Treatments for Recurring Glioblastoma Multiforme (First Part)

Here we are at the seventeenth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is the first part of chapter 13 of the guide which is quite long and has been divided into three parts. In this episode we talk about Avastin (bevacizumab). The advice is still to use this information to discuss with the medical team that is following you. At the end of the post you will find the references to supporting scientific works.
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The unfortunate nature of glioblastoma is that typically recurs. When the Stupp standard protocol is used as initial treatment, the median progression-free interval before relapse is detected is approximately 8 months from diagnosis. This means that the average patient will need to seek treatment for recurrence within the first year of diagnosis.
As mentioned, there are three treatments that have FDA approval for treating recurrent GBM: Avastin, gliadel, and the Novocure TTF device. However, these treatments do not run out of possibilities, as other forms of chemotherapy are used, including a new challenge with Temodar itself. In fact, all the treatments already presented for newly diagnosed patients can also be used in the case of recurrence. The question the patient is asked is which one to choose in order to optimize the chances of survival.

Avastin (bevacizumab)

Currently, the most frequently used treatment for recurrent GBM is Avastin (bevacizumab), the anti-angiogenic drug widely used in many different forms of cancer. In the previous chapters on complementary therapies to the Stupp protocol for initial treatment, Avastin had already been considered, but two different clinical trials failed to show any improvement in survival outcome compared to the Stupp protocol alone followed by Avastin only after relapse. detected. In this section we discuss the results of Avastin as a treatment for recurrent cancers. Its first use in brain tumors was reported at a 2005 European neuro-oncology conference (177). Avastin at a dose of 5 mg / kg was administered every two weeks to 29 patients with recurrent tumors (apparently including both glioblastomas and grade III tumors), followed by weekly infusions. Patients also received CPT-11 (irinotecan) concurrently with Avastin. Tumor regressions occurred for a high percentage of patients, with 19 patients with complete or partial regressions, some of which were evident after the first course of treatment. Long-term survival data was not yet ready at the time of the report. Avastin increases the risk of intracranial bleeding, but in the aforementioned clinical study, this occurred in only 1 of the 29 patients.
After the initial study just described, further studies have been reported. The largest of these, conducted at Duke University (178), involved 68 patients with recurrent tumors, 35 of whom had glioblastomas. For these, the PFS-6 was 46% and the median survival was 40 weeks. This result is considered disappointing given that a high percentage of patients had had tumor regressions at the start of treatment, although the 10-month survival for patients with GBM after relapse compares favorably to the typical value of 5-7 months. as reported in a retrospective analysis (179). A similar trend emerged from other trials: high response rates in terms of tumor regression, but then often rapid tumor regrowth. Long-term follow-up of the Duke study reported a two-year survival rate of 17% (180), typical survival in recurrent cancers.
One concern about the use of Avastin is that several researchers have observed that its use results in a greater likelihood of the tumor spreading to areas of the brain distant from the original tumor site. This problem remains controversial, in part because the spread of the tumor at a distance can occur in many treatments, not only in those that are based on the inhibition of angiogenesis.
Avastin, like other drugs, is generally administered until the tumor progresses. However, a report presented at the 2012 ASCO meeting suggests that this may not be optimal (182). Patients who received Avastin for recurrent cancers until treatment failure (N = 72) were compared to patients who started Avastin but stopped for reasons other than tumor progression (N = 18), either because they had completed a planned program, or as a result of toxicity. In the latter group, 1-year progression-free survival was 83% and the median progression-free interval was 27.6 months, much better than in patients who received Avastin until failure. of treatment (PFS-12 = 25% and median PFS 9.7 months).
An important question is the effectiveness of Avastin as a single agent without concomitant chemotherapy. In a large randomized study (N = 167) (183), Avastin alone was compared with Avastin + CPT-11 (irinotecan) in patients with recurrent glioblastoma. PFS-6 values ​​were 43% for Avastin alone and 50% for Avastin + CPT-11; the corresponding numbers for the percentage of tumor regressions were 28% and 38%. However, this outcome advantage for the combination group was offset by its higher adverse event rate (46% versus 66%). In addition, median survival times were slightly in favor of Avastin as a single agent (9.3 versus 8.9 months). A longer-term follow-up was reported at the 2010 ASCO meeting (184). The two-year survival rates were 16% and 17%, respectively. Overall, therefore, the addition of CPT-11 to Avastin appears to provide a marginal improvement in survival outcome.
The best results reported so far when Avastin has been used for recurrent cancers have come from its combination with hypofractionated stereotaxic irradiation, based on the idea that Avastin prevents the revascularization needed to repair the damage caused by radiation. Twenty patients with recurrent GBM received the standard biweekly infusions of Avastin in combination with radiation during the first five cycles (187). Fifty percent of patients experienced tumor regressions, including five with complete response. The PFS-6 value was 65% and the median survival time was 12.5 months. Positive results were obtained in a second study (188) which combined Avastin and stereotaxic radiosurgery with heavily pretreated patients. The median PFS was 5.2 months for those who received the combination compared to 2.1 months for those who received stereotaxic radiosurgery alone.
The important question of whether to administer Avastin to the first or subsequent relapses was addressed in a large retrospective study (310) published in the June 2014 edition of Neuro-Oncology. A large group of 468 patients with glioblastoma treated with Avastin were examined retrospectively, and included 80 patients treated with Avastin at diagnosis, 264 at the first relapse, 88 at the second and 36 at the third or greater relapse. Among all three relapse groups (first, second or third and above), no significant difference was found in progression-free survival with Avastin, overall survival from starting treatment with Avastin, or survival post-Avastin. In other words, treatment with Avastin resulted in “fixed” progression-free and overall median survival times from initiation of Avastin treatment, regardless of whether Avastin was initiated early or later relapses. . The implication of this finding is that delayed use of Avastin may be preferable and lead to a longer overall survival (from diagnosis) when administered to subsequent relapses rather than previous ones. This idea has yet to be tested in a prospective clinical trial.
This study also identified risk factors for the inability to receive further treatment in the event of a relapse, thus identifying patients who could benefit from previous Avastin therapy. The risk factors for the inability to receive further treatment at the first relapse are: age over 60 and having performed the biopsy alone. The only risk factor for the inability to receive further treatment at the second relapse was the age of over 60. The conclusion of this study is that delayed use of Avastin is not associated with reduced efficacy and may also be preferable for those patients who can afford to delay such treatment until subsequent progressions. On the other hand, older patients and patients with inoperable tumors, at risk of not being able to receive treatment in subsequent relapses, may benefit from early use of Avastin.
A study conducted at the MD Anderson Cancer Center that reached similar conclusions was published in the August 2014 edition of the Journal of Neuro-Oncology (311). This was a retrospective study that included patients with recurrent glioblastoma treated with Avastin between 2005 and 2011. 298 patient records were included in total and divided into 112 treated patients who received Avastin on their first relapse and 133 patients treated with Avastin at the second or subsequent relapse. There was no significant difference in progression-free survival in the two groups (PFS, 5.2 vs 4.3 months, p = 0.2). In contrast, the median overall survival from diagnosis was significantly shorter in the group treated with Avastin at the first relapse (OS, 20.8 vs 25.9 months, p = 0.005). There was no significant difference in the time from diagnosis to first relapse in the two groups. The authors concluded that the delayed use of Avastin is not inferior in terms of results to the use of Avastin at the first relapse. The apparent improvement in overall survival in patients receiving delayed, rather than early, Avastin requires further verification in a prospective clinical trial.
In a post-hoc analysis based on the results of the phase 3 AVAglio study that included the use of Avastin for newly diagnosed glioblastoma, patients who did not receive further therapy at relapse had a significant prolongation of both overall survival. which frees from progression with Avastin (346). This finding gives further strength to the two aforementioned studies, in which delayed Avastin did not lead to inferior results compared to the initial Avastin, and also points out that patients who are likely not able to tolerate further therapy in case of relapse (due to advanced age or general weakness, etc.) may benefit from early Avastin in terms of progression-free and overall survival. In this post-hoc analysis, considering only patients who did not receive further therapy upon disease recurrence, early Avastin improved both median and progression-free survival by 3.6 months and this improvement was statistically significant for both.

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(177) Stark-Vance, V., Bevacizumab (Avastin®) and CPT-11 (Camptosar®) in the Treatment of Relapsed Malignant Glioma. Presentation at the meeting of the European Society of Neuro-oncology, April, 2005.
(178. Vredenburgh, JJ, et al., Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin Oncol. 2007, 25 (30) 472-79. (179) Nghiemphu, P., et al. A retrospective single institutional analysis of bevacizumab and chemotherapy versus non-bevacizumab treatments for recurrent glioblastoma 2008 ASCO Proceedings, abstract # 2023. 
(180) Wagner, S. A., et al. Update on survival from the original phase II trial of bevacizumab and irinotecan in recurrent malignant gliomas. 2008 ASCO Proceedings, Abstract # 2021.
(181) Avgeropoulos, N.,Avgeropoulos, G., ARiggs, G., & Reilly, C. Survival outcomes with low-dose bevacizumab compared to standard dose regimens in recurrent glioblastoma. Abstract # NO-009, Proceedings of the 2013 meeting of the Society of Neuro-oncology. 
(182) Anderson, M. D., Puduvalli, V. K., Hamza, M. A., et al. Differences in outcome due to bevacizumab (BEV) discontinuation versus BEV failure in adults with glioblastoma. 2012 ASCO Proceedings, Abstract #2030. 
(183) Friedman, H. S., Prados, M. D., Wen, P. Y., et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol., 2009, 27(228), 4733-40. 
(184) Cloughesy, T., Vredenburgh, J. J., Day, B., et al. Updated safety and survival of patients with relapsed glioblastoma treated with bevacizumab in the BRAIN study. 2010 ASCO meeting, Abstract #2008. 
(185) Maron, R., et al. Bevacizumab and daily temozolomide for recurrent glioblastoma multiforme (GBM)) 2008 ASCO Proceedings, Abstract # 2074. 
(186) Desjardins, A., Reardon, D. A., Coan, A., et al. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer, 2011. 
(187) Gutin, P. H., et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int. J. Radiation Oncol Biol Phys., 2009, 75(1): 156-163. 
(188) Park, K.J., Kano, H., Iyer, A., et al. Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: A case-control study. Journal of Neuro-oncology, 2012, 107(2), 323-33. 
(310) Piccioni, David E et al. “Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy.” Neuro-oncology 16.6 (2014): 815-822. 
(311) Hamza, Mohamed A et al. “Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma.” J Neurooncol . 2014 Aug;119(1):135-40.

I hope you enjoyed reading, I was as faithful as possible. Soon the next chapter! See you soon!