Treatments for Recurring Glioblastoma (Part Two)

I apologize for this break which was due to the change of the hosting service manager which was more complicated than expected but will now allow us to provide a better, faster and above all less expensive service. In any case, this is the eighteenth episode of the translation project of Ben Williams’ guide on treatment options for Glioblastoma Multiforme. This is the second 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) at a lower dose, how to predict the efficacy of bevacizumab, Avastin and lomustine as a combination treatment, and Avastin and angiotensin system inhibitors. The advice is still to use this information to discuss it with the medical team that is following you, where you can also indicate references to supporting scientific works.
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Avastin at a lower dose

With the exception of Dr. Stark-Vance’s initial study, which used a dosage of 5 mg / kg, almost all other studies used a dosage of 10 mg / kg every two weeks. A paper presented at the 2013 Society of Neuro-oncology meeting (181) suggests that the lower dosage may have better results. Forty-eight patients who received the 5 mg / kg dose were compared retrospectively with all remaining patients who received the standard dose. Median survival for the standard dose was 8.6 months. Median survival for the 5 mg / kg patients was 14 months, a notable improvement.
A second retrospective analysis regarding the different Avastin dosing regimens included patients treated at Kaiser Permanente hospitals in northern California between 2008 and 2013 (347). During this period, the first author of the study (Victor A. Levin) treated patients with Avastin doses of 7.5 mg / kg or less every three weeks, lower than the standard dose of 10 mg / kg every two weeks. 181 patients were included in this study and the median dose of Avastin for these recurrent patients was found to be 3.6 mg / kg per week. When patients were divided into those who received less or more than 3.6 mg / kg per week, patients who received lower doses had a longer median survival from initiation of Avastin treatment than those who received who received higher doses, 60 weeks versus 45 weeks, a significant difference (p = 0.029). To check for the possibility of pseudo-progression, separate analyzes were performed for patients who progressed more than one month after completion of radiotherapy and more than three months after completion of radiotherapy. In all analyzes, patients who received less than the median dose of Avastin of 3.6 mg / kg per week survived longer than patients who received more than 3.6 mg / kg per week.
The standard dose of 10 mg / kg every two weeks is 5 mg / kg per week. This study therefore supports the use of doses of Avastin lower than the standard dose.
A third retrospective analysis published later in 2015 (348) by researchers from Tel Aviv, Israel, compared the results of 87 treated patients who received Avastin 5 mg / kg every two weeks with 75 patients treated with the standard dose of 10 mg / kg every two weeks. All patients were diagnosed with recurrent glioblastoma. Most patients in the 5 mg / kg group (65.5%) were treated with a combination of chemotherapy (mainly irinotecan) and Avastin. A minority of patients in the 10 mg / kg group (20%) were treated with a combination of chemotherapy (mainly TMZ) and Avastin. No statistically significant difference in PFS or OS was found in the 5 mg / kg versus 10 mg / kg cohorts. There was also no significant difference in PFS or OS for patients treated with Avastin 5 mg / kg or 10 mg / kg alone (without additional chemotherapy). The small subgroup of 15 patients treated with a combination of 10 mg / kg of Avastin plus chemotherapy showed better survival than the other groups (median survival from the start of treatment with Avastin 14.5 months, p = 0.007). The improvement in survival in this small subgroup may have been partly due to the fact that this group had a significantly higher median KPS at the start of treatment, as suggested by the authors, and could also be partly due to the superiority of temozolomide chemotherapy over to that with irinotecan. This study agrees with previous retrospective studies that lower doses of Avastin are not lower than the highest standard dose and can be administered with substantially reduced Avastin-related toxicities (proteinurea and hypertension).
An important effect of Avastin and other drugs that target VEGF is that they reduce the edema common to brain tumors which is a major cause of the need for steroids. VEGF produces a large number of tiny bleeding capillaries and these are eliminated when the effects of VEGF are blocked. Some claim that the initial phase of VEGF blocking increases blood flow to the tumor and thus makes it easier for chemotherapy agents to reach the tumor and be effective.

Baseline blood neutrophil counts predict the efficacy of bevacizumab in recurrent glioblastoma

Based on previous preclinical reports that blood neutrophils may promote tumor angiogenesis, a French research team has hypothesized that a high number of neutrophils may predict a better response to antiangiogenic therapy such as is achieved with Avastin (bevacizumab ) (362). To test this hypothesis, data from 265 glioblastoma patients treated at their institution were examined. 159 of these patients received Avastin, mainly in case of relapse, and the remaining 106 patients did not receive Avastin. Using the cutoff neutrophil count of 6000 / mm3 (which can also be expressed as 6 x 10 ³ / μL or 6 x 10⁹ / L), patients were divided into high and low neutrophil count groups at baseline. In the high neutrophil count group, use of Avastin was associated with significantly improved survival compared to absence of Avastin, while in the low neutrophil count group, use of Avastin did not significantly improve survival. .
Within the group that did not receive Avastin, elevated neutrophil counts were associated with worse survival, whereas in the group that received Avastin this combination was not present, and patients with elevated neutrophil counts achieved poorer survival. survival similar to that of the low neutrophil group. It was also found that the neutrophil count at recurrence (compared to baseline) predicts the efficacy of Avastin in these patients. Similar trends were observed in a group of 120 patients with unresectable glioblastoma who participated in the TEMAVIR clinical trial.
In a series of 12 cases of glioblastoma, the expression of the CSF3 gene (which is encoded as a colony stimulating factor of granulocytes, or G-CSF, a neutrophil growth factor) in the tumor bed was strongly correlated with the neutrophil count. Data on glioblastoma from the Cancer Genome Atlas also showed that CSF3 expression is linked to VEGFA-dependent angiogenesis. In the BELOB randomized clinical trial, high CSF3 expression was linked to better survival using lomustine + Avastin compared to lomustine alone. Conversely, for those patients with low CSF3 expression, there was a non-significant trend towards worse survival in those who received lomustine + Avastin compared to lomustine alone. This leads the authors to comment that the high production of G-CSF (encoded by the CSF3 gene) by tumors, which leads to an increase in VEGFA-dependent angiogenesis, may be the cause of the observed association between high blood counts. neutrophils and response to Avastin, with neutrophil count appearing to be a surrogate marker of high CSF3 expression.

Avastin combined with CCNU (lomustine)

A phase 2 randomized 3-arm study called BELOB, conducted at 14 centers in the Netherlands, tested Avastin alone, CCNU (lomustine) alone, or combined Avastin + lomustine for glioblastoma at first relapse or progression after standard radiochemotherapy (312). Overall, the patient group that received Avastin and lomustine combined had better median PFS, 6-month PFS rate, median overall survival, and better 12-month survival rate compared to both monotherapy groups. When the data were separated on the basis of MGMT methylation status, the group of patients with methylated MGMT who received the combination therapy had a 6-month progression-free survival rate that was approximately double (62%) of the methylated MGMT groups treated with Avastin alone (33%) or with lomustine alone (26%). Unsurprisingly, patients with unmethylated MGMT performed poorly on lomustine alone (0% were progression-free at 6 months) and better with combination therapy (6-month PFS rate of 23% vs. 8% with Avastin alone). The methylated group had an equal 9-month overall survival rate with combination therapy or Avastin alone (67%), while the unmethylated group had a better 9-month overall survival rate with combination therapy ( 58%). The combined treatment was well tolerated after an early dose reduction from 110 mg / m2 to 90 mg / m2. This study concluded with the interpretation that combined treatment with Avastin and lomustine was superior to single agent therapy and the combination is now being studied in a phase 3 EORTC study (NCT01290939).

Inhibitors of the angiotensin system and Avastin

The term angiotensin system inhibitor (ASI) refers to angiotensin converting enzyme (ACE) inhibitors, such as captopril and lisinopril, and angiotensin II receptor blockers (ARB), such as telmisartan and losartan.
Driven by studies such as those just discussed, Levin et al. performed a retrospective analysis of 1,186 patients with diffuse glioma (grades 2-4) in the Northern California Kaiser Permanente Cancer Registry treated between 2007 and 2015 (363). Approximately 318 of these patients had also been treated with an ASI drug while being treated with chemotherapy and / or Avastin. In a multivariate analysis (corrected for covariables such as age, GBM versus lower grade, extent of resection, and Avastin exposure), use of an ASI drug during chemotherapy and / or Avastin was associated significantly longer survival (hazard ratio 0.82 for ASI use versus non-use; p = 0.003). This apparent benefit of the use of ASI drugs was even more pronounced in patients who also received Avastin (HR 0.75, p = 0.002).
A smaller group of 181 patients with recurrent GBM treated with Avastin (with results previously published in a study involving low-dose Avastin and reviewed in this paper) were examined looking specifically at concomitant use of an ASI drug. for hypertension. In the previous study, patients who took Avastin less than 3.6 mg / kg / week had significantly better survival than those who received more than 3.6 mg / kg / week (median 60 weeks vs 45 weeks or 13.8 versus 10.4 months). The standard Avastin dose of 10 mg / kg every two weeks equals 5 mg / kg per week, so patients in the lowest Avastin dose group received less than 72% of the equivalent standard weekly dose. In the follow-up study, a lower dose of Avastin, as well as the use of an ASI drug were both associated with better survival (risk ratio of 0. 649 for those who received an ASI drug). Most patients in the ASI exposure group were on ACE inhibitor therapy (n = 78), ARB alone (n = 9), or both drug classes combined (n = 15).
Surprisingly, for all those who received low-dose Avastin (n = 89), those who also received drug treatment for ASI (n = 47) had a median survival of 99 weeks (22.8 months). ) compared with 55.6 weeks (12.8 months) for those who received low-dose Avastin and no ASI drug. Survival was measured from the first dose of Avastin for relapse, as was the case in the previous publication that analyzed this same group. This sizeable group of 47 patients who received lower doses of Avastin and concurrently took angiotensin system inhibitors for hypertension survived for a median of 22.8 months after relapse, and this is the best statistic. ever seen for recurrent glioblastoma. However, the same precautions that must be taken when analyzing the results of a retrospective study also apply to this case.


(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. 
(312) Taal, Walter et al. “Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.” The Lancet Oncology 15.9 (2014): 943-953. 
(347) Levin, Victor A et al. “Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma.” Journal of neuro-oncology 122.1 (2015): 145-150. 
(348) Blumenthal, D. T., L. Mendel, and F. Bokstein. “The Optimal Regimen of Bevacizumab for Recurrent Glioblastoma: Does Dose Matter?” J Neurooncol Journal of Neuro-Oncology 127.3 (2015): 493-502. 
(362) Bertaut, Aurélie, et al. “Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma.” Oncotarget, 2015, doi:10.18632/oncotarget.10898. 
(363) Levin VA, et al. “Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab.” Journal of Neuro-Oncology, 2017. Epub ahead of print. doi: 10.1007/s11060-017-2528-3.

Well, I hope you enjoyed reading, I have been as faithful as possible. Very soon the next episode that will complete the chapter! See you soon!