figures 2015. American Cancer Society website. cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed February 12, 2017.

7. Lo BM. Brain Neoplasms. Brain Neoplasms: Practice Essentials, Background, Pathophysiology. Medscape website. emedicine.medscape.com/article/779664-overview#showall. Published November 9, 2015. Accessed February 10, 2017.

8. Pomara C, Pascale N, Maglietta F, Neri M, Riezzo I, Turillazzi E. Use of contrast media in diagnostic imaging: medico-legal considerations. Radiol Med. 2015;120(9):802-809. doi: 10.1007/s11547-015-0549-6.

9. Ferris N, Goergen S. Gadolinium contrast medium (MRI contrast agents). Inside Radiology website. insideradiology.com.au/gadolinium-contrast-medium/. Updated November 22, 2016. Accessed February 10, 2017.

10. Conway ® [package insert]. Bloomington, IN: Guerbet LLC; 2016.

guerbet.com/fileadmin/user_upload/home/products/other-products/products/package-insert-conray.pdf. Accessed February 27, 2017.

11. Magnevist [package insert]. Whippany, NJ: Bayer Healthcare Pharmaceuticals Inc.; 2014.

labeling.bayerhealthcare.com/html/products/pi/Magnevist_PI.pdf. Accessed February 27, 2017.

12. Dexamethasone Sodium Phosphate [package insert]. Lake Zurich, IL: Fresenius Kabi, USA; 2014.

www.accessdata.fda.gov/drugsatfda_docs/label/2014/040572s002lbl.pdf. Accessed February 27, 2017.

13. Skirvin JA, King AC. Adult CNS malignancies: update on brain tumors. US Pharmacist website. www.uspharmacist.com/article/adult-cns-malignancies-update-on-brain-tumors. Published March 20, 2013. Accessed February 10, 2017.

14. Kaal EC, Vecht CJ. The management of brain edema in brain tumors. Curr Opin Oncol. 2004;16(6):593-600.

15. Dixit S, Hingorani M, Achawal S, Scott I. The sequential use of carmustine wafers (Gliadel) and post-operative radiotherapy with concomitant temozolomide followed by adjuvant temozolomide: a clinical review. Br J Neurosurg. 2011;25(4):459-469. doi: 10.3109/02688697.2010.550342.

16. McGirt MJ, Than KD, Weingart JD, et al. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg. 2009;110(3):583-588. doi: 10.3171/2008.5.17557.

17. Salvati M, D’Elia A, Frati A, Brogna C, Santoro A, Delfini R. Safety and feasibility of the adjunct of local chemotherapy with biodegradable carmustine (BCNU) wafers to the standard multimodal approach to high grade gliomas at first diagnosis. J Neurosurg Sci. 2011;55(1):1-6.