Dynamic susceptibility contrast MRI measures of relative cerebral blood volume as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 multicenter trial

Background

The study goal was to determine whether changes in relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI are predictive of overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) when measured 2, 8, and 16 weeks after treatment initiation.

Methods

Patients with recurrent GBM (37/123) enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide, consented to DSC-MRI plus conventional MRI, 21 with DSC-MRI at baseline and at least 1 postbaseline scan. Contrast-enhancing regions of interest were determined semi-automatically using pre- and postcontrast T1-weighted images. Mean tumor rCBV normalized to white matter (nRCBV) and standardized rCBV (sRCBV) were determined for these regions of interest. The OS rates for patients with positive versus negative changes from baseline in nRCBV and sRCBV were compared using Wilcoxon rank-sum and Kaplan–Meier survival estimates with log-rank tests.

Results

Patients surviving at least 1 year (OS-1) had significantly larger decreases in nRCBV at week 2 (P = .0451) and sRCBV at week 16 (P = .014). Receiver operating characteristic analysis found the percent changes of nRCBV and sRCBV at week 2 and sRCBV at week 16, but not rCBV data at week 8, to be good prognostic markers for OS-1. Patients with positive change from baseline rCBV had significantly shorter OS than those with negative change at both week 2 and week 16 (P = .0015 and P = .0067 for nRCBV and P = .0251 and P = .0004 for sRCBV, respectively).

Conclusions

Early decreases in rCBV are predictive of improved survival in patients with recurrent GBM treated with bevacizumab.     

Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma

Background

The anti-VEGF antibody, bevacizumab, is standard treatment for patients with recurrent glioblastoma. In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response. Here we evaluate the prognostic significance of pre- and posttreatment relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI to predict response to bevacizumab.

Methods

Thirty-six participants with recurrent high-grade gliomas who underwent rCBV imaging 60 days before and 20–60 days after starting bevacizumab treatment were enrolled. Tumor regions of interest (ROIs) were determined from deltaT1 maps computed from the difference between standardized post and precontrast T1-weighted images. Both pre- and posttreatment rCBV maps were corrected for leakage and standardized (stdRCBV) to a consistent intensity scale. The Kaplan–Meier method was used to determine if either the pre- or post-bevacizumab stdRCBV within the tumor ROI was predictive of overall survival (OS) or progression free survival (PFS).

Results

The OS was significantly longer if either the pre- (380d vs 175d; P=.0024) or posttreatment stdRCBV (340d vs 186d; P = .0065) was <4400. The posttreatment stdRCBV was also predictive of PFS (167d vs 78d; P = .0006). When the stdRCBV values were both above versus both below threshold, the OS was significantly worse (100.5d vs 395d; P < .0001). With a 32.5% decrease in stdRCBV, the risk of death was reduced by about 68% but increased by 140% with a 29% increase in stdRCBV.

Conclusions

Standardized rCBV is predictive of OS and PFS in patients with recurrent high-grade brain tumor treated with bevacizumab.     

Editor's choice: Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy

Background

The optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences.

Methods

We identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment.

Results

BV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age ≥60 years and low extent of resection.

Conclusions

Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.     

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

BackgroundThe optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy.MethodsThis was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0–2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS).ResultsOne hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64–1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82–1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately.ConclusionsAdding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

Clinical trials registration nr

ACTRN12610000915055.     

Implications of bevacizumab discontinuation in adults with recurrent glioblastoma

Background

Patients with recurrent glioblastoma benefiting from bevacizumab are often treated indefinitely due to concerns regarding rebound tumor recurrence upon discontinuation. However, treatment is discontinued for reasons other than disease progression in a subset of these patients, the characteristics and outcomes of which are poorly defined.

Methods

Of 342 adults with recurrent glioblastoma in our database treated with bevacizumab, 82 received treatment for ≥6 months; of these, bevacizumab was discontinued for reasons other than tumor progression in 18 patients (Bev-D) and for disease progression in the remainder (Bev-S). The impact of discontinuation on outcome was assessed with discontinuation as a time-dependent covariate in a Cox hazards model for progression-free survival.

Results

There was no difference in hazard rates for progression between Bev-D and Bev-S groups; the adjusted hazard ratio for progression using discontinuation as a time-dependent covariate was 0.91 (95% CI:0.47, 1.78). The median PFS after bevacizumab-discontinuation was 27 weeks (95% CI:15-NR). At progression, a higher proportion of Bev-D patients had local progression compared with the Bev-S patients. Salvage therapy in Bev-D patients yielded a PFS-26 weeks of 47% (95% CI:23%–94%) with a median PFS of 23 weeks (95% CI:12-NR), vs. 5% (95% CI: 1%–21%) and 9 weeks (95% CI: 6–11) in Bev-S patients (HR:0.3;CI, 0.1–0.6) (P = .0007).

Conclusions

Bevacizumab discontinuation unrelated to disease progression does not appear to cause rebound recurrence or worsen PFS in patients who benefit from bevacizumab. Additionally, Bev-D patients had an improved response to salvage therapy, findings which provide a strong basis for a prospective study.     

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab

Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.     

Quantitative volumetric analysis of conventional MRI response in recurrent glioblastoma treated with bevacizumab

Although the effects of bevacizumab on magnetic resonance images (MRIs) of recurrent glioblastoma multiforme (GBM) are well documented, to our knowledge, no studies have explicitly quantified the volumetric changes resulting from initial treatment, nor have there been studies examining the ability for volumetric changes in conventional MRI to predict progression-free survival (PFS) and overall survival (OS). In the current study, we retrospectively examined volumetric changes on conventional MRI scans in 84 patients with recurrent GBM. MRIs were obtained before (mean, 11 days) and after (mean, 42 days) treatment with bevacizumab. The volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal intensity, the volume of contrast enhancement, and the ratio of the 2 were quantified for each patient before and after initial treatment. Results demonstrated that initial treatment with bevacizumab resulted in a significant decrease in both the volume of abnormal FLAIR signal and the volume of contrast enhancement. Initial, residual, and change in FLAIR volume were not predictive of PFS or OS. Initial contrast-enhancing volume was predictive of PFS but not OS. The pretreatment relative nonenhancing tumor ratio, defined as the ratio of FLAIR to contrast-enhancing volume, was found to be predictive of both PFS and OS.     

Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab

Background

Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen.

Methods

In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment.

Results

Forty-two patients were identified (28 males) with a median age of 49 years (range, 24–78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3–4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen.

Conclusion

The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.     

Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.     

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.     

Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma

BackgroundPanobinostat is a histone deacetylase inhibitor with antineoplastic and antiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat combined with bevacizumab in patients with recurrent high-grade glioma (HGG).MethodsPatients with recurrent HGG were treated with oral panobinostat 30 mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrent glioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory arm of the study.ResultsAt interim analysis, the GBM arm did not meet criteria for continued accrual, and the GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 rate was 30.4% (95%, CI 12.4%–50.7%), median PFS was 5 months (range, 3–9 months), and median overall survival (OS) was 9 months (range, 6–19 months). Accrual in the AG arm continued to completion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%–73%), median PFS was 7 months (range, 2–10 months), and median OS was 17 months (range, 5 months–27 months).ConclusionsThis phase II study of panobinostat and bevacizumab in participants with recurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed. Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did not significantly improve PFS6 compared with historical controls of bevacizumab monotherapy in either cohort.     

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy

BACKGROUND:

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.

METHODS:

Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m² for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m² for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).

RESULTS:

All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.

CONCLUSIONS:

Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.     

超选择性颅内动脉灌注贝伐珠单抗治疗复发恶性脑胶质瘤的疗效及安全性

目的:观察超选择性颅内动脉灌注贝伐珠单抗治疗复发恶性脑胶质瘤的疗效及安全性。方法:纳入2017年10月至2020年11月在我院神经外科接受超选择性颅内动脉灌注贝伐珠单抗治疗的11例复发恶性脑胶质瘤患者,观察治疗后的无进展生存期、Karnofsky评分及不良反应,随访终点为肿瘤再次出现复发或转移。结果:经2个周期治疗后,11例复发恶性脑胶质瘤患者的疾病控制和客观反应人数分别为10例和8例,患者Karnofsky评分较治疗前显著提高(P<0.05)。中位无进展生存时间为6个月,11例患者中有1例出现皮肤过敏,1例患者出现白细胞减少。结论:采用超选择性颅内动脉灌注贝伐珠单抗治疗复发恶性脑胶质瘤安全、有效,值得临床进一步推广应用。     

Potential novel role of bevacizumab in glioblastoma and cervical cancer

The VEGF-A binding monoclonal antibody bevacizumab is a widely prescribed angiogenesis inhibitor and indicated for many types of cancer. As shown by three randomized phase 3 trials recently published in the New England Journal of Medicine, novel indications for this drug are still being explored. In the RTOG 0825 and AVAglio trials the effect of bevacizumab addition to standard therapy in newly diagnosed glioblastoma (radiotherapy plus temozolomide) was investigated, while in GOG 240 the combination of platinum-based chemotherapy plus bevacizumab was explored in advanced cervical cancer. In RTOG 0825, addition of bevacizumab to standard therapy did not result in survival benefit, and moreover, quality of life was more deteriorated in the bevacizumab arm. In AVAglio, however, progression-free survival (PFS) was significantly increased in the bevacizumab group and these patients also experienced a longer deterioration-free survival. These conflicting results do not fully support the incorporation of bevacizumab in the first-line treatment of glioblastoma. In contrast, in GOG 240 the bevacizumab group (including paclitaxel plus topotecan or paclitaxel) experienced a significant longer PFS and overall survival, and quality of life was not negatively affected in these patients. Thus, these results favor the use of bevacizumab in the treatment of advanced cervical cancer.     

Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: A pictorial review

Five cases of cerebral glioma are presented here that illustrate the benefit of functional CT imaging of blood-brain barrier permeability and cerebral blood volume. Functional CT uses Patlak analysis of a single location dynamic sequence to extract physiological information that is useful clinically in the assessment of cerebral gliomas. Functional CT offers distinct advantages over other functional modalities including clearer delineation of tumour, tumour grading, measurement of tumour activity and monitoring response to therapy.