valganciclovir and Glioblastoma

Glioblastoma is the most common and most fatal primary malignant brain tumor in adults. Despite progress in characterizing the genetic and molecular mechanisms of glioblastomas, advances in treatment that translate into substantial improvement in prognosis have yet to be realized. A role for cytomegalovirus in glioblastoma pathogenesis was proposed more than a decade ago and has generated considerable debate as a possible therapeutic target. Independent groups have had variable success in detecting cytomegalovirus infection in tumor cells; the overall consensus is that very low levels of viral proteins and nucleic acids can be observed. Although cytomegalovirus has not been found to be oncogenic in this context, a possible oncomodulatory role has been suggested. A recent clinical trial evaluating valganciclovir as an adjuvant therapy for the treatment of glioblastoma did not demonstrate a beneficial effect on tumor growth or overall survival, although retrospective analysis subsequently indicted a significant survival benefit. In light of the publicity of that report, patients and neuro-oncologists are requesting cytomegalovirus testing to justify antiviral treatment. Based on questions on the significance of cytomegalovirus infection in glioblastomas and the lack of a clear clinical benefit of valganciclovir, we reviewed this topic and conclude that, at this time, there is insufficient evidence to recommend routine testing and treatment.

Topics: Animals; Antiviral Agents; Brain Neoplasms; Cytomegalovirus; Ganciclovir; Glioblastoma; Humans; Treatment Outcome; Valganciclovir

First described in 2002, the presence and role of human cytomegalovirus (HCMV) infection in glioblastoma (GBM) has remained a controversial topic. New research indicates HCMV gene products likely promote GBM pathogenesis and that therapies aimed at HCMV might influence disease progression.. Recently, investigators have begun to analyze HCMV genome and proteins present in GBM cells in vivo. Furthermore, the research has demonstrated that several HCMV gene products that have oncomodulatory properties are expressed in GBM and may be impacting tumor pathogenesis in vivo. These HCMV gene products modulate GBM proliferation, apoptosis, angiogenesis, invasion and immune evasion. A recent mouse model provides mechanistic information as to how CMV may promote gliomagenesis in the setting of tumor suppressor dysfunction and STAT3 signaling. In addition, clinical outcomes of GBM patients are associated with the degree of HCMV infection. Novel therapies aimed at direct antiviral and immunotherapy approaches to HCMV suggest that these modalities may impact the future treatment of this disease.. A more precise understanding of the role of HCMV infection in gliomagenesis and GBM pathogenesis could reveal novel therapeutic and preventive strategies.

Topics: Animals; Antiviral Agents; Brain Neoplasms; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Glioblastoma; Humans; Male; Mice; Signal Transduction; STAT3 Transcription Factor; Tumor Virus Infections; Valganciclovir

Cytomegalovirus is highly prevalent in glioblastomas. In 2006, we initiated a randomized, double-blind, placebo-controlled, hypothesis-generating study to examine the safety and potential efficacy of Valganciclovir as an add-on therapy for glioblastoma. Forty-two glioblastoma patients were randomized in double-blind fashion to receive Valganciclovir or placebo in addition to standard therapy for 6 months. Magnetic resonance images were obtained before and immediately and 3 and 6 months after surgery to evaluate treatment efficacy by measuring contrast enhancing tumor volume (primary end point). Survival data were analyzed for patients and controls in explorative analyses to aid the design of future randomized trials. Trends but no significant differences were observed in tumor volumes in Valganciclovir and placebo patients at 3 (3.58 vs. 7.44 cm3, respectively, p = 0.2881) and 6 (3.31 vs. 13.75 cm3, p = 0.2120) months. Median overall survival (OS) was similar in both groups (17.9 vs. 17.4 months, p = 0.430). Patients could take Valganciclovir for compassionate use after the study phase. Explorative analyses showed an OS 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 < 0.0001) in patients receiving Valganciclovir for 0 or <6 months, and 13.7 months (95% CI, 6.9-17.3, p = 0.0031) in contemporary controls. OS at 4 years was 27.3% in Val>6M patients versus 5.9% in controls (p = 0.0466). Prolonged OS in Val>6M patients suggest that future randomized trials are warranted and should evaluate whether continuous antiviral treatment can improve outcome in glioblastoma patients.

Topics: Adult; Aged; Antiviral Agents; Brain Neoplasms; Cytomegalovirus; Double-Blind Method; Female; Ganciclovir; Glioblastoma; Humans; Male; Middle Aged; Valganciclovir

Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged survival in 50 patients with glioblastoma. Here, we present an updated retrospective analysis that includes an additional 52 patients.. From December 2006 to November 2019, 102 patients with newly diagnosed glioblastoma received valganciclovir as an add-on to standard therapy. No additional toxicity was observed. Contemporary controls were 231 patients with glioblastoma who received similar baseline therapy.. Patients with newly diagnosed glioblastoma receiving valganciclovir had longer median overall survival (OS 24.1 vs. 13.3 months,. Valganciclovir prolonged median OS of patients with newly diagnosed glioblastoma (with methylated or unmethylated

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Disease Progression; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Glioblastoma; Humans; Male; Middle Aged; Prognosis; Promoter Regions, Genetic; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome; Tumor Suppressor Proteins; Valganciclovir; Young Adult

Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy.. Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed.. TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy.. Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.

Topics: Adenoviridae; Animals; Antiviral Agents; Apoptosis; Cell Proliferation; Genetic Therapy; Genetic Vectors; Glioblastoma; Humans; Mice; Neoplasm Invasiveness; Prodrugs; Simplexvirus; Thymidine Kinase; Tumor Cells, Cultured; Valganciclovir; Xenograft Model Antitumor Assays

Nearly all glioblastomas (GBMs), brain tumours with very poor prognosis, are infected with human cytomegalovirus (CMV). The anti-CMV drug valganciclovir (VGCV) has shown promise as a treatment option for patients with GBM, but its penetration into the central nervous system (CNS) is unknown. Here we describe a patient with GMB receiving VGCV in whom an intracerebral microdialysis catheter was implanted and ganciclovir (GCV) concentrations in brain extracellular fluid (BECF) and serum were monitored. GCV was rapidly absorbed. Cmax values (at 3 h) in serum and BECF were 19.6 and 10.2 µmol/L, T½ values were 3.2 and 4.5 h, and plasma and BECF AUC0-∞ values were 90.7 and 75.9 µmol h/L, respectively. Thus, VGCV treatment results in significant intracerebral levels of GCV that may be sufficient for therapeutic effects. Further studies of this drug in patients with GBM are warranted.

Topics: Antiviral Agents; Brain; Brain Neoplasms; Cytomegalovirus; Cytomegalovirus Infections; Drug Monitoring; Extracellular Space; Follow-Up Studies; Ganciclovir; Glioblastoma; Humans; Male; Microdialysis; Middle Aged; Treatment Outcome; Valganciclovir

Topics: Antiviral Agents; Brain Neoplasms; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Prognosis; Survival Rate; Valganciclovir

Topics: Antiviral Agents; Brain Neoplasms; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Patient Selection; Prognosis; Valganciclovir

Topics: Antineoplastic Agents; Antiviral Agents; Brain Neoplasms; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Valganciclovir

Topics: Antineoplastic Agents; Antiviral Agents; Brain Neoplasms; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Valganciclovir

Topics: Antineoplastic Agents; Antiviral Agents; Brain Neoplasms; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Valganciclovir

Topics: Antiviral Agents; Brain Neoplasms; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Randomized Controlled Trials as Topic; Valganciclovir

Topics: Animals; Antiviral Agents; Brain Neoplasms; Drug Therapy, Combination; Ganciclovir; Glioblastoma; Humans; Kaplan-Meier Estimate; Retrospective Studies; Survival Rate; Valganciclovir

Topics: Antiviral Agents; Brain Neoplasms; Cancer Vaccines; Cell Transformation, Viral; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Glioblastoma; Humans; Oligonucleotide Array Sequence Analysis; Valganciclovir; Viral Proteins; Viral Vaccines