Ottenhausen, Malte; Bodhinayake, Imithri; Schaefer, Peter M.; Boockvar, John A.
The search for a game-changing therapeutical approach in Glioblastoma (GBM) is on-going. In the setting of the known immunosuppression in GBM patients, the role of human cytomegalovirus (HCMV) infection in GBM and the recent outcomes of a HCMV therapy-driven clinical trial at the Karolinska Institute are of great interest to the neurosurgical community.
HCMV is a herpesvirus and endemic in humans, with infection rates up to 90% in adults. Interestingly, infection and expression of HCMV in GBM is detected in well over 90% of cases. In vitro and in vivo data suggest that HCMV gene products can alter oncogenic pathways and promote gliomagenesis by creating an immunological microenvironment that is sustained by tumor-supportive monocytes. Notably, GBM patients with lower viral expression levels had significantly longer time to progression and overall survival compared to those with higher viral expression levels. A detailed review of these findings is provided by Cobbs (Cobbs CS. Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol 2013;25(6):682-688).
Based on this groundwork, Soderberg-Naucler's group at the Karolinska Institute initiated the Valcyte Treatment of Glioblastoma Patients in Sweden (VIGAS) trial to investigate the efficacy of anti-HCMV therapy in GBM (Stragliotto et al Effects of valganciclovir as an add-on therapy in patients with cytomegalyvirus-positive gliobalstoma: A randomized, double-blind, hypothesis-generating study. Int. J. Cancer. 2013;133(5):1204-1214). This double-blind, placebo-controlled study randomized 42 GBM patients post maximal surgical resection with histology-confirmed HCMV infection in the tumor to receive either valganciclovir (1800 mg for 3 weeks and then 900 mg for 21 weeks; 22 patients) or placebo (20 patients) in addition to standard chemoradiation therapy for 6 months.
Valganciclovir was safe and well tolerated as add-on therapy to the current standard of care. Although there were trends towards decreased 3- and 6-month post-treatment tumor volume (the primary end points) in treatment vs placebo groups, this difference was not significant. There was also no significant difference in progression-free or overall survival (PFS and OS) at 3 or 6 months. However, analysis of patients who took valganciclovir either beyond the initial 6-month period or as a prescription drug during the blind period when they were assigned to the placebo arm showed encouraging results. Patients taking valganciclovir for more than 6 months showed a mean OS of 24.1 months compared to 13.1 months in those who took valganciclovir short-term or took placebo (Figure). Explorative analyses showed that 50% of patients taking this drug beyond 6 months were alive at 24 months, 27.3% were alive at 4 years, and 13.6% at 5 years.
Figure. KaplanMeier ...Image Tools
Although there is a growing understanding of HCMV contributions to the immune microenvironment of gliomagenesis, much remains to be learned about how valganciclovir influences tumor cell signalling and growth. It remains to be seen whether the survival benefit of long-term valganciclovir use that was observed in this hypothesis-generating trial persists in larger sample populations. The relatively lower cost of this drug and its narrow side-effect profile make it an exciting starting point for further investigation as an add-on therapy in GBM.