Abstract
Purpose:
An increased incidence in hematologic toxicity has been reported with the addition of bevacizumab to lomustine for patients with recurrent or progressive high grade gliomas (HGG). Data regarding incidence of toxicity with combination bevacizumab and carmustine is limited. The purpose of this study is to compare toxicity of single agent carmustine and carmustine plus bevacizumab for patients with HGGs.
Methods:
This single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with age ≥18 years who received carmustine between January 2003 and May 2017.
Results:
Sixty-five patients with HGGs collectively received 110 doses of BCNU during the specified time period. Sixteen patients received single agent BCNU (30 doses); 49 patients received combination bevacizumab with BCNU (80 doses). There was no significant difference in incidence or grade of toxicity between single agent and combination therapy with respect to hepatotoxicity, leukopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Rates of grade 3 and 4 neutropenia (20% vs 13.8%, p=0.55) and thrombocytopenia (23.3% vs 23.8%, p=1) did not differ between single agent BCNU versus combination therapy. When stratified based on dose (<150mg/m2, 150mg/m2, >150mg/m2), there was no statistically significant difference between the two groups with respect to grade 3 and 4 neutropenia or thrombocytopenia.
Conclusions :
This is the first study to report the toxicity of carmustine with or without bevacizumab for the treatment of recurrent and refractory HGG. The addition of bevacizumab to carmustine did not increase incidence or grade of hematologic toxicity when compared to single agent carmustine.
Keywords: high grade glioma, carmustine, BCNU, nitrosurea, bevacizumab, glioblastoma
Introduction:
The up-front treatment of malignant high-grade gliomas (HGG) consists of maximal safe surgical resection followed by radiation and chemotherapy, most commonly temozolomide.[1] Despite an overall survival benefit with the utilization of temozolomide in addition to radiation in the first line setting for treatment of glioblastoma, prognosis remains poor with a 5 year overall survival of <10% and a median overall survival (OS) after recurrence of only 6.2 months. [2, 3] Additionally, nearly all patients diagnosed with glioblastoma will eventually recur or progress with no cure currently available. [4, 5] Presently, the only FDA approved second line agents for the treatment of high-grade malignant gliomas include carmustine (BCNU) wafers in combination with surgery, bevacizumab, and a medical device generating alternating electric fields (TTFields).[6–8]
Intravenous (IV) carmustine and oral lomustine are alkylating agents in the nitrosourea family that are frequently employed as systemic monotherapy options or in combination with bevacizumab as salvage therapy for recurrent or progressive high-grade malignant gliomas. [4] Carmustine is currently FDA approved for the treatment of brain tumors based on experiences and studies in the 1960s showing response rates up to 30%. [9] In certain circumstances, our institution utilizes intravenous carmustine in lieu of oral lomustine when there are issues of compliance with oral medications, patients’ inability to swallow, costs of outpatient oral chemotherapy, and patient preference. However, there is limited data reviewing the safety and efficacy of carmustine monotherapy and currently no data specifically reporting the use of carmustine in combination with bevacizumab in the setting of recurrent or progressive HGG. Previous studies only analyzed nitrosoureas collectively and after bevacizumab failure. Additionally, dosing for carmustine as monotherapy is not standardized and can range from 150 to 240 mg/m2 given over one to three days and the optimal dosing of carmustine is unknown when dosed in combination with bevacizumab.
The BELOB trial prospectively examined the outcomes of patients with glioblastoma in the first recurrence treated with bevacizumab, lomustine, or the combination of both.[10] Patients receiving lomustine were to receive lomustine 110 mg/m2 (max 200 mg) orally every 6 weeks with or without bevacizumab at 10 mg/kg intravenously every 2 weeks; however, after 5 out of the first 8 patients in the combination arm had grade 3 or 4 hematologic toxicity, the lomustine dose in the combination arm was reduced to 90 mg/m2. This dose was subsequently tolerated with hematologic toxicity comparable to the single agent lomustine group. In the more recent EORTC 26101 trial comparing lomustine with or without bevacizumab in progressive glioblastoma, patients in the combination arm received lomustine at a dose of 90 mg/m2 orally, which was increased to 110 mg/m2 after the first cycle if no more than grade 1 hematologic toxicity occurred.[11] The number of patients who were able to tolerate this dose escalation was not reported, however the occurrence of grade 3 to 5 hematologic effects was similar between the two arms. Additionally, in these previous studies, other class related side effects of each agent have not been shown to be intensified when used in combination (i.e. incidence of venous thromboembolism with bevacizumab and pulmonary toxicity with nitrosurea, etc.). Although, there is some evidence to suggest that there may be an increased incidence of hematologic toxicity with the addition of bevacizumab to lomustine for patients with recurrent or progressive HGGs, data regarding incidence of toxicity with combination bevacizumab and carmustine remains limited.
This retrospective study aims to determine if there is increased toxicity with the addition of bevacizumab to carmustine and to describe overall response rates of single agent carmustine and carmustine in combination with bevacizumab for patients with HGGs.
Methods
Study Design
This was an Institutional Review Board approved single-center observational retrospective study performed at Memorial Sloan Kettering Cancer Center evaluating patients with pathology confirmed HGG receiving carmustine with or without bevacizumab; previous bevacizumab was allowed. Patients were identified using the pharmacy database and electronic medical records. Inclusion criteria consisted of patients greater than or equal to 18 years of age who had progressed on at least one line of treatment for HGG and had received carmustine between January 2013 and May 2017; there was no limit on number of previous therapies
Endpoints and assessments
The primary objective of this study was to report and compare toxicity of single agent carmustine versus carmustine plus bevacizumab. Secondary objectives were to describe best overall response rate (ORR). Toxicity was characterized based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. ORR was determined based on radiographic response assessed according to Response Assessment in Neuro-Oncology (RANO) criteria approximately every 2 months or as clinically indicated.[12] Toxicity was compared using odds ratios calculated by the Fisher Exact test.
Results
Patient Characteristics
Eighty-one patients received carmustine during the specified time period. Sixteen patients were excluded from analysis: 6 patients received combination bevacizumab and carmustine therapy after more than 1 cycle of single agent carmustine; 3 patients did not have pathology confirmed HGG; 7 patients did not have adequate follow up or toxicity information available. Sixty-five patients who collectively received 110 doses of carmustine met criteria and were included in the analysis. Baseline characteristics are described in Table 1. Sixteen patients received single agent carmustine (30 doses); 49 patients received combination bevacizumab with carmustine (80 doses). The majority of patients in both arms had pathology confirmed glioblastoma (n=52, 80%) and received carmustine dosed at 150 mg/m2 administered approximately every 6 to 8 weeks alone or in combination with bevacizumab dosed at 10 to 15 mg/kg every 2 to 3 weeks (n=68, 62%). The median number of doses of carmustine administered was one dose (range one to eight). Patients receiving combination therapy were older than those receiving single agent lomustine (mean age 61 years vs 54 years). In those receiving combination carmustine and bevacizumab, patients had a lower median Karnofsky Performance Score (KPS) (70 vs 80) and were more heavily pre-treated (median number of prior therapies: 3 vs 2). Forty patients previously received and progressed on bevacizumab with 35 patients (71%) who received combination treatment and 5 patients (31%) who received single agent carmustine previously receiving bevacizumab. In those who were treated with single agent carmustine, no patients had previously received any nitrosourea therapy. One patient treated with combination carmustine and bevacizumab had previously received single agent nitrosourea therapy with lomustine. A higher percentage of patients who received single agent carmustine were MGMT methylated (37% vs 16%).
Table 1.
Baseline Characteristics
| Characteristic | Carmustine single agent n=16 | Carmustine + Bevacizumab n=49 |
|---|---|---|
| Age, year (range) | 54 (21-77) | 61 (38-80) |
| Gender: male, no. (%) | 10 (63) | 33 (67) |
| Diagnosis | ||
| Glioblastoma, no. (%) | 12 (75) | 40 (82) |
| Anaplastic astrocytoma, no. (%) | 4 (25) | 8 (16) |
| Gliosarcoma, no. (%) | 0 | 1 (2) |
| Performance status, KPS (range) | 80 (50-100) | 70 (40-100) |
| Number of prior therapies, median (range) | 2 (1-5) | 3 (1-5) |
| Previously received bevacizumab, no. (%) | 5 (31) | 35 (71) |
| MGMT status | ||
| Methylated, no. (%) | 6 (37) | 8 (16) |
| Unmethylated, no. (%) | 3 (19) | 31 (63) |
| Unknown, no. (%) | 7 (44) | 10 (20) |
| Number of BCNU cycles administered per patient, median (range) | 1 (1-8) | 1 (1-4) |
| Total BCNU doses administered, no | 30 | 80 |
| Dose of BCNU received | ||
| < 150 mg/m2, no. (%) | 8 (27) | 11 (14) |
| 150 mg/m2, no. (%) | 20 (67) | 48 (60) |
| > 150 mg/m2, no. (%) | 2 (7) | 21 (26) |
Toxicity
Toxicity was reported after each cycle of treatment. Toxicities analyzed in this study included hepatotoxicity and hematologic toxicity. Incidence of toxicity is listed in Table 2. Overall, the most common side effects in both treatment groups included hematologic toxicity consisting of leukopenia, lymphopenia, thrombocytopenia, and anemia. Grade 3 and 4 toxicities greater than or equal to 20% with single agent carmustine were leukopenia (20%), lymphopenia (20%), neutropenia (20%), and thrombocytopenia (23.3%). Grade 3 and 4 toxicities greater than or equal to 20% with combination carmustine and bevacizumab were lymphopenia (36.3%) and thrombocytopenia (23.8%). There was no statistically significant difference in incidence or grade of toxicity between single agent and combination therapy with respect to hepatotoxicity, lymphopenia, neutropenia, anemia, and thrombocytopenia as seen in Figure 1. Additionally, there was no difference in grade 3 or 4 hematologic toxicity when stratified by dose of carmustine (> 150 mg/m2, 150 mg/m2, < 150 mg/m2) whether administered with or without bevacizumab as per Figure 2.
Table 2:
Toxicity of carmustine with or without bevacizumab
| Grade 1 or 2 | Grade 3 or 4 | |||
|---|---|---|---|---|
| Carmustine single agent (n=30 cycles) | Carmustine + Bevacizumab (n =80 cycles) | Carmustine single agent (n=30 cycles) | Carmustine + Bevacizumab (n =80 cycles) | |
| ALT | 3 (10%) | 14 (17.5%) | 0 | 5 (6.3%) |
| AST grade | 1 (3.3%) | 5 (6.3%) | 0 | 1 (1.3%) |
| Bilirubin | 1 (3.3%) | 3 (3.8%) | 0 | 1 (1.3%) |
| Thrombocytopenia | 19 (63.3%) | 57 (71.3%) | 7 (23.3%) | 19 (23.8%) |
| Leukopenia | 14 (46.7%) | 43 (53.8%) | 6 (20%) | 9 (11.3%) |
| Lymphopenia | 15 (50%) | 35 (43.8%) | 7 (23.3%) | 29 (36.3%) |
| Neutropenia | 10 (33.3%) | 21 (26.3%) | 6 (20%) | 11 (13.8%) |
| Anemia Grade | 10 (33.3%) | 23 (28.8%) | 0 | 2 (2.5%) |
Figure 1:
Grade 3 and 4 toxicities
Figure 2:
Selected grade 3 & 4 toxicity by dose of carmustine
Two patients receiving single agent carmustine at 150 mg/m2 required dose reductions due to toxicity (one for grade 4 neutropenia and thrombocytopenia, one for grade 4 thrombocytopenia). In patients receiving combination treatment with carmustine and bevacizumab, 3 patients required dose reductions due to hematologic toxicity at carmustine doses of 125-160mg/m2 (one for grade 4 thrombocytopenia, one for prolonged leukopenia, and one for prolonged thrombocytopenia of less than 100,000/m3). Additionally, one patient receiving combination treatment with carmustine at 150 mg/m2 discontinued therapy due to hematologic toxicity (grade 3 neutropenia and grade 4 thrombocytopenia after the first dose).
Efficacy
Best ORR based on retrospective RANO assessment of MRI was evaluable in 14 patients receiving single agent carmustine and 46 patients receiving combination carmustine and bevacizumab. Best ORR in the single agent group was stable disease (n = 5, 35.7%) and progressive disease (n = 9, 64.3%). In those receiving combination treatment, the best ORR was partial response (n =3, 6.5%), stable disease (n =22, 47.8%), and progressive disease (n =21, 45.7%).
Discussion
Carmustine and lomustine are nitrosoureas commonly administered to patients with recurrent HGGs, however, the majority of nitrosourea trials utilized lomustine. Based on the literature, lomustine warrants an initial dose reduction when combined with bevacizumab due to the additive hematologic toxicity associated with this combination. There is currently limited data reported on the incidence of toxicity with carmustine as monotherapy or in combination with bevacizumab in recurrent or progressive HGGs, making it difficult to provide evidence-based dosing recommendations with combination therapy. This study is the first to describe the safety of carmustine with or without bevacizumab in this population.
In the BELOB trial, additive myelosuppression seen with concurrent lomustine and bevacizumab as compared to bevacizumab alone led investigators to reduce the dose of lomustine by approximately 20% in the combination arm (90 mg/m2 versus 110mg/m2). After this dose reduction was implemented, hematologic toxicity in the combination arm was comparable to single agent lomustine dosed at 110 mg/m2. This toxicity data inspired the question of whether the other commonly used nitrosourea, carmustine, should also be dose reduced when given concurrently with bevacizumab.
A study by Rahman et al did describe efficacy and toxicity of adding carmustine or lomustine to bevacizumab for patients with HGG previously treated with a bevacizumab containing regimen, though the results were reported collectively for nitrosoureas and not specifically for carmustine [13]. Only 9 of the 42 patients received carmustine. Overall, the authors showed that the addition of nitrosourea to bevacizumab significantly increased the incidence of grade 3-4 toxicities compared to previous bevacizumab containing regimens, and the combination did not provide much survival benefit. Our study included 49 patients receiving combined carmustine and bevacizumab.
In terms of efficacy with combined nitrosoureas and bevacizumab, it is important to note that while the results of BELOB indicated that combination bevacizumab and lomustine may have more activity than either drug alone with 12 month OS being 48% compared to 30% with lomustine monotherapy and 26% with bevacizumab alone, the larger phase 3 EORTC 26101 failed to show the same[10, 11]. This study compared concurrent oral lomustine (90-100 mg/m2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks to single agent oral lomustine 110mg/m2 every 6 weeks for recurrent GBM. While grade 3-5 hematologic toxicity was similar in both arms, there was no significant difference in OS between the two arms. Despite the results of this study, the combination of a nitrosourea (either lomustine or carmustine) plus bevacizumab is commonly utilized in practice and remains a viable option per NCCN guidelines for the treatment of recurrent HGGs[1]. Carmustine and lomustine are often considered comparable or even interchangeable based on mechanism, though most available data with combined nitrosourea and bevacizumab focuses on lomustine. We sought to fill in the literature gap regarding the specific toxicities associated with concurrent carmustine and bevacizumab.
In this study, we assessed differences in hepatotoxicity and hematologic toxicity given that the class related side effects of each agent have previously been well described in the literature and have not been shown to be intensified when used in combination (i.e. incidence of venous thromboembolism with bevacizumab and pulmonary toxicity with carmustine, etc.). This study found no difference in incidence of grade 3 and 4 hepatotoxicity or hematologic toxicity between patients receiving carmustine compared to patients receiving carmustine in combination with bevacizumab. There was also no difference in toxicity when stratified based on dose of carmustine. Dosing of carmustine significantly varies throughout clinical practice, commonly ranging from 150 to 240 mg/m2 given over one to three days. In this study, the most commonly used dose of carmustine in combination with bevacizumab was 150 mg/m2 given as an IV infusion once every 6 to 8 weeks which was overall well tolerated without an increase in grade 3 and 4 toxicity when compared to carmustine alone. Though previous studies have suggested an increase in hematologic toxicity when bevacizumab is added to lomustine, this study did not show an increase in toxicity when using bevacizumab with carmustine.[10] Additionally, as shown in table 4, the toxicity results are in range with what has been reported in pervious trials evaluating carmustine as a single agent in recurrent glioblastoma.[14–16]
Table 4:
Trials of Carmustine in Recurrent Glioblastoma
| Dosing of carmustine | N | Grade 3&4 hematologic toxicity | |
|---|---|---|---|
| Reithmeier et al [14] | 80 mg/m2 IV D1 -3 | 35 | T: 4/35 (11.4%) L: 5/35 (14.2%) A:1/35 (2.9%) |
| Brandes et al [15] | 80 mg/m2 IV D1-3 | 40 (100 cycles) | Per cycle T: 10/100 (10%) N: 8/100 (8%) |
| Van den Bent et al [16] | 80 mg/m2 IV D1-3 | 27 | T: 11/27 (40.7% ) L: 8/27 (29.6%) N:10/27 (37%) A: 1/27 (3.7%) |
| Own results | 100-200 mg/m2 IVD1 | Single agent: 16 (30 cycles) | Per cycle T: 7/30 (23.3%) L: 6/30 (20%) N: 6/30 (20%) A: 0 |
| with bevacizumab: 49 (80 cycles) | Per cycle T: 19/80 (23.7) L: 9/80 (11.3) N: 11/80 (13.8%) A: 2/80 (2.5%) |
D: day; T: thrombocytopenia; L: leucopenia; N: neutropenia; A: anemia
Overall response outcomes of this study are similar to what has been seen in previous trials with carmustine in recurrent glioblastoma, with majority being stable disease or progressive disease.[14–16] The majority of patients in these previous trials were treated with carmustine at their first recurrence. However, in this study, most patients were treated with carmustine with or without bevacizumab at their second or third recurrence. Three partial responses were seen with combination bevacizumab and carmustine. As with other studies with bevacizumab, it is unclear if this represents a true anti-tumor response or a bevacizumab pseudo-response due to normalization of the blood-brain barrier permeability.[17] It is also unclear if differences in MGMT status impacted efficacy given the small number of patients included in this study.
Our study has several limitations. Firstly, it was retrospective with a small sample size of patients, especially those receiving single agent carmustine. There also may be significant bias in why patients were chosen to receive single agent carmustine versus carmustine and bevacizumab, which may have affected clinical outcomes. Additionally, due to the significant heterogeneity of the two populations with regard to prior treatments and previous bevacizumab use, efficacy outcomes were not able to be compared. However, despite its limitations, this study is the first to report safety outcomes of patients receiving carmustine in combination with bevacizumab versus carmustine monotherapy.
In summary, this study did not find a difference in toxicity in patients receiving carmustine compared to patients receiving carmustine with bevacizumab, though the results of this study may be affected by its small sample size. Patients were able to tolerate the combination of bevacizumab and carmustine. Carmustine does not require a preemptive dose reduction when used in combination with bevacizumab unlike when lomustine was combined with bevacizumab in the previous BELOB trial.
Conclusions
This is the first study to report the toxicity of carmustine with or without bevacizumab for the treatment of recurrent and refractory HGG. There was no difference in grade 3 and 4 hematologic and hepatic toxicity between carmustine compared to carmustine plus bevacizumab, nor was there a difference when stratified based on dose of carmustine.
Table 3:
Best overall response rate
| Carmustine single agent n=16 | Carmustine + Bevacizumab n=49 | |
|---|---|---|
| Stable Disease, no. (%) | 5 (31) | 22 (45) |
| Partial Response, no. (%) | 0 | 3 (6) |
| Progressive Disease, no (%) | 9 (56) | 21 (43) |
Acknowledgments
Funding/Support:
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.
Footnotes
Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.
Conflicts of interest: The authors declare that they have no conflict of interest.
Availability of data and materials: Data are available on request to the authors.
Contributor Information
Prakirthi Yerram, Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
Samantha N Reiss, Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
Lisa Modelevsky, Department of Pharmacy, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
Igor T Gavrilovic, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
Thomas Kaley, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
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