Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme

James J. Vredenburgh, Duke University Medical Center, Durham, NC

Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4722-4729

Purpose: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab (Avastin) a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan (Camptosar).

Patients and Methods: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m², and patients not taking EIAEDs received 125 mg/m². After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging.

Results: The 6-month progression-free survival among all 35 patients was 46%. The 6-month overall survival was 77%. Twenty of the 35 patients (57%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli).

Conclusion: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

This study was conducted to improve the prognosis for recurrent GBM, for which response to therapy has generally been less than 20% and 6-month PFS less than 30%. Although temozolomide in combination with radiation therapy followed by 6 months of temozolomide has become the standard of care for newly diagnosed GBM, temozolomide has shown only minimal activity for recurrent GBM in patients who have received no chemotherapy or a nitrosourea-based regimen. In the trial reported by Yung et al, the response rate was 8% and the 6-month PFS 21%. In addition, the 6-month overall survival with bevacizumab and irinotecan was improved compared with temozolomide: 77% versus 60% respectively. Our trial of bevacizumab and irinotecan also compares favorably with the results detailed by Wong which represents patients with recurrent GBM, who were treated on one of eight different chemotherapy trials. Comparison of the current results show a 6-month PFS and median PFS in patients with GBM of 43% and 24 weeks, compared with the Wong et al results of 15% and 9 weeks, respectively, in patients with GBM. The 1-year overall survival is improved in our trial of bevacizumab and irinotecan compared with the Wong et al results: 37% versus 21%, respectively. Temozolomide in combination with other agents such as irinotecan, etoposide, or erlotinib has produced modest improvements in the response rates and survival compared with historical controls of temozolomide alone, but not as dramatic as bevacizumab and irinotecan.

Because the majority of patients fail to respond to temozolomide in the up-front or recurrent disease setting, clearly, new regimens are needed for the more formidable recurrent GBM. One approach has been to administer nitrosoureas, which are also alkylating agents, and for which the mechanisms of resistance are similar to those encountered with temozolomide therapy, particularly, the resistance enzyme MGMT. As with single-agent temozolomide, nitrosoureas alone produce response rates of less than 10%, 6-month PFS rates of less than 20%, and median survivals of 6 to 12 weeks. However, nitrosoureas in combination with procarbazine and vincristine have resulted in small improvements in response rates and survival. Nitrosoureas in combination with irinotecan have also produced similar, small increments in response rates and survival.

Topoisomerase 1 inhibitors, such as irinotecan and topotecan, have a different mechanism of cytotoxicity from that of alkylating agents. In addition, topoisomerase 1 inhibitors are not affected by the resistance enzyme MGMT. Therefore, topoisomerase 1 inhibitors are reasonable therapeutic options for recurrent GBM after failure of alkylating agents. Topoisomerase 1 inhibitors have excellent penetration through the blood-brain barrier, but the treatment results for glioblastomas have been disappointing. For example, the rates of response to single-agent irinotecan range from 0% to 17%, the 6-month PFS rates are consistently less than 20%, and median survival is less than 12 weeks. The reasons for the improved efficacy with the combination of irinotecan and bevacizumab are unclear. There are a number of potential mechanisms to explain the results, two of which may be particularly important. GBM is similar to other tumors, with a stem-like cell compartment as well as more differentiated tumor cells. Chemotherapy may be active against more differentiated cells but may not affect the tumor stem cells. Recently, Bao et aldemonstrated that bevacizumab suppresses the proangiogenic effect of glioma stem cells derived from human glioblastoma tumors and xenografts. Therefore, the combination of bevacizumab and irinotecan would treat both cellular compartments, the glioma stem cells and the more differentiated cells.

Another potential mechanism is normalization of the tumor vasculature as proposed by Jain Tumor angiogenesis produces abnormal vessels with increased tortuosity. The resultant high interstitial pressure produces hypoxia and a growth advantage for tumor cells. In addition, the elevated interstitial pressure limits perfusion of chemotherapeutic agents to the tumor cells.³¹ Also, chemotherapeutic agents and radiation therapy are not as effective in areas of hypoxia.In summary, the efficacy seen with the combination of bevacizumab and irinotecan could be explained by an antitumor stem-cell effect by bevacizumab and an anti–differentiated glioma tumor cell effect by irinotecan, as well as normalization of tumor vasculature, resulting in decreased interstitial pressure, less hypoxia, and increased delivery of irinotecan to the tumor.