In the United States, it was estimated that 27,070 patients would be affected with malignant primary brain cancer in 2017 and that these tumors would be responsible for approximately 16,947 deaths (Ostrom, Gittleman et al. 2015).
Primary brain tumors are a heterogeneous group of neoplasms, with varied outcomes and management strategies that range from the very uncommon, noninvasive, and surgically curable pilocytic astrocytomas to glioblastoma multiforme (GBM), the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable.
Likewise, anaplastic astrocytoma and several other histologic types of primary brain cancers grow rapidly, leading to profound morbidity and short survival.
For the past several decades, the survival outcomes for patients with GBM have changed very little, with a median survival time of 14-16 months. The current standard of care for newly diagnosed glioblastoma consists of maximal safe surgical resection followed by concurrent radiation therapy with temozolomide, followed by adjuvant temozolomide (Stupp, Hegi et al. 2009). This treatment resulted in an increase in median survival of 2.5 months (from 12.1 to 14.6 months) and an increase in 2-year survival of 26%, without a negative impact on the patients’ quality of life.
The most recent FDA approved adjuvant treatment adds the use of tumor treating fields to temozolomide (Stupp, Taillibert et al. 2015), which has increased median survival to 20 months.
Except in the treatment of oligodendroglioma, systemic chemotherapy, either with single agents or in combination, has not led to any major breakthrough.
When patients with GBM develop a recurrence of the disease, most available treatment options have a limited impact on overall outcome. The 6-month progression-free survival ranges from 8 to 15%, with a median ranging from 8 to 9 weeks, and overall survival extends to no more than 3 or 4 months.
The ability of temozolomide, a small lipophilic alkylating agent, to cross the blood-brain barrier effectively and become a viable chemotherapeutic option, reiterates the importance of the discovery and development of small molecules that are able to circumvent this physiological barrier, avoid being substrates for blood-brain barrier active transporters out of the brain, and be delivered to the tumor site.