Does valganciclovir have a role in glioblastoma therapy?

In 2002, we published the first evidence that cytomegalovirus (CMV) infection is associated with a high percentage of malignant gliomas and glioblastomas (GBM).1 These findings have been confirmed independently by several groups, yet other groups have found no evidence of CMV in GBM.2,3 Ongoing investigations related to low-level viral copy number and possible abortive infection of CMV suggest that the CMV infection detected in GBM by many groups is quantitatively different from the typical fulminant infections seen in fetuses and immunocompromised patients. Regardless of these unknowns, we and others have attempted to identify specific oncomodulatory proteins expressed by CMV in GBM and have shown how these might be participating in the “hallmarks” of glioma biology such as angiogenesis (pp71, US28, gB),4–6 invasion (US28, gB),5,6 mitogenensis (IE1),7 stem cell maintenance and immoralization (IE1),8 tyrosine kinase activation (gB),6 and immunomodulation (cmvIL-10).9 Given the grave prognosis of GBM, one of the earliest hopes upon detection of CMV in this cancer was that antiviral strategies might somehow ameliorate CMV-mediated tumor promotion. Based on data supporting this line of reasoning,10,11 Stragliotto and Söderberg-Naucler at the Karolinska Institute in Stockholm hypothesized that valganciclovir (Valcyte, the orally available form of the anti-CMV drug ganciclovir) might be efficacious as an add-on therapy for GBM. In 2006, they initiated a prospective, phase II randomized trial of 42 patients who had achieved at least a 90% resection of their GBM.12 The patients were randomized to receive either placebo or valganciclovir in combination with radiation therapy and temozolomide. The primary endpoint was tumor volume at 6 months. The analysis showed a trend, but no statistically significant difference in tumor volume, at the 6-month time point. After this time point, patients from the placebo arm were allowed to cross over to the valganciclovir arm, and many of the valganciclovir patients continued taking valganciclovir. The secondary end points, based on intention to treat, were thereafter rendered flawed because many patients had crossed over. However, subsequent explorative analyses showed an overall survival of 24.1 months (95% CI, 17.4–40.3) in patients receiving >6 months of valganciclovir (Val > 6M) versus 13.1 months (95% CI, 7.9–17.7, P < .0001) in patients receiving valganciclovir for 0 or <6 months, and 13.7 months (95% CI, 6.9–17.3, P = .0031) in contemporary controls. Overall survival at 4 years was 27.3% in Val> 6M patients versus 5.9% in controls (P = .0466). No serious side effects were identified from valganciclovir treatment of GBM patients. The results of this study were published in the International Journal of Cancer in 2013.12