Neuro-Oncology Neuro-Oncology 16(3), 330 –331, 2014 doi:10.1093/neuonc/nou009
Does valganciclovir have a role in glioblastoma therapy? Charles S. Cobbs Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, Washington
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 So¨derberg-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 ¼ .0031) in contemporary controls. Overall survival at 4 years was 27.3% in Val. 6M patients versus 5.9% in controls (P ¼ .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
Subsequent to this trial, the Karolinska group began offering valganciclovir to all GBM patients who had undergone tumor resection at their institution. These patients all began taking valganciclovir within 2 months of surgery and were followed. The authors then combined this group of patients with others from the original study who had been placed on valganciclovir within 2 months of diagnosis and remained on valganciclovir continuously. A retrospective analysis of these GBM patients continuously treated with valganciclovir was published as a letter to the New England Journal of Medicine.13 Strikingly, from this combined group of 25 patients who took valganciclovir continuously from the time of diagnosis, the 2-year survival rate was 90%, and the mean survival was 56.4 months. These patients were equally matched to the study patients who did not receive valganciclovir in terms of age, Karnofsky Performance Score, and MGMT methylation status. The authors concluded that these results are promising and are not likely due to chance. They suggest that further clinical trials are warranted to determine whether valganciclovir may improve survival in GBM patients. Since its publication, the letter to NEJM has been the center of controversy since many experts believe it falsely implies significance to a retrospective analysis from a previously published negative study. Because of the publicity it has received, many patients have self-advocated and requested valganciclovir from their practitioners. This has put the neuro-oncology community in an uncomfortable position because it is not standard practice to prescribe medications that have not been vetted through appropriately designed phase II trials. Although there are obvious limitations to the published valganciclovir studies in GBM, it is the opinion of this author that more investigation into the potential benefits of antiviral strategies (including CMV-based immunotherapy approaches and antiviral drugs such as valganciclovir) for GBM are warranted for several reasons: (1) Despite the issues in the original study design and the retrospective analysis of patients treated with valganciclovir, it seems unlikely that the 25 patients who received valganciclovir upfront and throughout their treatment would have a median survival of 56.4 months by chance. Of all the patients who were treated on study or afterwards with valganciclovir (n ¼ 50), the likelihood that the top 25 longest survivors would have a mean survival of 56 months, even if “cherry picked,” is low. Published data indicate that even with maximal extent of median, survival for GBM is usually in the
# The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
330
Downloaded from http://neuro-oncology.oxfordjournals.org/ at National Dong Hwa University Library on April 8, 2014
Corresponding Author: Charles Cobbs, MD, Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, 550 17th Ave, Suite 540, Seattle, WA 98122 ([email protected]).
Cobbs: Does valganciclovir have a role in glioblastoma therapy?
Thus, in terms of the usefulness of valganciclovir in GBM, preliminary evidence from the Karolinska Institute suggests that the drug is well tolerated by GBM patients and may also have significant benefit beyond currently available chemotherapeutic drugs. There are many issues that are unresolved, and certainly the data, as published to this point, do not clearly indicate that valganciclovir should be prescribed for GBM patients. To make any presumptions as to the mechanisms of action, or even the role of CMV in the process of glioma pathogenesis, would be premature. Nevertheless, many experts agree that another prospective randomized phase II trial with end points of 2-year survival, progression-free survival, and overall survival, possibly combined with studies on the mechanism of action, would be highly valuable in moving the field forward and making further recommendations regarding the clinical efficacy of valganciclovir in GBM.
2.
Cobbs CS. Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol. 2013;25(6):682–688.
3.
Dziurzynski K, Chang SM, Heimberger AB, et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012; 14(3):246 – 255.
4.
Matlaf LA, Harkins LE, Bezrookove V, et al. Cytomegalovirus pp71 protein is expressed in human glioblastoma and promotes pro-angiogenic signaling by activation of stem cell factor. PLoS One. 2013;8(7):e68176.
5.
Soroceanu L, Matlaf L, Bezrookove V, et al. Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res. 2011;71(21):6643– 6653.
6.
Soroceanu L, Akhavan A, Cobbs CS. Platelet-derived growth factoralpha receptor activation is required for human cytomegalovirus infection. Nature. 2008;455(7211):391– 395.
7.
Cobbs CS, Soroceanu L, Denham S, et al. Modulation of oncogenic phenotype in human glioma cells by cytomegalovirus IE1-mediated mitogenicity. Cancer Res. 2008;68(3):724–730.
8.
Straat K, Liu C, Rahbar A, et al. Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst. 2009;101(7):488–497.
9.
Dziurzynski K, Wei J, Qiao W, et al. Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res. 2011;17(14): 4642– 4649.
10. Pari GS, Netski D, St Jeor S, et al. Generation of a nude mouse tumor model for in vivo replication of human cytomegalovirus. J Infect Dis. 1998;177(3):523– 528. 11. Baryawno N, Rahbar A, Wolmer-Solberg N, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121(10):4043– 4055. 12. Stragliotto G, Rahbar A, Solberg NW, et al. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study. Int J Cancer. 2013;133(5):1204–1213. 13.
Soderberg-Naucler C, Rahbar A, Stragliotto G. Survival in patients with glioblastoma receiving valganciclovir. N Engl J Med. 2013; 369(10):985–986.
14. Hadaczek P, Ozawa T, Soroceanu L, et al. Cidofovir: a novel antitumor agent for glioblastoma. Clin Cancer Res. 2013;19(23):6473 – 6483. 15. Mitchell DA, Xie W, Schmittling R, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008;10(1):10– 18.
References
16. Dos Santos CJ, Stangherlin LM, Figueiredo EG, et al. High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients [published online ahead of print October 30, 2013]. J Med Virol. 2013. doi:10.1002/jmv.23820.
1.
17.
Cobbs CS, Harkins L, Samanta M, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002;62(12):3347– 3350.
Neuro-Oncology
Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413–422.
331
Downloaded from http://neuro-oncology.oxfordjournals.org/ at National Dong Hwa University Library on April 8, 2014
range of 15–18 months. Thus, while these data do not conform to the gold standard, placebo-controlled randomized study, they nevertheless provide information that suggests a treatment effect of valganciclovir. (2) The argument that valganciclovir should not be studied as a treatment for GBM because we do not have a clear understanding of the role of CMV in GBM is flawed. First, the drug is well tolerated and has minimal risk. Second, valganciclovir may represent a potentially novel chemotherapeutic agent for MGMT unmethylated GBM patients, who have notoriously poor responses to temozolomide. Third, historically the clinical utility of many chemotherapeutic drugs was observed prior to any clear understanding of mechanism. Indeed, valganciclovir may well have antineoplastic properties regardless of its effects on CMV. The active metabolite of valganciclovir is ganciclovir, which is a nucleoside analog similar to many chemotherapeutic drugs. We have recently shown that another anti-CMV drug, cidofovir, which is also a nucleoside analog, has potent antitumor properties in GBM above and beyond its antiviral effects.14 Our unpublished data also indicate that ganciclovir has similar effects on GBM cells. Finally, valganciclovir may have unexpected benefits for GBM patients unrelated to tumor burden. Two studies have reported that GBM patients are viremic for CMV, which is highly unusual in non-immunocompromised individuals.15,16 Since CMV viremia is independently associated with a 100% increased risk of death in non-immunocompromised patients, it is possible that the systemic antiviral effects of valganciclovir might be beneficial to GBM patients.17
Does valganciclovir have a role in glioblastoma therapy? Charles S. Cobbs Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, Washington
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 So¨derberg-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 ¼ .0031) in contemporary controls. Overall survival at 4 years was 27.3% in Val. 6M patients versus 5.9% in controls (P ¼ .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
Subsequent to this trial, the Karolinska group began offering valganciclovir to all GBM patients who had undergone tumor resection at their institution. These patients all began taking valganciclovir within 2 months of surgery and were followed. The authors then combined this group of patients with others from the original study who had been placed on valganciclovir within 2 months of diagnosis and remained on valganciclovir continuously. A retrospective analysis of these GBM patients continuously treated with valganciclovir was published as a letter to the New England Journal of Medicine.13 Strikingly, from this combined group of 25 patients who took valganciclovir continuously from the time of diagnosis, the 2-year survival rate was 90%, and the mean survival was 56.4 months. These patients were equally matched to the study patients who did not receive valganciclovir in terms of age, Karnofsky Performance Score, and MGMT methylation status. The authors concluded that these results are promising and are not likely due to chance. They suggest that further clinical trials are warranted to determine whether valganciclovir may improve survival in GBM patients. Since its publication, the letter to NEJM has been the center of controversy since many experts believe it falsely implies significance to a retrospective analysis from a previously published negative study. Because of the publicity it has received, many patients have self-advocated and requested valganciclovir from their practitioners. This has put the neuro-oncology community in an uncomfortable position because it is not standard practice to prescribe medications that have not been vetted through appropriately designed phase II trials. Although there are obvious limitations to the published valganciclovir studies in GBM, it is the opinion of this author that more investigation into the potential benefits of antiviral strategies (including CMV-based immunotherapy approaches and antiviral drugs such as valganciclovir) for GBM are warranted for several reasons: (1) Despite the issues in the original study design and the retrospective analysis of patients treated with valganciclovir, it seems unlikely that the 25 patients who received valganciclovir upfront and throughout their treatment would have a median survival of 56.4 months by chance. Of all the patients who were treated on study or afterwards with valganciclovir (n ¼ 50), the likelihood that the top 25 longest survivors would have a mean survival of 56 months, even if “cherry picked,” is low. Published data indicate that even with maximal extent of median, survival for GBM is usually in the
# The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
330
Downloaded from http://neuro-oncology.oxfordjournals.org/ at National Dong Hwa University Library on April 8, 2014
Corresponding Author: Charles Cobbs, MD, Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, 550 17th Ave, Suite 540, Seattle, WA 98122 ([email protected]).
Cobbs: Does valganciclovir have a role in glioblastoma therapy?
Thus, in terms of the usefulness of valganciclovir in GBM, preliminary evidence from the Karolinska Institute suggests that the drug is well tolerated by GBM patients and may also have significant benefit beyond currently available chemotherapeutic drugs. There are many issues that are unresolved, and certainly the data, as published to this point, do not clearly indicate that valganciclovir should be prescribed for GBM patients. To make any presumptions as to the mechanisms of action, or even the role of CMV in the process of glioma pathogenesis, would be premature. Nevertheless, many experts agree that another prospective randomized phase II trial with end points of 2-year survival, progression-free survival, and overall survival, possibly combined with studies on the mechanism of action, would be highly valuable in moving the field forward and making further recommendations regarding the clinical efficacy of valganciclovir in GBM.
2.
Cobbs CS. Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol. 2013;25(6):682–688.
3.
Dziurzynski K, Chang SM, Heimberger AB, et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012; 14(3):246 – 255.
4.
Matlaf LA, Harkins LE, Bezrookove V, et al. Cytomegalovirus pp71 protein is expressed in human glioblastoma and promotes pro-angiogenic signaling by activation of stem cell factor. PLoS One. 2013;8(7):e68176.
5.
Soroceanu L, Matlaf L, Bezrookove V, et al. Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res. 2011;71(21):6643– 6653.
6.
Soroceanu L, Akhavan A, Cobbs CS. Platelet-derived growth factoralpha receptor activation is required for human cytomegalovirus infection. Nature. 2008;455(7211):391– 395.
7.
Cobbs CS, Soroceanu L, Denham S, et al. Modulation of oncogenic phenotype in human glioma cells by cytomegalovirus IE1-mediated mitogenicity. Cancer Res. 2008;68(3):724–730.
8.
Straat K, Liu C, Rahbar A, et al. Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst. 2009;101(7):488–497.
9.
Dziurzynski K, Wei J, Qiao W, et al. Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res. 2011;17(14): 4642– 4649.
10. Pari GS, Netski D, St Jeor S, et al. Generation of a nude mouse tumor model for in vivo replication of human cytomegalovirus. J Infect Dis. 1998;177(3):523– 528. 11. Baryawno N, Rahbar A, Wolmer-Solberg N, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121(10):4043– 4055. 12. Stragliotto G, Rahbar A, Solberg NW, et al. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study. Int J Cancer. 2013;133(5):1204–1213. 13.
Soderberg-Naucler C, Rahbar A, Stragliotto G. Survival in patients with glioblastoma receiving valganciclovir. N Engl J Med. 2013; 369(10):985–986.
14. Hadaczek P, Ozawa T, Soroceanu L, et al. Cidofovir: a novel antitumor agent for glioblastoma. Clin Cancer Res. 2013;19(23):6473 – 6483. 15. Mitchell DA, Xie W, Schmittling R, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008;10(1):10– 18.
References
16. Dos Santos CJ, Stangherlin LM, Figueiredo EG, et al. High prevalence of HCMV and viral load in tumor tissues and peripheral blood of glioblastoma multiforme patients [published online ahead of print October 30, 2013]. J Med Virol. 2013. doi:10.1002/jmv.23820.
1.
17.
Cobbs CS, Harkins L, Samanta M, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002;62(12):3347– 3350.
Neuro-Oncology
Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413–422.
331
Downloaded from http://neuro-oncology.oxfordjournals.org/ at National Dong Hwa University Library on April 8, 2014
range of 15–18 months. Thus, while these data do not conform to the gold standard, placebo-controlled randomized study, they nevertheless provide information that suggests a treatment effect of valganciclovir. (2) The argument that valganciclovir should not be studied as a treatment for GBM because we do not have a clear understanding of the role of CMV in GBM is flawed. First, the drug is well tolerated and has minimal risk. Second, valganciclovir may represent a potentially novel chemotherapeutic agent for MGMT unmethylated GBM patients, who have notoriously poor responses to temozolomide. Third, historically the clinical utility of many chemotherapeutic drugs was observed prior to any clear understanding of mechanism. Indeed, valganciclovir may well have antineoplastic properties regardless of its effects on CMV. The active metabolite of valganciclovir is ganciclovir, which is a nucleoside analog similar to many chemotherapeutic drugs. We have recently shown that another anti-CMV drug, cidofovir, which is also a nucleoside analog, has potent antitumor properties in GBM above and beyond its antiviral effects.14 Our unpublished data also indicate that ganciclovir has similar effects on GBM cells. Finally, valganciclovir may have unexpected benefits for GBM patients unrelated to tumor burden. Two studies have reported that GBM patients are viremic for CMV, which is highly unusual in non-immunocompromised individuals.15,16 Since CMV viremia is independently associated with a 100% increased risk of death in non-immunocompromised patients, it is possible that the systemic antiviral effects of valganciclovir might be beneficial to GBM patients.17
