New beginnings for brain cancer treatment
SummaryWhile brain cancer may be one of the rarer cancers, the outlook for those diagnosed is bleak. For patients with glioblastoma multiforme (GBM) - the most aggressive form of brain cancer - average survival is approximately one year. However the recent supplementary approval of temozolomide for use in first-line treatment may represent the first step in a more 'personalized' approach to GBM.
In March 2005, Schering-Plough's temozolomide (Temodar/Temodal) garnered US FDA approval for the first-line treatment of patients with GBM and European approval followed in June 2005. Temozolomide given in combination with radiation therapy has been shown to increase survival by two months. While this improvement may at first glance seem modest, given the poor prognosis for these patients and the current dearth in pharmacotherapy, this represents an important advance.
Cancers of the brain and nervous system are relatively rare, accounting for less than 2% of new cancers diagnosed globally. The most common brain tumors are the gliomas, arising from glial cells which function to protect and support the neurons of the brain; but traditional chemotherapy drugs are largely ineffective for glioma treatment. This is primarily because a carefully regulated barrier (blood brain barrier) prevents toxic agents entering the brain. The double edged sword of this highly efficient protective system is that it excludes many chemotherapy drugs from reaching the required treatment area.
Among patients diagnosed with GBM, there appears to exist a subset of individuals who are even more responsive to temozolomide. The discovery of the reason behind differences between individual susceptibility to temozolomide treatment marks a major breakthrough in the treatment of this disease.
Patients with diminished levels of the enzyme involved in repairing damaged DNA have been found to have increased sensitivity to temozolomide and indeed improvements in overall survival. When temozolomide was administered with radiotherapy, patients with the diminished enzyme levels conferred a median survival advantage of 21.7 months, compared to 12.7 months in patients with normal enzyme status.
This is the first time that a molecular phenotype has been related to increased sensitivity and survival.
While these results offer hope to patients, they also offer hope to developers who are striving to find biomarkers predictive of response to drug treatment. The identification of prognostic indicators may allow prescribers to limit the administration of high-cost drugs to those patient groups who are most likely to benefit.
Targeted therapies offer new hope
A greater understanding of the molecular pathogenesis of glioma and the biochemical and genetic changes that occur en route to glioblastoma transformation will provide a plethora of potential drug targets. The lack of efficacious agents in glioblastoma will pave the way for the introduction of targeted therapies and innovative agents, particularly in combination with existing therapies such as temozolomide.
Opinion leaders are optimistic that, as with many tumor types, targeted therapy holds the greatest hope for glioblastoma patients. Epidermal growth factor receptor (EGFR) inhibition appears to be a lucrative target, with YM Biosciences/Center of Molecular Immunology/Oncoscience's nimotuzumab (TheraCIM h-R3) being the first EGFR-directed monoclonal antibody to reach late-stage trials for glioma. Phase II trial results are promising and a Phase III study is planned.
There is also excitement surrounding Eli Lilly's enzastaurin. Despite only being in phase II trials, opinion leaders are already aware of promising data surrounding this drug, which appears to demonstrate a response rate of 20% in heavily pre-treated patients. This is a remarkable feat in this particular patient cohort. Phase III trials are planned and Eli Lilly has exercised the astute move of combining enzastaurin with temozolomide for these trials as current evidence suggests that new targeted therapies are likely to be most effective when combined with existing cytotoxic agents.
The glioma market exhibits significant unmet needs and clearly new approaches to the management of this disease are required. Not only in terms of agents that will increase survival, but also drugs which will improve quality of life and delay or prevent tumor recurrence.
With the addition of temozolomide to radiotherapy conferring a survival advantage and the identification of a molecular marker predictive of responder patients, the future is now looking more hopeful. The introduction of targeted agents has potential to provide further improvements in survival and may mark the start of a more optimistic outlook for glioma patients.