In previous retrospective studies, we have showed that patients with newly diagnosed or secondary GBM seemed to survive significantly longer if they had been treated with valganciclovir as add on to standard therapy [28-30]. In the current study, we carried out a retrospective analysis on survival data for 29 patients with recurrent GBM who received valganciclovir as add on to second or third line therapy at our institution. Like in patients with primary GBM[29], we observed a distinctly increased survival rate among patients who had received valganciclovir as add on to their second (n=25) or third line therapy (n=4), as compared with contemporary control patients. All patients were treated at the same institution by the same clinical team. The median time to progression from first diagnosis to recurrence was 8 months in controls and 7.4 months in patients who subsequently were treated with valganciclovir, suggesting that the two groups had a comparable clinical prognosis (p=0.1992) before one group begun valganciclovir therapy that appeared to give them an improved survival chance (12.1 vs 7 months after their recurrence, p=0.0017). Thus, while we observed no difference in the time to tumor recurrence between patients who were later treated with valganciclovir or not, patients who received valganciclovir after their recurrence showed significantly enhanced survival rates, as compared to control patients.
The positive effect of valganciclovir therapy seemed to be most prominent in those who underwent surgery to lower their tumor burden. Patients who were operated trended to have a longer median survival after recurrence; 15.8 months compared with 10.3 months in those who did not undergo surgery, but the difference was not significant (p=0.7503), possibly due to low patient numbers. There was also no significant difference in survival between patients who underwent surgery or not among those who did not receive valganciclovir treatment. The median survival after recurrence was 8.3 months in patients undergoing surgery, and 6.9 months in those who were not operated (p=0.5928). Treatment with valganciclovir doubled the chance of being alive at one year and tripled the chance of being alive at 2 years after recurrence both in re-operated and in non re-operated patients.
Several other factors such as age, molecular phenotype and other treatments could affect the treatment results. To avoid possible bias in regards to age, the controls were age-matched with the valganciclovir treated patients at inclusion before survival analyses (median age 57 vs 54 years). We found that methylated MGMT promoter status was the most significant variable positively associated with survival after recurrence (p < 0.0001) followed by valganciclovir treatment (p=0.001). Gender or re-operation did not correlate with survival. It is well known that patients with the molecular phenotype unmethylated MGMT promoter status [33] respond poorly to therapies as they have an active MGMT enzyme that will prevent the anticipated effects of for example temozolomide therapy. The MGMT gene encodes for the enzyme O (6)-methylguanine DNA methyltransferase; when the promoter is methylated the gene is silenced. In its unmethylated state, DNA damage induced by cytotoxic drugs can rapidly be repaired by MGMT and thereby the desired cytotoxic effects induced by alkylating drugs such as temozolomide and CCNU are inhibited [34]. Patients with recurrent GBM who underwent valganciclovir treatment appeared to have prolonged survival regardless of their methylation status in the MGMT promoter. Valganciclovir therapy thereby show indications of a positive effect on survival also in patients with unmethylated MGMT promoter status, who are arguably more resistant to treatments currently in use such as alkylating agents. This is in coherence with the results of our previous study, where we showed that both patients with a methylated and unmethylated MGMT promoter status benefitted from valganciclovir therapy [29].
The KPS score is an important score relevant for survival in patients undergoing oncological therapies [35]. In this study, the patients KPS score was, as expected, associated with survival (p=0.005). Importantly, the patients treated with valganciclovir and the controls had the same median KPS at the time of recurrence thus significantly reducing the risk of having selected patients with higher possibility of surviving longer before their start of anti-viral therapy.
Goerig and colleagues recently demonstrated that patients with brain tumours who were CMV IgG positive and underwent chemo and radiotherapy often had reactivated latent CMV [36, 37]. It was proposed that the reactivated infection was primarily caused by radiation, as also patients with brain metastases who were not treated with chemotherapy reactivated CMV. If left untreated the patients´ prognosis was very poor. These findings are coherent with the data reported by Foster et al, showing a longer OS in patients with GBM who were CMV seronegative and should not be at risk for CMV reactivation [38]. It is therefore possible that patients with GBM undergoing radiotherapy reactivates a clinically relevant CMV infection and that valganciclovir therapy may be effective in treating encephalitis symptoms and clinical disease, which may affect the patient's prognosis. These observations are in line with our previously published data demonstrating that CMV is present in brain metastases of colon and breast cancer, and that higher CMV activity is associated with worse prognosis [39, 40]. Furthermore, we recently found that radiation mimicking drugs induced expression of a set of transcription factors that can activate the CMV immediate early promoter (submitted manuscript). This may explain why DNA damage can induce reactivation of CMV. Thus, radiation induced damage may reactivate CMV in a subset of patients and valganciclovir may prevent this and positively influence survival chances among these patients. As patients with brain tumors and CMV viremia who exhibited encephalitis like symptoms had a poor prognosis, diagnosing CMV reactivation following radiation therapy in GBM patients is therefore important so affected patients can be treated appropriately.
Once reactivated, CMV can affect the aggressiveness of tumor cells and promote development of recurrent disease by affecting all the Hallmarks of cancer. A persistent CMV infection may be more frequent in older patients and due to the virus effects on their immune system, this virus may put higher burden older patients. Under such circumstances, the effect of valganciclovir may be enhanced in older patients. To address this issue, we examined the effect of valganciclovir in patients younger or older than 60. We observed an increase in survival after recurrence in both patients younger and older patients who received valganciclovir treatment, but this treatment seemed to be even more significant in patients older than 60 when comparing p values to younger patients (p=0.0094 vs p=0.0116). This observation suggests a possible enhanced effect of valganciclovir in elderly patients. However, the data should be taken with caution due to the limited number of patients and the lack of data concerning CMV status. These factors will be studied in the ongoing randomized clinical trial, VIGAS2, evaluating the effect of valganciclovir in patients with primary glioblastoma.
Except for this potentially promising treatment option, the situation for patients with GBM is very concerning. A number of therapies have been evaluated in the attempt to find new therapy options for patients with GBM. These include innovations for radiotherapy, strategies to overcome blood tumor barrier for delivery of chemotherapy and innovations for delivery of anti-cancer drugs [41]. Techniques and drugs have aimed to locally destruct the tumor, and different immunotherapy and cell based therapy protocols have been evaluated along with gene therapy based attempts [41]. The intratumoral heterogeneity of GBMs is high, which is likely a reason for why personalized/precision medicine so far provided limited success for these patients. So far, the many attempts to develop new therapy protocols for patients with GBM did not lead to any major breakthrough and the prognosis for patients with GBM remain utterly poor. Tumor treating fields showed improved survival in patients with newly diagnosed GBM [42], but not for patients with recurrent disease [43]. Thus, the situation for these patients is even worse and has not even led to a standardized second line therapy protocol.
Here, we demonstrate promising prolonged survival times in patients with recurrent GBM who were treated with valganciclovir as add-on to second/third line therapy. This treatment is well tolerated, with few side effects also after many years on this treatment [29]. So far, we treated 139 patients with GBM with valganciclovir and included 79 patients in a randomized placebo controlled study (NCT04116411). No new side effects have been observed, and the longest treated patient has today received the drug for over 13 years. While the number of valganciclovir treated patients with recurrent GBM is only 29 in the current study and the results should be considered with caution, the effect is similar as we reported for patients with newly diagnosed and secondary GBM, and was statistically significant, even after removal of one identified outlier. This lowers the risk of a random effect by chance. Other study limitations include potential selection bias as patients (or their relatives) selected themselves to opt for this therapy and they may hence be in better clinical condition as they were able to seek new therapy options themselves. Nevertheless, their KPS scores were similar to controls, and they had similar time to recurrence as control patients before they started valganciclovir therapy. A strength of the study is that the patients were treated by the same physicians who followed them throughout the study and most patients in both groups received similar base line therapy.
As valganciclovir may have a potential positive effect on patients with recurrent GBM who lack any other effective treatment option, it is important to evaluate this well tolerated and potentially effective therapy in randomized clinical trials. If valganciclovir treatment turns out to be effective, it should reach patients on a global scale with no further delay.